Combination treatments of an estrogen-receptor antagonist and an AKT inhibitor

Abstract

The present disclosure provides, among other things, methods for treating an estrogen receptor-mediated disease, disorder, or condition in a subject comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof in combination with an AKT inhibitor, or a pharmaceutically acceptable salt thereof, and related combinations, compositions, uses, and kits.

Description

Attorney Docket No. 2012034-0384COMBINATION TREATMENTS OF AN ESTROGEN-RECEPTOR ANTAGONIST AND AN AKT INHIBITORBACKGROUND

[0001] Breast cancer is the most frequently diagnosed cancer in women. Around 5 to 10% of cases are metastatic at diagnosis, and close to 30% of patients with early-stage disease will go on to relapse and develop metastatic disease. Reinert, T., & Barrios, C. H., Therapeutic Advances in Medical Oncology, 7(6), 304-320 (2015); Sini, V., Cinieri, S., Conte, P., Laurentiis, M. D., Leo, A. D., Tondini, C., & Marchetti, P., Critical Reviews in Oncology / Hematology, 100, 57-68 (2016). Endocrine therapy is the first line of treatment for advanced stage estrogen receptor positive cancer. Most patients develop resistance to endocrine therapy over time, however. Alternative treatments, such as fulvestrant, a selective estrogen receptor degrader, exist but have limited potential due to poor bioavailability.SUMMARY

[0002] The present disclosure provides, among other things, methods of treating, stabilizing, or lessening the severity or progression of estrogen receptor-mediated diseases, disorders, and conditions via administration of an orally bioavailable estrogen receptor antagonist and an orally bioavailable protein kinase B (AKT) inhibitor.

[0003] In one aspect, the present disclosure provides a method of treating an estrogen receptor- mediated disease in a subject in need thereof comprising administering to the subject, a therapeutically effective amount of Compound 1 having the structure shown below,Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an AKT inhibitor, or a pharmaceutically acceptable salt thereof. In some particular embodiments of the method, the AKT inhibitor is capivasertib.

[0004] In yet a further aspect, the present disclosure provides a kit comprising Compound 1,Page 1 of 4013046802vlAttorney Docket No. 2012034-0384Compound 1, or a pharmaceutically acceptable salt thereof, and an AKT inhibitor, or a pharmaceutically acceptable salt thereof, optionally wherein the kit comprises a label indicating that Compound 1 and the AKT inhibitor are useful for the treatment of estrogen receptor-mediated diseases, disorders, and conditions.

[0005] In yet another aspect, provided is a therapeutic combination comprising Compound 1 or a pharmaceutically acceptable salt thereof, and an AKT inhibitor, or a pharmaceutically acceptable salt thereof, for treating estrogen receptor-mediated diseases, disorders, and conditions.

[0006] In yet a further aspect, provided is a use of Compound 1, or a pharmaceutically acceptable salt thereof, in combination with an AKT inhibitor, or a pharmaceutically acceptable salt thereof, for treating an estrogen receptor-mediated disease, disorder, or condition in a subject in need thereof.

[0007] In some embodiments related to each of the foregoing aspects and / or embodiments, Compound 1, or a pharmaceutically acceptable form thereof, is administered or provided in an amount that is about 30 mg to about 120 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable form thereof, is administered or provided in an amount that is about 30 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable form thereof, is administered or provided in an amount that is about 60 mg. In some additional embodiments, Compound 1, or a pharmaceutically acceptable form thereof, is administered or provided in an amount that is about 90 mg. In yet some other embodiments, Compound 1, or a pharmaceutically acceptable form thereof, is administered or provided in an amount that is about 120 mg. In some embodiments, each of the foregoing dosage amounts of Compound 1, or a pharmaceutically acceptable form thereof, is a daily dosage amount.

[0008] In some embodiments related to each of the foregoing aspects and / or embodiments, the AKT inhibitor, or a pharmaceutically acceptable salt thereof, is selected from, for example, capivasertib, ipatasertib, MK-2206, miransertib, BAY1125976, TAS-117, afursertib, andPage 2 of 4013046802vlAttorney Docket No. 2012034-0384 uprosertib. In some particular embodiments, the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof. In some additional embodiments, capivasertib is administered or provided in a daily dosage amount of about 200 mg to about 800 mg. In some additional embodiments, capivasertib is administered or provided in a daily dosage amount of about 800 mg per day.

[0009] In one or more embodiments related to the method of treating an estrogen receptor- mediated disease, disorder, or condition, or kit comprising a label, or use of Compound 1 or a pharmaceutically acceptable salt thereof in combination with an AKT inhibitor, Compound 1 is administered once daily.

[0010] In one or more embodiments related to the method of treating an estrogen receptor- mediated disease, disorder, or condition, or kit comprising a label, or use of Compound 1 or a pharmaceutically acceptable salt thereof in combination with an AKT inhibitor such as, for example, capivasertib, capivasertib is administered twice daily in an amount that is about 400 mg per dose.

[0011] In one or more further embodiments, Compound 1 and capivasertib are administered concomitantly.

[0012] In yet some other embodiments related to each of the foregoing aspects and embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is in the form of a capsule or a tablet.

[0013] In yet some other embodiments related to each of the foregoing aspects and embodiments, capivasertib, or a pharmaceutically acceptable salt thereof, is in the form of a capsule or a tablet.

[0014] In some additional embodiments, the estrogen receptor-mediated disease, disorder, or condition is a cancer.

[0015] In some further embodiments, the cancer is breast cancer.

[0016] In some particular embodiments, the breast cancer is ER+ / HER2- breast cancer.

[0017] In yet some further embodiments, the breast cancer has at least one mutation selected from a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a serine threonine kinase 1 (AKT1) mutation, and a phosphatase and tensin homolog (PTEN) mutation.

[0018] In yet some additional embodiments, the cancer has metastasized to another organ.Page 3 of 4013046802vlAttorney Docket No. 2012034-0384

[0019] In some further embodiments, the cancer has metastasized to the brain, bone, lungs, and / or liver.

[0020] In some embodiments, the subject has previously received endocrine therapy.

[0021] In some further embodiments, the present disclosure provides a method of treating a cancer in a subject, wherein the cancer is an estrogen-receptor positive cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is a mutant breast cancer. In some further embodiments, the breast cancer is a mutant breast cancer, wherein the mutant breast cancer has at least one mutation selected from a PIK3CA, AKT1, or a PTEN mutation.BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIGs. 1A-1C are dose response curves for T47D (FIG. 1A), CAMA-1 (FIG. IB), and MCF7 (FIG. 1C) immortalized breast cancer cells treated with serial dilutions of capivasertib, fixed concentrations of Compound 1 (palazestrant, 0.05 nM, 0.5 nM, and 5 nM) and 100 pM estradiol for 8 days.

[0023] FIGs. 1D-1F are synergy plots for provided combinations of Compound 1 (palazestrant) and capivasertib on T47D (FIG. ID), CAMA-1 (FIG. IE), and MCF7 (FIG. IF) cells.

[0024] FIG. 2A is a scatter plot of tumor volume (mm3) of a 28-day T47D xenograft tumor model for mice treated with either vehicle, palazestrant at 10 mg / kg, fulvestrant at 25 mg / kg, capivasertib at 100 mg / kg, or combinations thereof.

[0025] FIG. 2B is a plot of tumor volume over time of a 28-day T47D xenograft tumor model for mice treated with either vehicle, palazestrant at 10 mg / kg, fulvestrant at 25 mg / kg, capivasertib at 100 mg / kg, or combinations thereof.

[0026] FIG. 2C is a waterfall plot of the 28-day T47D xenograft study described above and in Example 1.

[0027] FIG. 3 is a PCA plot analyzing similarity between treatment group clusters for the 28- day T47D xenograft study described above and in Example 1.

[0028] FIGs. 4A and 4B are plots illustrating significant differential regulation of hallmark gene signatures with fulvestrant (FIG. 4A) and Compound 1 (palazestrant) combination treatments (FIG. 4B).Page 4 of 4013046802vlAttorney Docket No. 2012034-0384DETAILED DESCRIPTION

[0029] The present disclosure provides, among other things, methods of treating estrogen receptor-mediated diseases in a subject comprising administering Compound 1Compound 1 or a pharmaceutically acceptable salt thereof, in combination with a protein kinase B (AKT) inhibitor, or a pharmaceutically acceptable salt thereof. In particular, the present disclosure encompasses an insight that certain advantageous synergies may be achieved when combining Compound 1 and an AKT inhibitor, such as, for example, capivasertib, when treating an estrogen receptor-mediated disease relative to administration of Compound 1 or the AKT inhibitor administered in isolation (e.g., as a monotherapy).Definitions

[0030] As used herein, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0031] About: As used herein, the term “about” refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may 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 referred value. In some embodiments, “about” refers to ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1% of a referenced value.

[0032] Administration: As used herein, the term “administration” typically refers to the administration or introduction of a composition to a subject or system, for example, to achieve delivery of an agent that is, or is included in or otherwise delivered by, the composition.Page 5 of 4013046802vlAttorney Docket No. 2012034-0384

[0033] Agent: As used herein, the term “agent” refers to an entity (e.g., for example, a small molecule, a lipid, metal, nucleic acid, polypeptide, polysaccharide, etc., or complex, combination, mixture or system [e.g., cell, tissue, organism] thereof), or phenomenon (e.g., heat, electric current or field, magnetic force or field, etc.).

[0034] Antagonist: As used herein, the term “antagonist” refers to an agent or condition whose presence, level, degree, type, or form is associated with a decreased level or activity of a target. An antagonist may include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that shows the relevant inhibitory activity. In some embodiments, an antagonist may be a “direct antagonist”, in that it binds directly to its target; in some embodiments, an antagonist may be an “indirect antagonist”, in that it exerts its influence by means other than binding directly to its target; e.g., by interacting with a regulator of the target, so that the level or activity of the target is altered. In some embodiments, an “antagonist” may be referred to as an “inhibitor”.

[0035] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level, degree, type and / or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, protein, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and / or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.

[0036] Biological Sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow;Page 6 of 4013046802vlAttorney Docket No. 2012034-0384 blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an 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 appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0037] Biomarker: The term “biomarker” is used herein, consistent with its use in the art, to refer to an entity (or form thereof) whose presence, or level, correlates with a particular biological event or state of interest, so that it is considered to be a “marker” of that event or state. To give but a few examples, a biomarker may be or comprise a marker for a particular disease state, or for likelihood that a particular disease, disorder or condition may develop, occur, or re-occur. Additionally, a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof. In some embodiments, a biomarker is predictive; in some embodiments, a biomarker is prognostic; in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest.

[0038] Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is concomitantly exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents) over a course of treatment; that is, wherein one therapeutic regimen or agent is used alongside another one or more therapeutic regimens or agents. In somePage 7 of 4013046802vlAttorney Docket No. 2012034-0384 embodiments, the two or more regimens are administered concomitantly; in some embodiments, such regimens are administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of a combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties 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).

[0039] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features 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 indicative of the variation in those features that are varied.

[0040] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” refers to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject, such as, for example, Compound I, or an AKT inhibitor. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., within a therapeuticPage 8 of 4013046802vlAttorney Docket No. 2012034-0384 dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0041] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time, and may encompass administration of unit doses of one or more therapeutic agents. 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 comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0042] 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, and causes no significant adverse toxicological effects to a subject. Suitable pharmaceutical excipients include but are not limited to, 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.

[0043] Improved, increased or reduced: As used herein, the terms “improved,” “increased,” or “reduced,”, or grammatically comparable comparative terms thereof, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with an agent or combination of interest may be “improved” relative to thatPage 9 of 4013046802vlAttorney Docket No. 2012034-0384 obtained with a comparable reference agent. Alternatively or additionally, in some embodiments, an assessed value achieved in a subject or system of interest may be “improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc.).

[0044] Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

[0045] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition or agent is or may 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, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0046] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the active agent is present in unit dose amounts appropriate for administration in a therapeutic regimen to a relevant subject (e.g., in amounts that have been demonstrated to show 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 that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc.). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a givenPage 10 of 4013046802vlAttorney Docket No. 2012034-0384 context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance.

[0047] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which 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.

[0048] Pharmaceutically acceptable carrier / excipient: As used herein, the term “pharmaceutically acceptable carrier or excipient” means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material comprised in a composition typically comprising an active agent, and may, for example, be involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. 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 which can serve 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 carboxymethyl cellulose, ethyl cellulose 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, com 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; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations. Illustrative pharmaceutically acceptable excipients suitable for use in a pharmaceutical composition can be found, e.g., in, “The Handbook of Pharmaceutical Excipients”, 9thed., Sheskey, P.J., et al., Pharmaceutical Press, 2020.

[0049] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, 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 andPage 11 of 4013046802vlAttorney Docket No. 2012034-0384 the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66: 1-19 (1977). Exemplary pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, 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, 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 salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0050] Prevent or prevention: As used herein, the terms “prevent” or “prevention”, when used in connection with the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0051] Reference: As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some instances, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference orPage 12 of 4013046802vlAttorney Docket No. 2012034-0384 control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0052] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule having a mass that is less than about 5 kilodaltons (kD) or a molar mass that is less than about 5000 g / mol. In some embodiments, a small molecule has a mass that is less than about 4 kD, is less than about 3 kD, is less than about 2 kD, or is less than about 1 kD in size. In some embodiments, a small molecule has a molecular mass that is less than about 800 daltons (D), or is less than about 600 D, or is less than about 500 D, or is less than about 400 D, or is less than about 300 D, or is less than about 200 D, or is less than about 100 D. In some embodiments, a small molecule has a molar mass that is less than about 2000 g / mol, or is less than about 1500 g / mol, or is less than about 1000 g / mol, or is less than about 800 g / mol, or is less than about 500 g / mol. In some embodiments, a small molecule is not a polymer. As used herein, a mass of a compound in daltons is considered to be numerically equal to its mass in grams per mole.

[0053] In some embodiments, a small molecule does not include a polymeric moiety (i.e., a polymeric moiety is absent). In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and / or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc. In some embodiments, a small molecule is not and / or does not comprise a lipid.

[0054] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.Page 13 of 4013046802vlAttorney Docket No. 2012034-0384

[0055] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0056] Those of ordinary skill 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 a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.

[0057] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.

[0058] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;nC,13C or14C for12C;13N or15N for14N;17O or18O for16O;36C1 for35 / 37Cl;18F for19F;131I for127I; etc). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0059] In some embodiments, reference to a particular small molecule compound may relate 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., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0060] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and / or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of thePage 14 of 4013046802vlAttorney Docket No. 2012034-0384 preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists 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 to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0061] Therapeutic agent: As used herein, the phrase “therapeutic agent” in general refers to any agent that elicits a desired pharmacological effect when administered to an organism, although in some instances, such desired pharmacological effect can be demonstrated in vitro. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.

[0062] 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 onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to aPage 15 of 4013046802vlAttorney Docket No. 2012034-0384 subject who exhibits only early signs of the disease, disorder, and / or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0063] 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 therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features 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.

[0064] It is understood by one skilled in the art that compounds referred to herein may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D).

[0065] Compounds as provided herein, or their pharmaceutically acceptable salts, may contain chiral centers, which, unless specified otherwise, may be either of the (R) or (S) configuration, or may comprise a mixture thereof. Accordingly, the present application includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions. 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 compounds of the present application.Page 16 of 4013046802vlAttorney Docket No. 2012034-0384Methods of Treating Estrogen Receptor-mediated Diseases

[0066] The present disclosure provides, among other things, a method of treating a disease, disorder, or condition described herein comprising administering to a subject in need thereof, Compound 1 :Compound 1, or a pharmaceutically acceptable salt thereof, and an AKT inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 and the AKT inhibitor are administered to a subject as separate compositions, each comprising one or more suitable pharmaceutically acceptable excipients.

[0067] The present disclosure, including the above-described methods and therapeutic combinations, encompasses an unexpected and advantageous insight into the subject combination — that is, that particular synergies may be achieved when administering Compound 1 in combination with an AKT inhibitor, such as, e.g., capivasertib, to a subject suffering from a provided disease, disorder, or condition, such as an estrogen receptor-mediated disease. See, for example, supporting data provided in Example 1. Moreover, the methods, combinations, uses, etc., provided herein may exhibit benefits over currently available methods of treatment such as fulvestrant in combination with an AKT inhibitor, since Compound 1 is orally bioavailable, and can be administered to a patient in any suitable form, including as a capsule or tablet or the like.

[0068] The estrogen receptor (“ER”) is involved in a variety of biological processes, relating to, for example, development of the female reproductive system, maintenance of bone mass, protection of cardiovascular and / or central nervous system components, etc. (see, for example, Pearce & Jordan Crit. Rev. One Hem 50:3, 2004; Heldring Phys. Rev. 87:905, 2007). The ER has been implicated in a variety of cancers. In many tumors that express the estrogen receptor (i.e., ER+tumors, also referred to herein as hormone positive or HR+ tumors), active ERa signaling has been demonstrated to drive cell proliferation (although ER signaling has been reported to achievePage 17 of 4013046802vlAttorney Docket No. 2012034-0384 tumor suppressor effects; see, for example, Nilsson & Gustafson Clin. Pharmacol. Ther. 89:44, 2011). Typically, tumors (e.g., breast tumors) with as few as 1% of cells staining positive for ER are classified as “ER+”. Therapies targeting the ER are standard of care for many patients with ER+tumors (see, for example, Cardoso et al Annals One. 2017; Rugo et al. J. Clin. Oncol. 34:3069, 2016; Senkus et al. Annal One. 26:v8, 2015; Sareddy & Vadlamudi Clin. J Nat. Med, 13:801, 2015). For early-stage breast cancer patients, for example, 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 mainstay.

[0069] Among other things, presence or development of certain ER mutations has been reported to impact effectiveness of various ER-targeted therapies (see, for example, Jeselsohn et al. Nature Rev. Clin. One. 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; some activating mutations have been reported that can render the ER ligand-independent (i.e., constitutively active). For example, particular mutations in the ER ligand binding domain, including D538G and Y537S, have been demonstrated to constitutively activate the ER; other mutations including deletions and / or fusions that remove the ligand binding domain, can have similar effects (see, for example, Li et al. Cell Repts 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 have indicated that as many as 50% of women with metastatic breast cancer may have activating ER mutations detectible in circulating tumor DNA.

[0070] Nevertheless, regardless of mechanism of action of a particular agent, clinical experience thus far has revealed that incomplete effects (e.g., within an individual patient and / or across patient populations) and / or development of resistance remain a problem.

[0071] In some embodiments described herein, an estrogen receptor-mediated disease is a cancer. In some embodiments, the cancer is breast cancer. In some further embodiments, a cancer (e.g., breast cancer) has metastasized to another organ (such as, e g., the brain, bones, lungs, and / or liver). In some particular embodiments, an organ having metastases is the brain of the subject. In some embodiments, an organ having metastases is a bone of the subject. In some embodiments, an organ having metastases is a lung of the subject. In some embodiments, an organ having metastases is the liver of the subject.Page 18 of 4013046802vlAttorney Docket No. 2012034-0384

[0072] In some embodiments, a subject is suffering from ER+ / HER2- (also referred to as HR+ / HER2-) metastatic breast cancer. In some embodiments, a subject is suffering from cancer that has metastasized to another organ (e.g., brain, lung, liver, and / or bone). In some embodiments, a subject is suffering from histologically or cytologically confirmed advanced or metastatic breast cancer (e.g., for which standard curative measures do not exist).

[0073] In some embodiments, a subject is suffering from a breast cancer that has at least one mutation selected from a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a serine threonine kinase 1 (AKT1) mutation, and a phosphatase and tensin homolog (PTEN) mutation. In some embodiments, a subject is suffering from a breast cancer that has a PIK3CA mutation. In some embodiments, a subject is suffering from a breast cancer that has an AKT1 mutation. In some embodiments, a subject is suffering from a breast cancer that has a PTEN mutation. In some embodiments, the subject is suffering from a breast cancer, wherein the subject has a tumor having at least one mutation selected from a phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit alpha (PHC3CA) mutation, a serine threonine kinase 1 (AKT1) mutation, and a phosphatase and tensin homolog (PTEN) mutation. In some embodiments, the subject has a tumor having a PIK3CA mutation. In some embodiments, the subject has a tumor having an AKT1 mutation. In some embodiments, the subject has a tumor having a PTEN mutation.

[0074] In some embodiments, a subject suffering from a disease described herein has previously been administered an endocrine therapy. In some embodiments, a subject has received at least 6 months of a prior continuous endocrine therapy for locally advanced or metastatic breast cancer. In some embodiments, a subject has received no more than 2 prior hormonal regimens for advanced or metastatic disease.

[0075] In some embodiments, a subject suffering from a disease described herein has previously been administered chemotherapy (e.g., chemotherapy for locally advanced or metastatic disease). In some embodiments, a subject has previously been administered no more than one chemotherapy regimen for locally advanced or metastatic breast cancer.

[0076] In some embodiments of a method of treatment as disclosed herein, the method is a method of preventing tumor growth in a subject comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof. Also provided herein, in some other aspects and / or embodiments, is aPage 19 of 4013046802vlAttorney Docket No. 2012034-0384 method of causing tumor regression in a subject, the method comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof.

[0077] Also provided herein, in some further aspects and / or embodiments, is a method of downregulating genes associated with cell cycle progression, comprising contacting a cell with Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof.Compound 1

[0078] The methods, combinations, uses, kits, and the like provided herein comprise Compound 1 - a compound which possesses a unique feature and a particular usefulness, since the compound is a complete estrogen receptor antagonist. 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, it is understood that a complete estrogen antagonist is an agent (e.g., a small molecule compound) that shows ER antagonism and no ER agonism in one or more of ERa protein level assays, MCF-7 cell line assays, Ishikawa cell line assays (measuring wild type ER and certain mutants including mutants lacking AF1 and / or AF2 domains), and rodent uterine weight gain assays. See, generally, e.g., International Patent Publication No. WO 2017 / 059139. Alternatively or additionally, a complete estrogen receptor antagonist has three characteristics: it (1) inhibits both activation function 1 (AF1) and activation function 2 (AF2), as complete anti-estrogen activity requires inactivation of both AF1 and AF2; (2) promotes ER degradation; and (3) lacks the partial ER agonist activity observed with certain other agents. Without being bound by theory, it is understood that complete inhibition of both AF1 and AF2 is required for complete estrogen receptor activity, as activating mutations in the gene that codes for estrogen receptor 1 allows for activation of both AF1 and AF2 even in the absence of estrogen.

[0079] Given the importance of ER signaling in many cancers, as well as in certain cardiovascular, inflammatory, and neurodegenerative diseases, significant effort has been invested in developing therapeutic agents and modalities that target the ER. Although there is some fluidity / flexibility in terminology that has been used to describe ER-targeting agents, a variety of agents, with different mechanisms of action, have been developed and / or studied.Page 20 of 40I3046802vlAttorney Docket No. 2012034-0384

[0080] Currently, fulvestrant is the only approved therapy that has each characteristic of a complete estrogen receptor antagonist described above. However, fulvestrant suffers from numerous shortcomings, including poor oral bioavailability and an inability to cross the blood brain barrier.

[0081] Compound 1,Compound 1, overcomes the shortcomings of fulvestrant, and is an orally bioavailable Complete Estrogen Receptor ANtagonist (“CERAN”). Compound 1 is described in International Patent Publication No. WO 2017 / 059139, as Compound B, otherwise referred to as (lR,3R)-2-(2-fluoro-2- methylpropyl)-3 -methyl- l-(4-((l -propylazetidin-3-yl)oxy)phenyl)-2, 3,4, 9-tetrahydro-lH- pyrido[3,4-b]indole. The synthesis and certain attributes of Compound 1 are reported in International Patent Publication No. WO 2017 / 059139.

[0082] Compound 1 potently competes with the endogenous activating estrogenic ligand, 17- beta estradiol, for binding in the ligand binding pocket. More particularly, Compound 1 blocks estrogen-driven transcriptional activity, inhibits estrogen-driven breast cancer cell growth, and induces degradation of the ER. Compound 1, as a CERAN, both completely inactivates the ER and degrades ER, as well as completely inactivates the ER by inactivating both the activation function 1 (AF1) and activation function 2 (AF2) transcriptional activation functions. Compound 1 robustly degrades the estrogen receptor in ER+ cell lines. In vivo studies demonstrated that Compound 1 has no agonist activity in the immature ovari ectomi zed mouse uterus and blocks estrogen-driven uterine weight increase. Previous therapies, such as traditional selective estrogen receptor degraders (SERDs), which only degrade the ER, or selective estrogen receptor modulators (SERMs), which have mixed agonist and antagonist effects, fail to achieve the complete estrogen receptor antagonism achieved by Compound 1.Page 21 of 4013046802vlAttorney Docket No. 2012034-0384

[0083] Unless otherwise indicated, as used herein “Compound 1 ” refers to Compound 1 in any available form, such as, e.g., a salt form and / or solid form. It will be understood, therefore, that reference to an amount (e.g., in mg) of Compound 1 means the amount of Compound 1 in free base form. Accordingly, Compound 1 may be provided and / or utilized as, e.g., a salt form of Compound 1 such that the amount of the salt (or other form) is an amount that corresponds to the “free base equivalent” of Compound 1.

[0084] 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, pharmaceutically acceptable compositions described herein, e.g., comprising Compound 1, may 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 admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. When aqueous suspensions are required for oral use, the active ingredient, e.g., Compound 1, is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0085] 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, polyvinylpyrrolidone, 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 retarding agents 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 form may also comprise buffering agents. The active compound can also be in micro-encapsulated form with one or more excipients as noted above.Page 22 of 4013046802vlAttorney Docket No. 2012034-0384

[0086] Solid compositions of a similar type may also be employed as fdlers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings (i.e. buffering agents) and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or 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.

[0087] Regarding suitable dosage amounts, in some embodiments, Compound 1 is administered to the subject in an amount that is from about 15 mg to about 360 mg. In some other embodiments, Compound 1 is administered to the subject in an amount that is from about 30 mg to about 360 mg. In some further embodiments, Compound 1 is administered to the subject in an amount that is from about 30 mg to about 300 mg. In some additional embodiments, Compound 1 is administered to the subject in an amount that is from about 30 mg to about 120 mg. Yet, in some additional embodiments, Compound 1 is administered to the subject in an amount that is from about 60 mg to about 120 mg. In some other embodiments, Compound 1 is administered to the subject in an amount that is from about 15 mg to about 100 mg. In some further embodiments, Compound 1 is administered to the subject in an amount that 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. In some embodiments, Compound 1 is administered to the subject in an amount that is about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is about 30 mg. In some other particular embodiments, Compound 1 is administered to the subject in an amount that is about 60 mg. In some further embodiments, Compound 1 is administered to the subject in an amount that is about 90 mg. In some additional embodiments, Compound 1 is administered to the subject in an amount that is about 120 mg.

[0088] Suitable daily amounts of Compound 1 for administration to the subject include the following. In some embodiments, Compound 1 is administered to the subject in an amount that is about 15 mg to about 360 mg per day (QD). In some other embodiments, Compound 1 is administered to the subject in an amount that is about 30 mg to about 360 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is about 30 mgPage 23 of 4013046802vlAttorney Docket No. 2012034-0384 to about 300 mg per day (QD). In some further embodiments, Compound 1 is administered to the subject in an amount that is about 30 mg to about 120 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is about 60 mg to about 120 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is from about 15 mg to about 100 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that 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, Compound 1 is administered to the subject in an amount that is about 120 mg, about 150 mg, about 210 mg, or about 300 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is about 30 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is about 60 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is about 90 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is about 120 mg QD.

[0089] In some embodiments, Compound 1 is administered to the subject in a unit dosage form. In some embodiments, a unit dosage form is a capsule or tablet. In some embodiments, a unit dosage form comprises about 15 mg to about 120 mg of Compound 1. In some embodiments, a unit dosage form comprises about 15 mg to about 100 mg of Compound 1. In some embodiments, a unit dosage form comprises about 60 mg to about 120 mg of Compound 1. In some embodiments, a 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, a unit dosage form comprises about 15 mg of Compound 1. In some embodiments, a unit dosage form comprises about 30 mg of Compound 1. In some embodiments, a unit dosage form comprises about 60 mg of Compound 1. In some embodiments, a unit dosage form comprises about 90 mg of Compound 1. In some embodiments, a unit dosage form comprises about 120 mg of Compound 1. In some embodiments, a unit dosage form is a capsule. In some embodiments, a unit dosage form is a tablet.

[0090] In some embodiments, a total daily dose of Compound 1 administered to the subject is about 15 mg to about 360 mg per day (QD). In some embodiments, a total daily dose of Compound 1 administered to the subject is about 30 mg to about 360 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 30 mg to about 300 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 30 mg toPage 24 of 4013046802vlAttorney Docket No. 2012034-0384 about 120 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 60 mg to about 120 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is from about 15 mg to about 100 mg QD. In some embodiments, a total daily dose of Compound 1 administered to the 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, a total daily dose of Compound 1 administered to the subject is about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is in an amount that is about 30 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 60 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 90 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 120 mg.

[0091] In some embodiments, Compound 1 is administered to the subject once daily for a 28- day cycle. In some embodiments, Compound 1 is administered to the subject once daily for two 28-day cycles. In some embodiments, Compound 1 is administered to the subject once daily for three, four, five, or more 28-day cycles. In some embodiments, Compound 1 is administered to the subject once daily for six, seven, eight, nine, ten, eleven, twelve, or more 28-day cycles. In some embodiments, Compound 1 is administered to the subject once daily until symptoms of disease are no longer measurable. In some embodiments, Compound 1 is administered for the duration of the subject’s life. In some embodiments, Compound 1 is administered once daily for one or more 28-day cycles, followed by a dose holiday. A “dose holiday” as used herein refers to a period of time wherein an agent (e.g., Compound 1) is not administered to the subject. In some embodiments, a dose 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 dose holiday, and then resumption of administration of Compound 1 once daily at the same dose level prior to the dose holiday.AKT Inhibitors

[0092] The present disclosure encompasses, among other things, the surprising discovery that administration of Compound 1 in combination with an AKT inhibitor, such as one described herein, exhibits synergistic effects in the treatment of breast cancer. Such synergies arePage 25 of 4013046802vlAttorney Docket No. 2012034-0384 exemplified in the examples provided herein, for example, in Example 1 . An insight revealed by the illustrative examples is that certain cell lines are only weakly inhibited by AKT inhibitors, including T47DD, CAMA-1, MCF-7, and ER+ / HER2- immortalized breast cancer cell lines. While Compound 1 has been shown to inhibit these cell lines with low nanomolar potencies, synergy scores show that the combination of Compound 1 and the exemplary AKT inhibitor, capivasertib, inhibits the proliferation of these cell lines more than either agent alone, and in some embodiments, in more than a simply additive manner.

[0093] In some embodiments, an AKT inhibitor, or a pharmaceutically acceptable salt thereof, is selected from capivasertib, ipatasertib, MK-2206, miransertib, BAY1125976, TAS-117, afursertib, and uprosertib. In some embodiments, an AKT inhibitor is selected from capivasertib, ipataserbib, miransertib, afursertib, and uprosertib. In some embodiments, an AKT inhibitor is capivasertib. In some embodiments, an AKT inhibitor is ipatasertib. In some embodiments, an AKT inhibitor is MK-2206. In some embodiments, an AKT inhibitor is miransertib. In some embodiments, an AKT inhibitor is BAY1125976. In some embodiments, an AKT inhibitor is TAS-117. In some embodiments, an AKT inhibitor is afursertib. In some embodiments, an AKT inhibitor is uprosertib.

[0094] In some embodiments, an AKT inhibitor is capivasertib, or a pharmaceutically acceptable salt thereof. In some related embodiments, capivasertib is administered in an amount from about 200 mg to about 800 mg per day. In some embodiments, capivasertib is administered 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 per day. In some embodiments, capivasertib is administered in an amount of about 800 mg per day.

[0095] In some embodiments, an AKT inhibitor is administered once or twice per day. In some embodiments, an AKT inhibitor is administered once per day. In some embodiments, an AKT inhibitor is administered twice per day. In some embodiments, an AKT inhibitor is capivasertib, which is administered once daily. In some embodiments, an AKT inhibitor is capivasertib, which is administered twice day.

[0096] In some embodiments, capivasertib is administered in an amount of 400 mg twice per day.Page 26 of 4013046802vlAttorney Docket No. 2012034-0384

[0097] In some embodiments, capivasertib is administered as a unit dosage form. In some embodiments, capivasertib is administered as an oral dosage form. In some embodiments, capivasertib is administered as a capsule or a tablet. In some embodiments, capivasertib is administered as a capsule. In some embodiments, capivasertib is administered as a tablet.

[0098] In some embodiments, capivasertib is administered to a subject according to a treatment cycle wherein capivasertib is administered each day for four days, followed by three days without treatment. In some embodiments, the treatment cycle is repeated for 28 days.

[0099] In some embodiments, capivasertib is administered according to a dosing regimen as reported in accessdata.fda.gov / drugsatfda_docs / label / 2023 / 218197s0001bl.pdf, which is incorporated by reference in its entirety.Combination Therapies

[0100] The instant disclosure provides a recognition that a combination of certain agents can beneficially be used to treat estrogen receptor-mediated cancers. Additionally, the present disclosure provides an insight that particular combinations of agents can be particularly useful in treating cancers (e.g., estrogen receptor-mediated cancers) that are resistant to first line therapies, e.g., endocrine therapies. In some embodiments, provided combination therapies are useful in the treatment of a cancer having at least one mutation selected from a phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a serine threonine kinase 1 (AKT1) mutation, and a phosphatase and tensin homolog (PTEN) mutation. Accordingly, provided is a method of treating a subject suffering from an ER-associated disorder (e.g., a cancer or breast cancer) comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, in combination with an AKT inhibitor, or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, a combination therapy comprises administration of Compound 1 and capivasertib. As illustrated in the supporting examples, it has been recognized that certain synergies may be achieved when combining Compound 1 and capivasertib in the treatment of an estrogen receptor-mediated disease relative to administration of Compound 1 or capivasertib administered in isolation, i.e., as a monotherapy.

[0102] In some embodiments, provided herein is a method of treating a disease, disorder, or condition comprising administering once daily to a subject about 15 mg to about 360 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 150 mg toPage 27 of 4013046802vlAttorney Docket No. 2012034-0384 about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof In some embodiments, provided is a method of treating a disease, disorder, or condition comprising administering once daily to a subject about 15 mg to about 360 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 150 mg to about 450 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating a disease, disorder, or condition as described herein comprises administering once daily to a subject about 30 mg to about 120 mg or Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating a disease, disorder, or condition comprises administering once daily to a subject about 30 mg of Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating a disease, disorder, or condition comprises administering once daily to a subject about 60 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating a disease, disorder, or condition comprises administering once daily to a subject about 90 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating a disease, disorder, or condition comprises administering once daily to a subject about 120 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, Compound 1 is administered daily for a 28-day cycle, and capivasertib is administered daily for 4 days of an overlapping 7 day cycle. In some embodiments, Compound 1 and capivasertib are administered for one, two, three, four, five, or more cycles.

[0104] It is understood that administration of Compound 1 and capivasertib can be administered concomitantly (e.g., simultaneously) or separately. For example, in some embodiments, Compound 1 and capivasertib are administered concomitantly (e.g., simultaneously). In some embodiments, Compound 1 and capivasertib are administered at approximately the same time each day. In some embodiments, capivasertib is administered prior to administration of Compound 1. In some embodiments, capivasertib is administered after administration of Compound 1.Page 28 of 4013046802vlAttorney Docket No. 2012034-0384

[0105] In some embodiments, provided is a method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subj ect who has received or is receiving capivasertib (e.g., according to a regimen provided herein). In some embodiments, provided is a method comprising administering capivasertib to a subject who has received or is receiving Compound 1 (e.g., according to a regimen provided herein).

[0106] In some embodiments, the present disclosure provides an improvement in a method of treating a disease, disorder, or condition comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, in combination, wherein the improvement comprises administering from about 30 mg to about 120 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 800 mg of capivasertib. In some embodiments, each of Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, is administered as a composition (e.g., a pharmaceutical composition). In some embodiments, each of Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, is administered as a separate composition (e.g., a pharmaceutical composition). In some embodiments, each of Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, is administered as an oral dosage form. In some embodiments, each of Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, is administered as a separate oral dosage form. In some embodiments, each of Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, is individually administered as a capsule or a tablet. In some embodiments, each of Compound 1, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, is individually administered as a tablet. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as a capsule and capivasertib, or a pharmaceutically acceptable salt thereof, is administered as a tablet. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as a tablet and capivasertib, or a pharmaceutically acceptable salt thereof, is administered as a capsule.Page 29 of 4013046802vlAttorney Docket No. 2012034-0384Kits

[0107] Further provided herein is a kit comprising Compound 1 or a pharmaceutically acceptable salt thereof, and an AKT inhibitor, or a pharmaceutically acceptable salt thereof. The kit typically comprises one or more doses of Compound 1 or a pharmaceutically acceptable salt thereof, and one or more doses of the AKT inhibitor, e.g., capivasertib, ipatasertib, MK-2206, miransertib, BAY1125976, TAS-117, afursertib, or uprosertib, or a pharmaceutically acceptable salt thereof. Such doses are typically provided in unit dosage forms. In some embodiments, a kit comprises one or more compositions (such as, e.g., unit dosage forms) comprising Compound 1, or a pharmaceutically acceptable salt thereof, and one or more compositions (such as, e.g., unit dosage forms) comprising capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a composition comprising Compound 1 and a composition comprising capivasertib (e.g., as separate compositions, e g., unit dosage forms). In some embodiments, the composition comprising Compound 1 or a pharmaceutically acceptable salt thereof is in the form of a capsule or a tablet. In some embodiments, the composition comprising capivasertib or a pharmaceutically acceptable salt thereof is in the form of a capsule or a tablet.

[0108] In one or more embodiments, a kit comprises one or more doses of Compound 1, wherein each dose is from about 30 mg to about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some cases, a kit comprises one or more doses of about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some cases, a kit comprises one or more doses of capivasertib, wherein each dose of capivasertib is from about 200 mg to about 800 mg. In some embodiments, a kit comprises about 30 mg to about 360 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and about 400 mg to about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises a composition comprising about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises a composition comprising about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and about 800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and aboutPage 30 of 4013046802vlAttorney Docket No. 2012034-0384800 mg of capivasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit further comprises packaging material that comprises a label which indicates that Compound 1 and capivasertib can be used for treating an estrogen receptor-mediated disease, disorder, or condition, such as, for example, a cancer. Cancers for treatment by way of administration of the kit components include, e.g., breast cancer. One particular type of cancer is ER+ / HER2- breast cancer. Additional cancers for treatment by way of administration of the kit components include, for example, breast cancer having at least one mutation selected from a phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a serine threonine kinase 1 (AK.T1) mutation, and a phosphatase and tensin homolog (PTEN) mutation. The kit components can also be used to treat a cancer such as those described herein that has metastasized to another organ.EXAMPLESEXAMPLE 1Biological Evaluation of an Exemplary Complete Estrogen-Receptor Antagonist, Compound 1, and an Exemplary AKT Inhibitor, CapivasertibCell Proliferation Assays

[0109] Cells (T47D, CAMA-1, MCF-7 immortalized breast cancer cell lines) were plated in 96-well plates at optimized densities in appropriate complete medium and incubated overnight. Cells were treated with serial dilutions of capivasertib, fixed concentrations of Compound 1 (referred to as palazestrant in the present example and related figures) and 100 pM estradiol for 8 days. Cell number was assessed using CellTiter-Glo® (CTG) or CyQuant™ and normalized to T=0.Drug Combination Analysis

[0110] Synergy was evaluated using SynergyFinder 3.0 tools, specifically the Zero Interaction Potency (ZIP) model, which assumes that the combined effect of two molecules is the sum of their individual responses, without any interaction. Combinations were normalized to the monotherapy response; deviations >10 from this predicted combined effect indicate synergy (greater effect), between -10 and +10 indicate additive (equal) effect, and <10 indicate antagonism (lesser effect).Xenograft StudiesPage 31 of 4013046802vlAttorney Docket No. 2012034-0384

[0111] Female, immune-deficient nonobese diabetic (NOD) severe combined immunodeficiency (SCID) mice were supplemented with estradiol and implanted subcutaneously with an ER+ breast cancer cell line, T47D, in the mammary fat region. Mice were randomized into groups when the tumor volume reached -150 mm3and were treated for 28 days with either vehicle, palazestrant at 10 mg / kg, fulvestrant at 25 mg / kg, capivasertib at 100 mg / kg or combinations thereof.Immunohistochemistry (IHC)

[0112] IHC staining of human ERa and human Ki67 in mouse xenograft tumors was conducted on the LeicaBond RXm platform using standard chromogenic methods. Staining intensity in non-necrotic tumors was scored on a scale of 0 to 4 (0, no staining; 1, 25% staining; 2, 25%-50% staining; 3, 50%-75% staining; 4, 75%-100% staining).RNA-Sequencing (RNA-Seq)

[0113] Total RNA was extracted from snap-frozen xenograft tumors using the Qiagen RNeasyPlus Universal Mini Kit following the manufacturer’s instructions. RNA sequencing libraries were prepared using the NEBNext® Ultra™ II RNA Library Prep kit for Illumina® and sequenced on an Illumina NovaSeq X as paired-end 150-nt reads. Sequence reads were trimmed using Trimmomatic v.0.36 and referenced to the GRCh38 human reference genome using the STAR aligner v2.5.2b. Differential gene expression analysis was performed using DESeq2 vl.16.1.RT-qPCR Assays

[0114] T47D cells were treated with compounds for 24-hours, cells were lysed, and RNA was extracted using the QIAwave RNA mini kit. RNA was quality controlled, quantified and cDNA was prepared. Specific genes were amplified using SYBR-green technology on a QuantStudio 5.Results

[0115] FIGs. 1A-1C are dose response curves for T47D (FIG. 1A), CAMA-1 (FIG. IB), and MCF7 (FIG. 1C) cells. These illustrative assay results show that capivasertib alone weakly inhibited T47D, CAMA-1 and MCF-7 ER+ / HER2- immortalized breast cancer cell lines. Compound 1 (palazestrant) alone inhibited proliferation of these cell lines with low nanomolar potencies.

[0116] FIGs. ID- IF are synergy plots for provided combinations of Compound 1 (palazestrant) and capivasertib in T47D (FIG. ID), CAMA-1 (FIG. IE), and MCF7 (FIG. IF) cells.Page 32 of 4013046802vlAttorney Docket No. 2012034-0384Scores from synergy plots show that combining Compound 1 (palazestrant) and capivasertib inhibited cell proliferation more than either agent alone (i.e., in a synergistic manner).

[0117] FIG. 2A is a scatter plot of a 28-day T47D xenograft tumor model as described above. FIG. 2B is a plot of tumor volume over time of a 28-day T47D xenograft tumor model as described above, and FIG. 2C is a waterfall plot of the 28-day T47D xenograft study. As monotherapies, Compound 1 (palazestrant) was more effective than the combination of fulvestrant and capivasertib in inhibiting tumor growth.

[0118] The fulvestrant / capivasertib combination resulted in greater tumor growth inhibition compared to monotherapy treatments; however, the effect was only significant compared to fulvestrant alone. The combination of fulvestrant and capivasertib primarily resulted in tumor growth inhibition, while strikingly, combination of Compound 1 (palazestrant) and capivasertib resulted in complete tumor regression in all animals in the study.

[0119] FIG. 3 is a PCA plot analyzing similarity between treatment group clusters. FIGs. 4A and 4B are plots illustrating significant differential regulation of hallmark gene signatures with fulvestrant (FIG. 4A) and Compound 1 (palazestrant) combination treatments (FIG. 4B).

[0120] Sequenced RNA isolated from xenograft tumors indicated that palazestrant treatment altered gene expression to a greater degree than treatment with capivasertib or fulvestrant, particularly when specific hallmark gene signatures were analyzed. Gene sets identified to be enriched following combination treatment with either fulvestrant or palazestrant were broadly mirrored (FIGs. 4A and 4B); however, greater downregulation of genes associated with the MYC, G2M, and E2F gene signatures was observed with palazestrant compared to fulvestrant combination treatment.

[0121] The present example illustrates that palazestrant and capivasertib in combination demonstrate synergistic activity in ER+ breast cancer models, both in vitro and in vivo. In the described preclinical xenograft model, the combination of Compound 1 (palazestrant) and capivasertib was found to increase downregulation of genes associated with cell cycle progression. In these studies, Compound 1 (palazestrant) demonstrates superior antitumor efficacy over fulvestrant when in combination with capivasertib. Among other findings, these data support clinical investigation of the combination of palazestrant and capivasertib.

[0122] The embodiments of the disclosure described herein are intended to be merely exemplary, numerous variations and modifications will be apparent to those skilled in the art. AllPage 33 of 4013046802vlAttorney Docket No. 2012034-0384 such variations and modifications are intended to be within the scope of the present disclosure as defined in any appended claims.Page 34 of 4013046802vl

Claims

Attorney Docket No. 2012034-0384CLAIMS1. A method of treating an estrogen receptor-mediated disease, disorder, or condition in a subject in need thereof comprising administering a therapeutically effective amount of Compound 1,or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an AKT inhibitor, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 30 milligrams (mg) to about 120 mg.

3. The method of claim 1 or 2, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 30 mg.

4. The method of claim 1 or 2, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 60 mg.

5. The method of claim 1 or 2, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 90 mg.

6. The method of claim 1 or 2, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount that is about 120 mg.

7. The method of any one of claims 1-6, wherein the AKT inhibitor, or a pharmaceutically acceptable salt thereof, is selected from capivasertib, ipatasertib, MK-2206, miransertib, BAY1 125976, TAS-117, afursertib, and uprosertib.Page 35 of 4013046802vlAttorney Docket No. 2012034-03848. The method of claim 7, wherein the AKT inhibitor is capivasertib, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein capivasertib is administered in an amount that is about 200 mg to about 800 mg per day.

10. The method of claim 9, wherein capivasertib is administered in an amount that is about 800 mg per day.

11. The method of any one of claims 1-10, wherein Compound 1 is administered once daily.

12. The method of any one of claims 1-11, wherein capivasertib is administered twice daily in an amount that is about 400 mg per dose.

13. The method of any one of claims 1-12, wherein Compound 1 and capivasertib are administered concomitantly.

14. The method of any one of claims 1-13, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is in the form of a capsule or a tablet.

15. The method of any one of claims 1-14, wherein capivasertib, or a pharmaceutically acceptable salt thereof, is in the form of a capsule or a tablet.

16. The method of any one of claims 1-15, wherein the estrogen receptor-mediated disease, disorder, or condition is a cancer.

17. The method of claim 16, wherein the cancer is breast cancer.

18. The method of claim 17, wherein the breast cancer is ER+ / HER2- breast cancer.Page 36 of 4013046802vlAttorney Docket No. 2012034-038419. The method of claim 17 or 18, wherein the breast cancer has at least one mutation selected from a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a serine threonine kinase 1 (AKT1) mutation, and a phosphatase and tensin homolog (PTEN) mutation.

20. The method of any one of claims 16-19, wherein the cancer has metastasized to another organ.

21. The method of claim 20, wherein the cancer has metastasized to the brain, bone, lungs, and / or liver.

22. The method of any one of claims 1-21, wherein the subject has previously received endocrine therapy.

23. A kit comprising Compound 1,or a pharmaceutically acceptable salt thereof, and an AKT inhibitor, or a pharmaceutically acceptable salt thereof.

24. The kit of claim 23, wherein the kit comprises one or more doses of Compound 1, wherein each dose is from about 30 mg to about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

25. The kit of claim 24, wherein the kit comprises one or more doses of about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof.Page 37 of 4013046802vlAttorney Docket No. 2012034-038426. The kit of any one of claims 23-25, wherein Compound 1 is in the form of a capsule or a tablet.

27. The kit of any one of claims 23-26, wherein the AKT inhibitor, or a pharmaceutically acceptable salt thereof, is selected from capivasertib, ipatasertib, MK-2206, miransertib, BAY1 125976, TAS-117, afursertib, and uprosertib.

28. The kit of claim 27, wherein the AKT inhibitor, or a pharmaceutically acceptable salt thereof is capivasertib, or a pharmaceutically acceptable salt thereof.

29. The kit of claim 28, wherein the kit comprises one or more doses of capivasertib, wherein each dose of capivasertib is from about 200 mg to about 800 mg.

30. The kit of claims 28 or 29, wherein capivasertib is in the form of a capsule or a tablet.

31. The kit of any one of claims 23-30, wherein the kit further comprises packaging material that comprises a label which indicates that Compound 1 and capivasertib can be used for treating an estrogen receptor-mediated disease, disorder, or condition.

32. The kit of claim 31, wherein the estrogen receptor-mediated disease, disorder, or condition is a cancer.

33. The kit of claim 32, wherein the cancer is breast cancer.

34. The kit of claim 33, wherein the breast cancer is ER+ / HER2- breast cancer.

35. The kit of claim 33, wherein the breast cancer has at least one mutation selected from a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a serine threonine kinase 1 (AKT1) mutation, and a phosphatase and tensin homolog (PTEN) mutation.Page 38 of 4013046802vlAttorney Docket No. 2012034-038436. The kit of any one of claims 32-35, wherein the cancer has metastasized to another organ.

37. The kit of claim 36, wherein the cancer has metastasized to the brain, bone, lungs, and / or liver.

38. Use of Compound 1,or a pharmaceutically acceptable salt thereof, in combination with an AKT inhibitor, or a pharmaceutically acceptable salt thereof, for treating an estrogen receptor-mediated disease, disorder, or condition in a subject in need thereof.

39. The use of claim 38, wherein the AKT inhibitor, and / or dosage amount of Compound 1, and / or dosage amount of the AKT inhibitor, and / or estrogen receptor-mediated disease, and / or dosage form, and / or cancer, and / or subject condition, is as described in any one of the previous claims.

40. Use of Compound 1,or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an estrogen receptor-mediated disease, disorder, or condition according to the method of any one of the preceding claims.Page 39 of 4013046802vl

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