WO2023059714A1 - Methods of treating estrogen receptor-mediated disorders - Google Patents

Abstract

The present disclosure provides methods of treating certain diseases, disorders, or conditions in a subject comprising administering to the subject a composition comprising Compound (1) or a pharmaceutically acceptable salt thereof.

Description

METHODS OF TREATING ESTROGEN RECEPTOR-MEDIATED DISORDERS RELATED APPLICATIONS

[0001] This applications claims priority to and benefit of U.S. Application No. 63/252,857, filed October 6, 2021, and U.S. Application No. 63/284,553, filed November 30, 2021, the entire contents of each of which are hereby incorporated by reference.

BACKGROUND

[0002] 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). An estimated 150,000 women were living with metastatic breast cancer in the United States in 2017. Mariotto, A. B., Etzioni, R., Hurlbert, M., Penberthy, L., & Mayer, M., Cancer Epidemiology Biomarkers & Prevention, 26(C), 809-815 (2017). 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

[0003] 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. In some embodiments, the present disclosure provides a method of treating an estrogen-receptor mediated disease comprising treating a subject with a composition comprising Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof. [0004] In some embodiments, the present disclosure provides, among other things, providing treatment of Compound 1 to a subject who has been determined to exhibit a biomarker identified by, for example, analysis of a tissue sample and/or circulating tumor DNA (ctDNA), wherein the biomarker is selected from Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53.

[0005] In some embodiments, the present disclosure provides a method of administering a composition comprising Compound 1 to a subject who has been determined to exhibit a biomarker selected from Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53. In some embodiments, a biomarker is determined by analysis of a tissue sample from the subject. In some embodiments, the tissue sample is from a tumor.

[0006] In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 15 mg to about 360 mg. 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 embodiments, Compound 1 is administered to the subject each day for one or more 28-day cycles. In some embodiments, Compound 1 is administered to the subject in an amount that is about 120 mg each day for one or more 28-day cycles.

[0007] In some embodiments, Compound 1 is administered to the subject as 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 60 mg of Compound 1. In some embodiments, one or more unit dosage forms are administered to a subject each day. For example, in some embodiments, two unit dosage forms, each comprising 60 mg of Compound 1, are administered to a subject each day.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 summarizes study design of a first-in-human Phase 1/2 clinical study of Compound 1.

[0009] FIG. 2 is a graph illustrating plasma concentrations of Compound 1 (Cmpd 1) observed following repeat oral administration on Cycle 2, Day 1. ^a24-h Compound 1 imputed using the observed predose value. ^bTarget efficacious average plasma concentration (Cavg) value (200 ng/mL) based on xenograft and cell culture observations. ⁵Faslodex [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. [0010] FIG. 3 is a graph illustrating treatment duration and response in all patients (N=41) as of a first cutoff date in the study of treatment with Compound 1 (Cmpdl) as described in Example 2. Each lane represents one study patient. *Three patients in the 300 mg cohort dose reduced (two to 120 mg, one to 60 mg with most occurring at the beginning of cycle 2); these patients were included in the RP2D CBR calculation. Al = aromatase inhibitor; PD = progressive disease; PR = partial response.

[0011] FIG. 4 is a graph of best response of target lesion in patients with measurable disease (N=22) in the study of treatment with Compound 1 as described in Example 2. *Patient’s response unconfirmed due to progression with a new non-target lesion at follow-up visit. Efficacy-evaluable patients included those with measurable disease at baseline and at least one post-baseline scan. Al = aromatase inhibitor; SD = stable disease; PD = progressive disease; PR = partial response. From left to right, patient received the following dose: 120 mg, 90 mg, 300 mg, 210 mg, 90 mg, 120 mg, 30 mg, 90 mg, 120 mg, 210 mg, 60 mg, 210 mg, 300 mg, 30 mg, 120 mg, 210 mg, 300 mg, 30 mg, 60 mg, 60 mg, 120 mg, 30 mg.

[0012] FIG. 5 is an image of scans of target lesions at baseline and at Cycle 5 of treatment with Compound 1 in a late-line patient with peritoneal carcinomatosis and bone metastasis.

[0013] FIG. 6 is an image of scans of target lesions at baseline and at Cycle 7 of treatment with Compound 1 in a late-line patient with multiple liver metastasis.

[0014] FIG. 7 is a graph illustrating plasma concentrations of Compound 1 (Cmpd 1) observed following repeat oral administration on Cycle 2, Day 1. The dashed line shows the target efficacious exposure based on preclinical models (Cmin = 226 ng/mL). The dotted line shows Cmax (28 ng/mL) of fulvestrant.

[0015] FIG. 8 is a graph illustrating treatment duration and response in all patients (N=41) as of a third cutoff date in the study of treatment with Compound 1 (Cmpdl). Each lane represents one study patient. ^a Solid boxes in the ESRI column indicate that baseline ESRI status was assessed and noted as a mutation. Empty boxes in the ESRI column indicate that baseline status was assessed and noted as wild type. The absence of a box in the ESRI column indicates that ESRI status was not evaluated at baseline. *Four patients in the 300 mg cohort dose reduced (three to 120 mg, one to 60 mg with most occurring at the beginning of cycle 2); these patients were included in the RP2D CBR calculation. Al = aromatase inhibitor; PD = progressive disease; PR = partial response. [0016] FIG. 9 is a graph of best response of target lesion in patients with measurable disease (N=25) in the study of treatment with Compound 1, as of a third cutoff date. *Patient’s response unconfirmed due to progression with a new non-target lesion at follow-up visit. Efficacy- evaluable patients included those with measurable disease at baseline and at least one postbaseline scan. Al = aromatase inhibitor; SD = stable disease; PD = progressive disease; PR = partial response. From left to right, patient received the following dose: 120 mg, 90 mg, 300 mg, 210 mg, 90 mg, 120 mg, 30 mg, 30 mg, 90 mg, 120 mg, 30 mg, 210 mg, 210 mg, 300 mg, 90 mg, 150 mg, 30 mg, 60 mg, 120 mg, 210 mg, 300 mg, 60 mg, 60 mg, 120 mg, 30 mg.

[0017] FIG. 10 is a graph illustrating treatment duration and response in all patients (N=48) as of a third cutoff date in the study of treatment with Compound 1 (Cmpdl). Each lane represents one study patient. ^a Solid boxes in the ESRI column indicate that baseline ESRI status was assessed and noted as a mutation. Empty boxes in the ESRI column indicate that baseline status was assessed and noted as wild type. The absence of a box in the ESRI column indicates that ESRI status was not evaluated at baseline.

[0018] FIG. 11 is a graph of best response in patients (N=31) as of a third cutoff date. Efficacy evaluable patients include those with measurable disease at baseline and at least one post-baseline scan, na = ESRI mutation status not collected. *Patient had unconfirmed response at first scan (cycle 3); pending confirmatory scan. **Patient had unconfirmed response at cycle 7; pending confirmatory scan. From left to right, patient received the following dose: 120 mg, 120 mg, 120 mg, 60 mg, 120 mg, 120 mg, 60 mg, 60 mg, 60 mg, 60 mg, 60 mg, 120 mg, 60 mg, 120 mg, 60 mg, 60 mg, 60 mg, 120 mg, 120 mg, 120 mg, 120 mg, 60 mg, 60 mg, 60 mg, 120 mg, 60 mg, 120 mg, 60 mg, 120 mg, 120 mg, 60 mg.

[0019] FIG. 12 is a graph illustrating plasma concentrations of Compound 1 (Cmpd 1) observed following repeat oral administration on Cycle 2, Day 1 from Phase la and Phase lb studies described in Example 1 and Example 5. The top dashed line shows the target efficacious exposure based on preliminary estradiol dependent preclinical models (Cmin = 226 ng/mL). The bottom dashed line shows target efficacious exposure based on estradiol independent preclinical model (Cmin = 36 ng/mL).

[0020] FIG. 13 is a graph illustrating overall tumor response in a Phase lb study with Compound 1 (Cmpd 1). Each lane represents one study patient. Flvst = fulvestrant; Al = aromatase inhibitor. [0021] FIG. 14 is a graph of best change from baseline of a target lesion evaluated by sum of the longest diameter in a Phase lb study with Compound 1. Al = aromatase inhibitor; Fulv = fulvestrant. From left to right, patient received the following dose: 120 mg, 120 mg, 60 mg, 120 mg, 120 mg, 60 mg, 120 mg, 60 mg, 120 mg, 120 mg, 60 mg, 120 mg, 60 mg, 60 mg, 120 mg, 120 mg, 60 mg, 60 mg, 60 mg, 120 mg, 60 mg, 120 mg, 60 mg, 60 mg, 60 mg, 60 mg, 120 mg, 120 mg, 120 mg, 120 mg, 120 mg, 60 mg, 60 mg, 120 mg, 60 mg, 120 mg, 60 mg, 120 mg, 60 mg, 60 mg, 60 mg, 120 mg, 120 mg, 120 mg, 120 mg, 60 mg.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0022] The present disclosure provides, among other things, methods of treating estrogen receptor-mediated diseases in a subject comprising administering a composition comprising Compound 1. In some embodiments, a biomarker has been detected in a biological sample derived from the subject, wherein the biomarker is selected from Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53.

Definitions

[0023] 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.

[0024] Administration'. As used herein, the term “administration” typically refers to the administration 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.

[0025] Agent'. As used herein, the term “agent” refers to an entity (e.g., for example, a lipid, metal, nucleic acid, polypeptide, polysaccharide, small molecule, 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.). [0026] Antagonist'. As used herein, the term “antagonist” may refer to an agent, or condition whose presence, level, degree, type, or form is associated with a 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”.

[0027] 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, 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.

[0028] 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; 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.

[0029] 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, in some embodiments, 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 reoccur. In some embodiments, a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof. Thus, 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.

[0030] Combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered 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 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).

[0031] 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 there between 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.

[0032] Corresponding to: As used herein, the phrase “corresponding to” refers to a relationship between two entities, events, or phenomena that share sufficient features to be reasonably comparable such that “corresponding” attributes are apparent. For example, in some embodiments, the term may be used in reference to a compound or composition, to designate the position and/or identity of a structural element in the compound or composition through comparison with an appropriate reference compound or composition. For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as “corresponding to” a residue in an appropriate reference polymer. For example, those of ordinary skill will appreciate that, for purposes of simplicity, residues in a polypeptide are often designated using a canonical numbering system based on a reference related polypeptide, so that an amino acid “corresponding to” a residue at position 190, for example, need not actually be the 190^th amino acid in a particular amino acid chain but rather corresponds to the residue found at 190 in the reference polypeptide; those of ordinary skill in the art readily appreciate how to identify "corresponding" amino acids. For example, those skilled in the art will be aware of various sequence alignment strategies, including software programs such as, for example, BLAST, CS- BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH/GLSEARCH, Genoogle, HMMER, HHpred/HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSLBLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHLLS, SWIMM, or SWIPE that can be utilized, for example, to identify “corresponding” residues in polypeptides and/or nucleic acids in accordance with the present disclosure.

[0033] Dosage form or unit dosage form-. Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined 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., with a therapeutic 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.

[0034] Dosing regimen or therapeutic regimen-. Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. 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).

[0035] Excipient'. As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0036] 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 of interest may be “improved” relative to that 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.).

[0037] 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.

[0038] Parenteral'. The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. [0039] Patient or subject'. As used herein, the term “patient” or “subject” refers to any organism to which a provided composition 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.

[0040] Pharmaceutical composition'. As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in 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 given context, a degree and/or prevalence of difference that is required or sufficient to achieve such statistical significance.

[0041] 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.

[0042] Pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, 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, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; 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.

[0043] 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 and 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 detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, 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, dodecylsulfate, 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.

[0044] 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.

[0045] Reference: As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, 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 or 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.

[0046] 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 that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer.

[0047] In some embodiments, a small molecule does not include a polymeric moiety. 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 a lipid.

[0048] 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.

[0049] 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.

[0050] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric 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.

[0051] 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.

[0052] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g., ²H or ³H for H; ⁿC, ¹³C or ¹⁴C for ¹²C; ¹³N or ¹⁵N for ¹⁴N; ¹⁷O or ¹⁸O for ¹⁶O; ³⁶C1 for ^35/37Cl; ¹⁸F for ¹⁹F; ¹³¹I for ¹²⁷I; 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.

[0053] 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 baseaddition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0054] 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 the 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.

[0055] 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. 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.

[0056] 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 a 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.

[0057] 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 such 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. [0058] 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).

[0059] The compounds of the invention, or their pharmaceutically acceptable salts, may contain chiral centers, which, unless specified otherwise, may be either of the (R) or (S) configuration, or which 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.

Estrogen Receptor Mediated Diseases

[0060] The estrogen receptor (“ER”) is involved in a variety of biological processes, relating, for example, to 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. Onc/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 ERP signaling has been reported to be able to achieve 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. https://doi.org/10.1093/announc/mdmx036, 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.

[0061] 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 (/'.<?., 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.

[0062] 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.

[0063] In some embodiments described herein an estrogen receptor-mediated disease is a cancer. In some embodiments, a cancer is breast cancer. In some embodiments, a cancer (e.g., a breast cancer) has metastasized to another organ. In some 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.

[0064] In some embodiments, a disease, disorder, or condition described herein is a HR+/HER2- (hormone receptor positive/human epidermal growth factor 2 negative tumor). It will be appreciated that, throughout the present disclosure, “HR+” and “ER+” are used interchangeably.

Complete Estrogen Receptor Antagonists

[0065] In some embodiments, the present disclosure teaches particular usefulness of a compound (e.g., Compound 1) that is a complete estrogen receptor antagonist. In some embodiments, a “complete estrogen receptor antagonist,” as that term is used herein, is characterized by complete antagonism of the estrogen receptor with no or minimal residual estrogen receptor agonist activity. For example, 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, WO 2017/059139. Alternatively or additionally, in some embodiments, a complete estrogen receptor antagonist has three characteristics: it (1) inhibits both activating function 1 (AF1) and activating 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, 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.

[0066] 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. There is some fluidity/flexibility in terminology that has been used to describe ER-targeting agents, but a variety of agents, with different mechanisms, have been developed and/or studied.

[0067] Currently, fulvestrant is the only approved therapy that has each characteristic. But, as noted above, fulvestrant suffers from numerous shortcomings, including poor oral bioavailability, and an inability to cross the blood brain barrier, making it entirely ineffective for the treatment of brain metastases related to ER-associated diseases or disorders.

[0068] The present disclosure provides methods of treating a subject suffering from an estrogen receptor mediated disease, e.g., a cancer such as breast cancer.

[0069] In some embodiments, a complete estrogen receptor antagonist is Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof.

[0070] Compound 1 is described in 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 WO 2017/059139, which is incorporated herein by reference in its entirety. The usefulness of Compound 1 as a complete estrogen receptor antagonist is reported, for example, in WO 2017/059139, WO 2021/007146, and WO 2021/178846, each of which is incorporated herein by reference in its entirety.

[0071] Compound 1 is a small molecule Complete Estrogen Receptor ANtagonist (CERAN). Compound 1 potently competes with the endogenous activating estrogenic ligand 17-beta estradiol for binding in the ligand binding pocket. Compound 1 blocks estrogen-driven transcriptional activity, inhibits estrogen-driven breast cancer cell growth, and induces degradation of the ER. CERANs both completely inactivate ER and degrade ER, unlike some SERDs which only degrade ER, or selective estrogen receptor modulators (SERMs) which have mixed agonist and antagonist effects. Compound 1 completely inactivates 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 demonstrate that Compound 1 has no agonist activity in the immature ovariectomized mouse uterus and blocks estrogen-driven uterine weight increase.

[0072] In some embodiments, the present disclosure provides a method of treating an estrogen receptor-mediated disorder in a subject, comprising administering to the subject a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has been determined to express a particular biomarker identified by, for example, analysis of a tissue sample and/or circulating tumor DNA (ctDNA) to identify one or more biomarkers selected from Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53. In some embodiments, a biomarker is selected from Ki-67, ER, and PR. In some embodiments, a biomarker is selected from ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53. In some embodiments, a biomarker is selected from ERBB2, KRAS, AKT, and TP53. In some embodiments, a biomarker is ESRI.

[0073] In some embodiments, response to a therapy, e.g., Compound 1, is assessed by analysis of a level of a biomarker described herein following administration of Compound 1. [0074] In some embodiments, a biomarker is detected in a tissue sample from the subject. In some embodiments, the tissue sample is from a tumor.

[0075] In some embodiments, Compound 1 is administered to a subject in a fasted state. In some embodiments, Compound 1 is administered to a subject in a fed state.

[0076] In some embodiments, a subject is suffering from ER+/HER2- recurrent, locally advanced, or metastatic breast cancer. In some embodiments, a subject is suffering from cancer that has metastasized to another organ (e.g., brain, lung, liver, or bone).

[0077] In some embodiments, a subject suffering from a disease described herein has previously been administered an endocrine therapy. In some embodiments, a subject has previously been administered no more than four endocrine therapies. In some embodiments, a disease described herein (e.g., a tumor, such as an ER+/HER2- tumor) has progressed on endocrine therapy.

[0078] 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 one chemotherapy regimen. In some embodiments, a subject has previously been administered one or two chemotherapy regimens.

[0079] In some embodiments, a subject has previously received at least one of a CDK4/6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.

[0080] In some embodiments, a subject is harboring a ESRI mutation (e.g., Y537S and D538G).

[0081] In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 15 mg to about 360 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 30 mg to about 360 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 30 mg to about 300 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 60 mg to about 120 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about 15 mg to about 100 mg. 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. 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 embodiments, Compound is administered to the subject in an amount that is about 60 mg. In some embodiments, Compound is administered to the subject in an amount that is about 90 mg. In some embodiments, Compound is administered to the subject in an amount that is about 120 mg.

[0082] 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 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 mg to about 300 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.

[0083] 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. In some embodiments, one or more unit dosage forms are administered to a subject each day, i.e., to achieve a total daily dose. For example, in some embodiments, two unit dosage forms, each comprising 60 mg of Compound 1, are administered to a subject each day for a total daily dose of 120 mg of Compound 1.

[0084] In some embodiments, a total daily dose of Compound 1 administered to the subject is in an amount that 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 60 mg to about 120 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is in an amount that 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 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, 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 QD. 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.

[0085] 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. [0086] In some embodiments, an AUC in a subject post administration of Compound 1 is about 2000 ng*h/mL to about 4000 ng*h/mL. In some embodiments, an AUC in a subject post administration of Compound 1 is about 4000 ng*h/mL. In some embodiments, an AUCo-24 is from about 1950 ng*h/mL to about 26000 ng*hr/mL. In some embodiments, an AUCo-24 is from about 5000 ng*h/mL to about 10000 ng*hr/mL. In some embodiments, an AUCo-24 is about 5000 ng*hr/mL, about 7500 ng*hr/mL, about 10000 ng*hr/mL, about 12500 ng*hr/mL, about 15000 ng*hr/mL, about 20000 ng*hr/mL, or about 25000 ng*hr/mL.

[0087] In some embodiments, an average plasma concentration (Cavg) of Compound 1 post administration is about 100 ng/mL. In some embodiments, a Cavg is from about 100 ng/mL to about 200 ng/mL post administration of Compound 1. In some embodiments, a Cavg is about 100, 125, 150, 175, or 200 ng/mL post administration of Compound 1. In some embodiments, a Cavg is about 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, or 450 ng/mL post administration of Compound 1. In some embodiments, an average plasma concentration (Cavg) post administration of Compound 1 is about 80 ng/mL to about 1070 ng/mL. In some embodiments, an average plasma concentration (Cavg) post administration of Compound 1 is about 200 ng/mL to about 450 ng/mL. In some embodiments, an average plasma concentration (Cavg) post administration of Compound 1 is about 210 ng/mL to about 410 ng/mL. In some embodiments, a Cavg is about 200 ng/mL, about 300 ng/mL, about 400 ng/mL, about 500 ng/mL, about 800 ng/mL, or about 1000 ng/mL.

[0088] In some embodiments, a maximum plasma concentration (Cmax) of Compound 1 post administration is about 200 ng/mL. In some embodiments, a Cmax is about 200 to about 400 ng/mL post administration of Compound 1. In some embodiments, a Cmax is about 200, 225, 250, 275, 300, 325, 350, 375 or 400 ng/mL post administration of Compound 1. In some embodiments, a Cmax is about 250, 300, 350, 400, 450, 500, 550, 600, or 650 ng/mL post administration of Compound 1. In some embodiments, a Cmax is from about 135 ng/mL to about 1410 ng/mL. In some embodiments, a Cmax is from about 290 ng/mL to about 620 ng/mL. In some embodiments, a Cmax is about 150 ng/mL, about 300 ng/mL, about 600 ng/mL, about 900 ng/mL, about 1200 ng/mL, or about 1500 ng/mL. In some embodiments, a Cmax is from about 30 ng/mL to about 300 ng/mL. In some embodiments, a Cmax of Compound 1 is greater than a Cmax of fulvestrant (e.g., about 28 ng/mL). In some embodiments, a Cmax of Compound 1 is greater than a particular efficacy threshold (e.g., about 226 ng/mL). [0089] In some embodiments, Compound 1 is administered according to a regimen established to achieve one or more of the following characteristics when administered to a population of comparable subjects:

(i) a mean Cmax from about 135 ng/mL to about 1410 ng/mL;

(ii) a median t_max from about 2 h to about 4 h;

(iii) a mean Cavg from about 80 ng/mL to about 1070 ng/mL;

(iv) a mean AUCo-24 from about 1950 ng*h/mL to about 26000 ng*hr/mL; and

(v) a mean effective ti/2 from about 50 h to about 75 h.

[0090] In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean Cmax from about 135 ng/mL to about 1410 ng/mL when administered to a population of comparable subjects. In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean Cmax from about 290 ng/mL to about 620 ng/mL when administered to a population of comparable subjects. In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean Cmax of about 150 ng/mL, about 300 ng/mL, about 600 ng/mL, about 900 ng/mL, about 1200 ng/mL, or about 1500 ng/mL when administered to a population of comparable subjects.

[0091] In some embodiments, Compound 1 is administered according to a regimen established to achieve a median t_max from about 2 h to about 4 h when administered to a population of comparable subjects.

[0092] In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean Cavg from about 80 ng/mL to about 1070 ng/mL when administered to a population of comparable subjects. In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean Cavg from about 210 ng/mL to about 410 ng/mL when administered to a population of comparable subjects. In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean Cavg of about 200 ng/mL, about 300 ng/mL, about 400 ng/mL, about 500 ng/mL, about 800 ng/mL, or about 1000 ng/mL when administered to a population of comparable subjects.

[0093] In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean AUCo-24 from about 1950 ng*h/mL to about 26000 ng*hr/mL when administered to a population of comparable subjects. In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean AUCo-24 from about 5000 ng*h/mL to about 10000 ng*hr/mL when administered to a population of comparable subjects. In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean AUCo-24 of about 5000 ng*hr/mL, about 7500 ng*hr/mL, about 10000 ng*hr/mL, about 12500 ng*hr/mL, about 15000 ng*hr/mL, about 20000 ng*hr/mL, or about 25000 ng*hr/mL when administered to a population of comparable subjects.

[0094] In some embodiments, Compound 1 is administered according to a regimen established to achieve a mean effective ti/2 from about 50 h to about 75 h when administered to a population of comparable subjects.

[0095] 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 measureable. 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 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.

[0096] In some embodiments, an amount of Compound 1 administered to a subject is adjusted in view of certain biomarkers described herein. For example, in some embodiments, the present disclosure provides a method of treating a subject suffering from an estrogen-receptor mediated disease comprising administering to a subject a composition comprising Compound 1, analyzing an amount of Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53 in a biological sample from the subject, and adjusting a dose of Compound 1 accordingly. In some embodiments, a biomarker is selected from ERBB2, KRAS, AKT, and TP53. In some embodiments, a biomarker is ESRI. Combination Therapies

[0097] The present disclosure encompasses the recognition that a combination of certain agents can beneficially be used to completely antagonize the estrogen receptor. Accordingly, in some embodiments, the present disclosure provides a method of treating a subject suffering from an ER-associated disorder (e.g., a cancer or breast cancer) comprising administering a complete estrogen receptor antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) and an anti-cancer agent. For example, in some embodiments, the anti-cancer agent is a CDK 4/6 inhibitor, a PI3Kalpha inhibitor, or an mTOR inhibitor.

[0098] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from a cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) and an anti-cancer agent that is a CDK4/6 inhibitor (i.e., inhibits one or both of CDK4 and CDK6). In some embodiments, an anti-cancer agent is a CDK4/6 inhibitor selected from palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, and SHR6390. In some embodiments, the CDK 4/6 inhibitor is palbociclib. In some embodiments, the CDK4/6 inhibitor is ribociclib. In some embodiments, the CDK4/6 inhibitor is abemaciclib. In some embodiments, the CDK4/6 inhibitor is lerociclib. In some embodiments, the CDK4/6 inhibitor is trilaciclib. In some embodiments, the CDK 4/6 inhibitor is SHR6390.

[0099] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from a cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) and an anti-cancer agent, wherein the anti-cancer agent is a PI3Kalpha inhibitor. In some embodiments, the PI3Kalpha inhibitor is selected from alpelisib, taselisib, and LY3023414. In some embodiments, the PI3Kalpha inhibitor is alpelisib. In some embodiments, the PI3Kalpha inhibitor is taselisib. In some embodiments, the PI3Kalpha inhibitor is LY3023414.

[0100] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from a cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) and an anti-cancer agent, wherein the anti-cancer agent is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is selected from sirolimus, temsirolimus, everolimus, and LY3023414. In some embodiments, the mTOR inhibitor is sirolimus. In some embodiments, the mTOR inhibitor is temsirolimus. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the mTOR inhibitor is LY3023414.

[0101] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from a cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) and two or more anti-cancer agents. In some embodiments, each of the two or more anti-cancer agents are selected from a CDK 4/6 inhibitor, a PI3Kalpha inhibitor, an mTOR inhibitor, and a HER2 inhibitor. In some embodiments, one anti-cancer agent is a CDK 4/6 inhibitor, and the other anti-cancer agent is a HER2 inhibitor. In some embodiments, one anti-cancer agent is ribociclib, abemaciclib, or palbociclib, and the other anti-cancer agent is tucatinib. In some embodiments, one anti-cancer agent is ribociclib, and the other anti-cancer agent is tucatinib.

[0102] It is understood that administering a complete estrogen receptor antagonist and an anti-cancer agent described herein can be administered simultaneously or separately. For example, in some embodiments, a complete estrogen receptor antagonist and an anti-cancer agent are administered simultaneously. In some embodiments, an anti-cancer agent is administered prior to administration of a complete estrogen receptor antagonist. In some embodiments, an anti-cancer agent is administered after administration of a complete estrogen receptor antagonist.

Exemplary Embodiments

[0103] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the present disclosure.

1. A method of treating a disease, disorder, or condition in a subject comprising administering a composition comprising Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof, wherein presence of one or more biomarkers selected from Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53 has been detected in a biological sample derived from the subject.

2. A method of treating a disease, disorder, or condition in a subject comprising administering a composition comprising Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof, wherein from about 30 mg to about 360 mg of Compound 1 are administered to the subject once daily.

3. A method of treating a disease, disorder, or condition in a subject comprising administering Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof, according to a regimen established to achieve one or more of the following characteristics when administered to a population of comparable subjects:

(i) a mean Cmax from about 135 ng/mL to about 1410 ng/mL;

(ii) a median t_max from about 2 h to about 4 h;

(iii) a mean Cavg from about 80 ng/mL to about 1070 ng/mL;

(iv) a mean AUCo-24 from about 1950 ng*h/mL to about 26000 ng*hr/mL; and

(v) a mean effective ti/2 from about 50 h to about 75 h.

4. The method of any one of embodiments 1-3, wherein the composition is administered in a unit dosage form. 5. The method of embodiment 4, wherein the unit dosage form is a capsule or tablet.

6. The method of any one of embodiments 1-5, wherein the composition is administered to the subject once daily.

7. The method of any one of embodiments 1-6, wherein the composition is administered to the subject one daily for one or more 28 day cycles.

8. The method of any one of embodiments 1-7, wherein the composition is administered to the subject once daily for two, three, four, or five 28 day cycles.

9. The method of any one of embodiments 1-8, wherein an amount of Compound 1 administered to the subject daily is from about 30 mg to about 360 mg.

10. The method of any one of embodiments 1-9, wherein an amount of Compound 1 administered to the subject daily is from about 30 mg to about 100 mg.

11. The method of any one of embodiments 1-10, wherein an amount of Compound 1 administered to the subject daily is about 30 mg.

12. The method of any one of embodiments 1-9, wherein an amount of Compound 1 administered to the subject daily is from about 60 mg to about 120 mg.

13. The method of embodiment 12, wherein an amount of Compound 1 administered to the subject daily is about 60 mg.

14. The method of embodiment 12, wherein an amount of Compound 1 administered to the subject daily is about 90 mg.

15. The method of embodiment 12, wherein an amount of Compound 1 administered to the subject daily is about 120 mg.

16. The method of any one of embodiments 1-15, wherein an average plasma concentration (Cavg) of Compound 1 in the subject post administration is from about 80 ng/mL to about 1070 ng/mL.

17. The method of any one of embodiments 1-16, wherein an average plasma concentration (Cavg) of Compound 1 in the subject post administration is from about 210 ng/mL to about 410 ng/mL.

18. The method of any one of embodiments 1-16, wherein an average plasma concentration (Cavg) of Compound 1 in the subject post administration is from about 100 ng/mL to about 200 ng/mL. 19. The method of any one of embodiments 1-18, wherein a maximum plasma concentration (Cmax) of Compound 1 in the subject post administration is from about 135 ng/mL to about 1410 ng/mL.

20. The method of any one of embodiments 1-19, wherein a maximum plasma concentration (Cmax) of Compound 1 in the subject post administration is from about 290 ng/mL to about 620 ng/mL.

21. The method of any one of embodiments 1-18, wherein a maximum plasma concentration in the subject post administration of Compound 1 is from about 200 ng/mL to about 400 ng/mL.

22. The method of any one of embodiments 1-21, wherein an AUCo-24 in the subject post administration of Compound 1 is from about 1950 ng*h/mL to about 26000 ng*hr/mL.

23. The method of any one of embodiments 1-22, wherein an AUCo-24 in the subject post administration of Compound 1 is from about 5000 ng*h/mL to about 10000 ng*hr/mL.

24. The method of any one of embodiments 1-22, wherein an AUC in the subject post administration of Compound 1 is from about 2000 ng*h/mL to about 4000 ng*h/mL.

25. The method of any one of embodiments 1-24, wherein the disease, disorder, or condition is a cancer.

26. The method of embodiment 25, wherein the cancer is a breast cancer.

27. The method of any one of embodiments 1-26, wherein the biological sample is a tissue sample.

28. The method of embodiment 27, wherein the tissue sample is derived from a tumor.

29. The method of any one of embodiments 1-28, wherein the composition is administered in combination with an anti-cancer agent.

30. The method of embodiment 29, wherein the anti-cancer agent is a CDK 4/6 inhibitor, a PI3Kalpha inhibitor, or an mTOR inhibitor.

31. The method of any one of embodiments 1-30, wherein the subject has previously received endocrine therapy.

32. The method of embodiment 31, wherein the subject’s disease has progressed while receiving endocrine therapy.

33. The method of any one of embodiments 1-32, wherein the biomarker is detected analysis of circulating tumor DNA (ctDNA).

34. A method of treating a disease, disorder, or condition in a subject comprising; (i) analyzing circulating tumor DNA of a biological sample derived from the subject to detect the presence of one or more biomarkers selected from Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53; and

(ii) administering a composition comprising Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof to the subject.

35. The method of any one of embodiments 1-34, wherein the subject has ER+/HER2- recurrent, locally advanced, or metastatic breast cancer.

36. The method of any one of embodiments 1-35, wherein the subject has previously received one or two prior chemotherapy regimens for locally advanced or metastatic disease.

37. The method of any one of embodiments 1-36, wherein the subject has received one prior chemotherapy regimen for locally advanced or metastatic disease.

38. The method of any one of embodiments 1-37, wherein the subject has previously received no more than four endocrine therapies.

39. The method of any one of embodiments 1-38, wherein the subject is harboring a

ESRI mutation (e.g., Y537S).

EXEMPLIFICATION

Example 1. A Phase I Dose Escalation and Dose Expansion and Phase II Monotherapy Open-label, First-in-Human, Multicenter Study of Compound 1 in Adult Subjects with Advanced and/or Metastatic Hormone Receptor (HR)-positive, HER2-negative Breast Cancer

[0104] The present example provides an exemplary study of dose escalation and related endpoints associated with administration of Compound 1. There are two parts of this example: Phase I: Dose Escalation and Expansion; and Phase II: Estimate and/or Identify an Objective Response Rate (ORR) of Compound 1. Study Objectives

Phase I

[0105] Primary Objectives:

• To identify the DLT, MTD, and/or RP2D of Compound 1 (Part A)

• To confirm the RP2D of Compound 1 (Part B)

• To assess the safety and tolerability of Compound 1 (Parts A and B)

• To assess the PK of Compound 1 (Parts A and B)

[0106] Secondary Objectives (Parts A and B):

• To estimate the Overall Response Rate (ORR) defined as the Complete Response (CR) + Partial Response (PR) rate of Compound 1

• To estimate the Clinical Benefit Rate (CBR) (CR + PR + Stable Disease [SD] >24 weeks) of Compound 1

[0107] Exploratory Objectives (Parts A and B):

• To evaluate the pharmacodynamic effects of treatment with Compound 1 on biomarkers in tissue, plasma, and circulating tumor DNA (ctDNA)

• To evaluate the effect of Compound 1 on the QTc interval

• To evaluate the effect of food on Compound 1 PK

Phase II

[0108] Primary Objectives

• To estimate the ORR of Compound 1 in subjects with HR+/HER2- metastatic or locally advanced breast cancer with no evidence of central nervous system (CNS) metastases who have progressed following at least 1 hormonal therapy regimen in the metastatic or locally advanced setting. Progression during adjuvant hormonal therapy or within 12 months of stopping adjuvant hormonal therapy will be considered a metastatic regimen for the purposes of this study

• To assess the safety and tolerability of Compound 1

• To assess the plasma PK of Compound 1

[0109] Secondary Objectives

• To estimate the CBR of Compound 1 in subjects with HR+/HER2- metastatic or locally advanced breast cancer with no evidence of CNS metastases who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic or locally advanced setting.

[0110] Exploratory Objectives

• To estimate the anti-tumor activity of Compound 1 in subjects with HR+/HER2- metastatic or locally advanced breast cancer who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic setting and have CNS disease. For subjects with brain metastatic disease enrolled in the study, assessment of response rate will be determined according to Response Evaluation Criteria in Solid Tumors Criteria (RECIST) 1.1 (which determines response in both the CNS and non-CNS compartments) and the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria (which addresses the CNS component)

• To estimate the ORR of Compound 1 in subjects with HR+/HER2- and mutESRl or wtESRl metastatic breast cancer with no evidence of CNS metastases who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic setting

• To estimate the CBR of Compound 1 in subjects with HR+/HER2- and mutESRl or wtESRl metastatic breast cancer with no evidence of CNS metastases who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic or locally advanced setting

• To evaluate the pharmacodynamic effects of treatment with Compound 1 on biomarkers in tissue, plasma, and ctDNA

• To evaluate treatment duration and best response to therapy of Compound 1 as compared to duration and best response of the last documented endocrine anticancer therapy in subjects whose last therapy prior to entering the study was not an investigational agent

• To evaluate whether mutESRl in ctDNA can be correlated with response and/or activity of Compound 1

• To evaluate the effect of Compound 1 on the QTc interval

• To evaluate the effect of food on Compound 1 PK

Study Endpoints

[0111] The study endpoints of each of the two parts of the study are provided below.

Phase I

[0112] Primary Endpoints • Incidence and nature of DLTs as defined in the protocol

• MTD and/or RP2D of Compound 1 when used as a single agent

• Incidence, nature, and severity of Treatment-Emergent Adverse Events (TEAEs) and serious adverse events (SAEs) according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0

• Plasma levels of Compound 1 at pre-defined intervals to establish PK parameters (includes maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), area under the curve (AUC), half-life (t* ), and Compound 1 trough concentration at steady state)

[0113] Secondary Endpoints:

• ORR by evaluation of tumor response assessments using RECIST 1.1

• CBR as defined by percent of subjects with CR + PR + SD for >24 weeks in subjects without evidence of CNS metastases

[0114] Exploratory Endpoints:

• To explore candidate biomarkers in ctDNA pre- and post-therapy (such as Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53)

• Duration of response (DoR) and DoR compared to last prior endocrine therapy

• Exploratory analyses of metabolites of Compound 1 in plasma may also be conducted, and if so, the results of those analyses will be reported separately by the Sponsor

• Baseline QTc and post-dose plasma concentration on Cycle 1 Day 1 (C1D1) and at steady state will be evaluated

• Plasma levels of Compound 1 at pre-defined intervals to establish PK parameters; includes Cmax, Cmin, Tmax, AUC, t* , and Compound 1 concentration at steady state in the fed state

Phase II

[0115] Primary Endpoints:

• ORR by evaluation of tumor response assessments using RECIST 1.1 in subjects without evidence of CNS metastases

• Incidence, nature, and severity of TEAEs and SAEs according to NCI-CTCAE version 5.0 Plasma levels of Compound 1 at pre-defined intervals to establish PK parameters (includes Cmax, Cmin, Tmax, AUC, t* , and Compound 1 trough concentration at steady state)

[0116] Secondary Endpoints:

• CBR as defined by percent of subjects with a CR + PR + SD for ~24 weeks in subjects without evidence of CNS metastases

• Duration of Response (DoR), time to progression, and progression free survival (PFS) in subjects without evidence of CNS metastases

[0117] Exploratory Endpoints:

• ORR by evaluation of tumor response assessments in subjects with CNS metastases using RECIST 1.1 (for disease in the CNS and non-CNS components) and RANO-BM (for the CNS component)

• Intracranial CBR (iCBR) defined as intracranial CR + intracranial PR + intracranial SD for >24 weeks will also be determined in subjects with CNS disease

• Evaluation of ORR and CBR using RECIST 1.1 in subjects with mutESRl without evidence of CNS metastases

• Evaluation of ORR and CBR using RECIST 1.1 in subjects with wtESRl without evidence of CNS metastases

• Quantitative estrogen receptor alpha (ERa) and progesterone receptor (percent and Allred score) in biopsy samples obtained at baseline and pre-Cycle 2

• Ki67 percent in biopsies obtained at baseline and pre-Cycle 2

• To explore candidate biomarkers in ctDNA pre- and post-therapy (such as Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53)

• Duration of response (DoR) and DoR compared to last prior endocrine therapy

• Exploratory analyses of metabolites of Compound 1 in plasma may also be conducted, and if so, the results of those analyses will be reported separately by the Sponsor

• Baseline QTc and post-dose plasma concentration on C1D1 and at steady state will be evaluated Plasma levels of Compound 1 at pre-defined intervals to establish PK parameters; includes Cmax, Cmin, Tmax, AUC, t* , and Compound 1 concentration at steady state in the fed state

Number of Subjects Planned

[0118] Phase I, Part A: Dose Escalation: Approximately 42 subjects will be enrolled. Part B: Dose Expansion: Approximately 30 subjects will be enrolled. To allow for replacement of subjects who are not evaluable, up to a total of approximately 80 subjects may participate in the Phase I portion of the study.

[0119] Phase II: This portion of the study further explores the clinical activity, safety, and pharmacology of Compound 1 at the RP2D and will estimate preliminary anti-tumor efficacy. Approximately 88 additional subjects will be enrolled in Phase II: Cohort A will enroll approximately 50 subjects with measurable disease without evidence of CNS metastases; Cohort B will enroll approximately 15 subjects in the cohort with non-measurable (evaluable) disease without evidence of CNS metastases; and Cohort C will consist of approximately 15 subjects in the cohort with CNS metastases. To allow for replacement of subjects who are not evaluable, a total of approximately 88 subjects may participate in the Phase II portion of the study.

Diagnosis and Inclusion/Exclusion Criteria

[0120] Individuals eligible to participate in the Phase I Dose Escalation Phase and the Expansion Phase and the Phase II portion of the study must meet all of the following criteria: Inclusion Criteria

1. Age > 18 years, including males and females

2. Subject is willing and able to participate and comply with all trial requirements and to provide signed and dated informed consent prior to initiation of any trial procedures

3. Subject has histologically or cytologically confirmed locally advanced or metastatic breast cancer for which standard curative measures do not exist

4. Tumor must be estrogen receptor (ER)-positive and HER2 negative as determined in the most recently obtained archival tumor tissue sample, using locally accepted criteria by the local pathology report

5. Subject must be willing to provide paraffin blocks or a minimum of 10 unstained slides of archival tumor tissues if available from the most recently obtained tumor biopsy The subject must have received at least 1 prior hormonal regimen for locally advanced or metastatic disease. (Progression during adjuvant hormonal therapy or within 12 months of stopping adjuvant hormonal therapy will be considered a metastatic regimen for the purposes of this study) Subject must have received at least 6 months of a prior continuous endocrine therapy for locally advanced or metastatic breast cancer Subject has a life expectancy >6 months in the opinion of the investigator Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 Male subjects must agree to use an effective form of contraception during the study and for 90 days following the last study drug administration. Effective forms of birth control include barrier methods used in conjunction with a spermicidal cream or jelly (according to standard local practices), non-hormonal intrauterine devices in female partners, or permanent sterilization. Abstinence is acceptable only if this is a previously practiced life-style choice. Withdrawal and/or rhythm methods (natural family planning or fertility awareness) are not acceptable Female subjects of child-bearing potential must meet all of the following criteria: a. Not pregnant b. Not breastfeeding c. Willing to use an effective non-hormonal form of birth control prior to the first study drug administration to 90 days following the last study drug administration. Effective forms of birth control include barrier methods used in conjunction with a spermicidal cream or jelly (according to standard local practices), non-hormonal intrauterine devices, or permanent sterilization. Abstinence is acceptable only if this is a previously practiced life-style choice. Withdrawal and/or rhythm methods (natural family planning or fertility awareness) are not acceptable

NOTE: A female subject is considered to be of child-bearing potential unless she has had: a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy • has medically documented ovarian failure (with serum estradiol and follicle- stimulating hormone levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin)

• or is menopausal (amenorrhea for >12 months) d. Pre- or perimenopausal female subjects must be willing to take a luteinizing hormone-releasing hormone (LHRH) agonist > 2 weeks before first study drug administration and for the duration of the trial Subjects must have not taken proton pump inhibitors (PPI) for 7 days prior to first study drug administration and agree to avoid taking PPI therapy for at least the first 2 cycles of therapy Subjects must have a corrected QT interval (QTcF) < 470 ms for females and <450 ms for males (as calculated by the Fridericia correction formula) Subjects must not have received prior endocrine therapy (including fulvestrant), CDK4/6 inhibitors, alpelisib, everolimus, or poly-ADP ribose polymerase (PARP) inhibitors within 2 weeks prior to the first administration of study drug Subjects must not have received prior chemotherapy, or investigational therapy within 2 weeks prior to the first administration of study drug or antibody therapy within 4 weeks prior to first administration of study drug. Prior radiotherapy must have been completed at least 2 weeks prior to start of Cycle 1 with recovery of any toxicity to < Grade 1 (except for alopecia) Subjects must have had at least 4 weeks from major surgery Subjects must have had any toxicities from prior therapy resolved or be < Grade 1 as defined by CTCAE 5.0 at the time of starting study treatment with the exception of alopecia Subjects have the following laboratory values (obtained < 28 days prior to first dose): a. Serum creatinine < upper limit of normal (ULN) or if higher than the normal range, calculated creatinine clearance (CrCl) must be > 50 mL/min (eg, by Cockcroft-Gault formula); actual body weight must be used for CrCl unless body mass index (BMI) > 30 kg/m2 then lean body weight must be used b. Total bilirubin < 1.5 x ULN unless prior history of Gilbert’s syndrome c. Aspartate transaminase and alanine transaminase < 2.5 x ULN, or < 5 x ULN if due to liver involvement by tumor d. Hemoglobin > 9.0 g/dL without requirement for red blood cell (RBC) transfusion within the last 4 weeks e. Platelets >100 x 10⁹ cells/L f. Absolute neutrophil count (ANC) >1.5 xlO⁹ cells/L (without the use of hematopoietic growth factors within the prior 3 weeks) g. Prothrombin time (PT) and international normalized ratio < 1.5 x ULN, activated partial thromboplastin time (PTT) <1.5 x ULN. If on chronic anticoagulation, the INR must be in the therapeutic range

Additionally, for individuals eligible to participate in the Phase I, Part A (Dose Escalation) of the study:

20. The subject must have received no more than 2 prior chemotherapy regimens for locally advanced or metastatic disease

21. Subjects must have evaluable disease. Subjects with both measurable and non- measurable disease are eligible.

Additionally, for individuals eligible to participate in the Phase I, Part B (Dose Expansion) and Phase II:

22. Subjects must have measurable disease by RECIST 1.1 criteria

23. The subject must have received no more than 1 prior chemotherapy regimen for locally advanced or metastatic disease

24. The subject must have had at least one and no more than 4 prior endocrine based therapies for locally advanced, recurrent, or metastatic disease

Phase II Cohort A:

25. Subjects must have measurable disease by RECIST 1.1 criteria

26. Subject must not have evidence of CNS metastases. (Imaging of the brain is NOT required if the subject does not have symptoms suggesting CNS disease)

Phase II Cohort B:

27. Subjects must have non-measurable and evaluable disease

28. Subject must not have evidence of CNS metastases. (Imaging of the brain is NOT required if the subject does not have symptoms suggesting CNS disease) Additionally, for individuals eligible to participate in the Phase II Cohort C (CNS cohort)

29. The subject must have received no more than 3 prior chemotherapy regimens for locally advanced or metastatic disease

30. The subject must have had at least one prior endocrine based therapy for locally advanced, recurrent, or metastatic disease

31. Subjects must have evaluable disease. (Subjects with either measurable or non- measurable disease are eligible.

32. Subjects with brain metastases are eligible for the study if they meet all the following criteria: a. Their brain metastases have been treated or do not require urgent local treatment at the time of study enrollment b. Have been off dexamethasone or are on a stable dose of dexamethasone of < 2 mg daily (or an alternate steroid dosed at a level equal to < 2 mg daily) for at least 2 weeks prior to first study drug administration

Exclusion Criteria

[0121] Individuals who meet any of the following exclusion criteria will not be eligible to participate in either the Phase I or Phase II part of the study:

1. Subjects with a prior or concurrent malignancy whose natural history or treatment may interfere with the safety or efficacy assessment of the investigational regimen as determined by the Investigator

2. Subjects with known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, congestive heart failure (New York Heart Association Functional Classification Class 2B-4) and uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg on anti-hypertensive medications)

3. Subjects with myocardial infarction or unstable angina within 6 months prior to the first administration of study drug

4. Subject with a history of cerebral vascular disease within 6 months prior to the first administration of study drug

5. Subject has an active infection that requires antimicrobial therapy

6. Subject has a history of leptomeningeal disease or spinal cord compression 7. Subject has a history of allergic reactions attributed to compounds of similar chemical composition to Compound 1

8. Subject has a history of a pulmonary embolism or deep venous thrombosis within the last 6 months or subject has an increased risk of thrombosis as determined by the investigator. (Subjects on chronic anticoagulation are allowed)

9. Medical history or ongoing gastrointestinal disorders that could affect absorption of Compound 1 (such as active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper GI surgery including gastric resection and including difficulties with swallowing capsules)

10. Subjects requiring therapy with strong CYP3A4 inhibitors and inducers

11. Subjects requiring medications with known risk of QT interval prolongation or increased risk of Torsades de Pointes

12. Subject has a known Human Immunodeficiency Virus (HIV) infection

13. Subject has a known clinically significant history of liver disease consistent with Child- Pugh Class B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis

14. Subject has clinically significant co-morbidities, such as uncontrolled pulmonary disease, CNS metastases that require treatment or steroid doses of > 2 mg, active infection, psychiatric disease, or any other condition that could impact the ability of the subject to participate in this study or otherwise has the potential to confound the study results

Study Treatment

[0122] Compound 1 will be supplied in tamper-resistant high density polyethylene (HDPE) bottles as capsules containing 15 mg or 60 mg dose strengths which the pharmacist or study staff will supply the appropriate dose for each dose cohort.

Dosing Regimen:

[0123] The starting dose is 30 mg once daily. The subject should take the capsules orally once at approximately the same time of day on an empty stomach. The subject should be fasting 2 hours before taking Compound 1 and remain fasting until 1 hour after Compound 1 administration. In order to allow for PK evaluations, subjects should take Compound 1 in the morning during the first 2 cycles and on C3D1. In cases where a subject misses his/her normal dosing time, the subject may still take the dose within 12 h of the regular dosing time (subjects should not take 2 consecutive daily doses within 12 h of each other). Cycles are repeated every 4 weeks (28 days).

Dose Levels:

[0124] Dose escalation for Phase I, Part A will be per the table below. Dose escalation will follow a rolling 6 design. See Skolnik, et al., J. of Clin. Oncology, 26(2), 190-195 (2008).

[0125] The available safety and PK data will be reviewed, and intermediary dose levels may be tested. Up to a maximum dose of 360 mg once a day will be evaluated.

Phase I - Part A Dose Escalation: Dose levels Compound 1

*Intermediate dose levels will be tested.

Dose Escalation Rules

Phase I, Part A - Dose Escalation Rules

[0126] The following rolling 6 dose escalation rules noted below will be employed, considering DLTs observed in Cycle 1. Cohorts of 3 to 6 subjects will be treated at each dose level. In the rolling six design, up to 6 subjects may be concurrently enrolled at each dose level in the study. The decisions to escalate to the next highest dose level are made by the principal investigators (PI) participating in the Phase I study and representatives of the Sponsor at a cohort review meeting after at least 3 subjects have completed Cycle 1. Decisions as to whether to enroll a new subject onto the current, next highest, or next lowest dose level are made by the Sponsor based on available data at the time of new subject enrollment. Dose level assignments are based on the number of participants currently enrolled in the cohort, the number of DLTs observed, the number of participants at risk for developing a DLT (i.e., participants enrolled but who were not yet evaluable for toxicity), and the available PK results. If 2 or more DLTs at a given dose level are observed, the dose level will be de-escalated. Intermediate dose levels will be tested.

Maximum Tolerated Dose Determination and Cohort Expansion

Definition of Dose Limiting Toxicity

[0127] A Dose Limiting Toxicity (DLT) is defined as any of the following TEAEs that occur despite optimal medical management, graded using NCLCTCAE v5.0 during Cycle 1; except those that are clearly and incontrovertibly due to disease progression or extraneous causes:

• Any death not clearly due to the underlying disease or extraneous causes

• Grade >3 non-hematologic toxicity (unless otherwise noted below)

• Grade >3 nausea and/or vomiting and/or Grade 3 diarrhea not resolving within 72 h with optimal treatment

• Grade 3 neutropenia accompanied with fever and/or infection

• Grade 3 thrombocytopenia associated with bleeding

• Grade >4 hematologic toxicity

• AST or ALT > 3x the ULN and a total bilirubin > 2x times the ULN without initial findings of cholestasis (elevated serum alkaline phosphatase) and no other reason for the increase in transaminases and total bilirubin • AST or ALT > 8x ULN or AST or ALT > 5x ULN for >14 days

• ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

• Grade >3 blurred vision or retinopathy

• Grade >3 fatigue that does NOT resolve to Grade < 1 within 7 days

• Grade >2 TEAEs that result in omission of treatment for >7 days during Cycle 1 or delay of Cycle 2 for >7 days

• Multiple concurrent adverse events (AEs) in a single subject leading to DLT will be considered a single DLT

[0128] Subjects must receive at least 75% (21 days) of planned Compound 1 doses in Cycle 1 in order to be evaluated for determination of DLTs. Subjects who withdraw from study before receiving 75% of the planned doses in the first cycle of treatment for reasons unrelated to study drug toxicity will be considered to have inadequate data to support dose escalation. Subjects who receive less than 75% of the study drug due to the occurrence of a DLT are considered DLT evaluable and will not be replaced. (Subjects receiving less than 75% of the planned dose in Cycle 1 without a DLT will be evaluated in the overall safety analysis but not for the purposes of dose escalation.)

Definition of MTD or RP2D:

[0129] For purposes of defining the MTD and/or expansion phase recommended dose of Compound 1, subjects will be evaluated according to the actual starting dose of Compound 1 during the first treatment cycle. For most subjects, this will be the dose cohort to which they were assigned. Subjects who receive at least 75% (21 days) of the planned doses in Cycle 1 will be considered to have sufficient safety data/follow-up to support dose escalation. In such cases, replacement subjects may be enrolled to receive the same starting dose of Compound 1 as the subjects who withdraw prematurely.

[0130] The MTD is defined as the highest feasible dose tested in which fewer than 33% of subjects experienced DLT attributable to the study drug, when at least 6 subjects were treated at that dose and were assessable for toxicity.

Dose Modifications for Phase I and Phase II: [0131] All AEs should be assessed according to the CTCAE, v5.0. In event of multiple toxicities, dose delays and modifications should occur in accordance with the highest Grade AEs observed.

[0132] Subjects who experience a DLT or any of the following AEs in Cycle 2 and beyond will have study drug treatment interrupted.

[0133] Modified doses are provided below:

Concomitant Medications

[0134] Pre- and perimenopausal women must take an LHRH agonist of physician’s choice.

[0135] Proton pump inhibitors should be avoided. The use of H2 blockers is strongly discouraged. If the subject experiences symptoms of gastric acid reflux that are not relieved with conservative measures (small meals, no eating after 6 PM, avoiding foods that stimulate stomach acid such as caffeine, alcohol, tomatoes, spicy foods). The PI or designee may prescribe H2 blockers to be taken once or twice a day provided they are taken at least 4 h prior to the Compound 1 dose.

[0136] Subjects should not take strong CYP3A4 inhibitors (including grapefruit and inducers) along with Compound 1 as they may interfere with the drug levels of Compound 1 in the plasma. [0137] Use of P-gp, CYP2C8, and CYP2C9 sensitive substrates with Compound 1 should be done with caution as Compound 1 may increase drug levels of these concomitant medications in the plasma.

[0138] Subjects should avoid medications with known risk of QT interval prolongation or increased risk of Torsades de Pointes.

[0139] If the PI or designee considers that it is in the best interest of the subject to be treated with one of the drugs listed below, this may be allowed with notification of the Medical Monitor.

[0140] Medications considered necessary for the subject’s safety and well-being may be given at the discretion of the PI or designee.

[0141] Bisphosphonates or other bone modifying agents are allowed provided the subject has been on these agents for at least 4 weeks prior to Cycle 1.

[0142] Medications for nausea, vomiting, diarrhea, and constipation may be given according to the standard of care guidelines at the discretion of the PI or designee.

[0143] Subjects who have febrile neutropenia (FN) should receive antibiotics per standard of care. Granulocyte colony stimulating factor (G-CSF) may be used at the PI or designee’s discretion.

[0144] No other cancer therapies or investigational agents are permitted during the entire duration of the study treatment.

Duration of Treatment

[0145] In the absence of unacceptable Compound 1 treatment-related toxicity or disease progression, subjects may receive Compound 1 treatment for up to 1 year and beyond 1 year with the agreement of the PI or designee and the Sponsor.

[0146] Treatment will continue until any 1 of the following occurs:

• SAE or AE that require dose discontinuation

• Progressive disease as determined by RECIST 1.1

• Initiation of non-protocol anticancer therapy

• Illness or condition that may interfere with the subject’s participation or require treatment discontinuation

• Treating PI or designee’s determination that continuation of protocol therapy is not in the subject’s best interests

• Pregnancy

• Noncompliance

• Voluntary withdrawal of consent

• Sponsor termination of the study

Criteria for Evaluation

[0147] Safety:

[0148] Safety will be assessed by periodic physical examinations, 12-lead electrocardiograms (ECGs), clinical laboratory assessments, and monitoring of AEs. 12-lead ECGs will be evaluated at baseline (Screening) and at prespecified timepoints during treatment and at the end of treatment. Additional clinical laboratory assessments and 12-ECGs will also be obtained when clinically indicated. AEs will be graded using NCI-CTCAE version 5.0 criteria. [0149] Site teleconferences between the Sponsor and all participating sites will be held during the dose escalation phase to discuss any suspected AEs/DLTs that have occurred in each cohort. The Safety Committee will include Pls participating in the study, the Medical Monitor, and the Sponsor’s Medical Director. Study drug-related toxicities from the current cohort will be reviewed during the site teleconferences before escalating to the next dose level.

[0150] PK and ECG determinations:

[0151] The PK profile will be assessed by determining the plasma levels of Compound 1 at intervals. In addition to the scheduled samples, an unscheduled PK blood sample should be drawn as soon as possible after a SAE and following a dose reduction of Compound 1. Following a dose reduction, the pre-dose sample will be collected at the next clinic visit that is least 1 week after the subject has taken Compound 1 at a reduced dose.

[0152] All subjects will have ECGs in triplicate at multiple timepoints.

[0153] Subjects should be supine for 10 minutes before obtaining the ECG and 2 minutes should elapse between each ECG. The ECG should be obtained immediately prior to PK blood draws and prior to assessment of blood pressure and other vital signs.

[0154] All subjects are eligible to participate in 1 of 2 sub-studies: Frequent ECG and Food Effect. Subjects in the Frequent ECG sub-study will have additional triplicate ECGs performed. Subjects participating in a Food Effect sub-study will have additional 24-hour PK samples collected on C2D15 and C2D16.

[0155] Subjects may participate in either the Frequent ECG sub-study or the Food Effect sub-study but not both.

[0156] Pharmacodynamics:

[0157] Tumor samples and blood will be collected for pharmacodynamic assessments. ER, PR, and Ki67 by immunochemistry will be evaluated in tumor biopsies and mutESRl and other biomarkers of interests in ctDNA from blood collections. ER and PR will be assessed by percent and scored using the Allred method. In addition, for ER, PR and Ki67 the absolute and percent change from baseline will be evaluated.

[0158] Predictive Markers of Compound 1 Activity: [0159] Biomarkers that may predict Compound 1 activity will be evaluated in archival tumor tissues. These include quantitative levels of ER and PR by immunohistochemistry (percent cells positive and Allred score), phosphoinositide 3-kinase alpha catalytic subunit (PIK3CA), phosphatase variants and potentially other biomarkers, e.g., Ki-67, ESRI, ERBB2, KRAS, AKT, and TP53.

[0160] Efficacy:

[0161] Radiographic and/or physical assessments of the malignancy will be made at Screening/baseline (within 28 days prior to the first study drug administration) and after every 2 cycles of treatment. Subjects who have been determined to have obtained a clinical benefit from Compound 1 may decrease the frequency of radiographic and physical assessments of malignancy to every 3 months after radiographic assessment following the completion of 8 cycles of therapy. Overall response (CR and PR) as determined by the subject’s best tumor response, DoR, time to progression, and PFS will be assessed using RECIST 1.1. For subjects with brain metastatic disease enrolled in the study, assessment of response rate in the non-CNS and CNS compartments will be defined according to RECIST 1.1 and RANO-BM criteria. Additional imaging studies and tumor measurements will be performed in subjects obtaining a PR or CR on a second examination > 4 weeks after initial response determination. CBR will be determined as follows: CR + PR + subjects with SD for > 24 weeks. iCBR will be determined as follows: intracranial CR + intracranial PR + subjects with intracranial SD for > 24 weeks in the CNS.

Statistical Methods

[0162] Safety Analyses:

[0163] Safety data analysis will be conducted on all subjects receiving at least 1 full or partial dose of Compound 1. DLT summary will be conducted on DLT evaluable subjects, defined as subjects in the dose escalation portion of the study receiving at least 75% of Compound 1 doses or experience a DLT in Cycle 1. All treatment-emergent AEs regardless of attribution will be summarized by cohort, as follows:

• All DLTs (regardless of grade)

• All AEs (regardless of grade or attribution)

• All Grade 3/4/5 AEs

All drug-related AEs (regardless of grade) • All AEs leading to study drug or study discontinuations

• All SAEs, including deaths

• All AEs of special interest (regardless of grade)

[0164] A separate listing of all on-study deaths will be presented.

[0165] Efficacy Analyses:

[0166] An analysis of ORR will be conducted for subjects with measurable disease enrolled in the study who have completed at least 1 cycle of Compound 1 and have a post-treatment tumor assessment. The number and percentage of subjects experiencing an overall response (CR + PR) will be summarized. The DoR will be summarized descriptively using the Kaplan-Meier method. The DoR is defined as the number of days from the start date of PR or CR (whichever response is achieved first) to the first date that progressive disease is objectively documented. CBR will be summarized.

[0167] Subjects without measurable disease will not be included in the determination of ORR; however, they will be included in safety, secondary, and exploratory analyses where appropriate.

[0168] Subjects with CNS metastases will be analyzed in a separate cohort. ORR in subjects with CNS metastases will be performed using both RECIST 1.1 (for disease in the CNS and non- CNS components) and RANO-BM (for the CNS component). iCBR defined as intracranial CR +, intracranial PR + subjects with intracranial SD for >24 weeks in the CNS will also be determined.

[0169] The ORR in the expansion phase will also be examined by mutation status (mutESRl, wtESRl). The respective mutation status cohort may be expanded further if the ORR indicates favorable risk/safety ratio for these subjects with metastatic or locally advanced breast cancer for which standard curative measures do not exist.

[0170] Pharmacokinetic Analyses:

[0171] Pharmacokinetic parameters will be determined for the PK Analysis Set using standard compartmental or non-compartmental methods. A listing of subjects excluded from the analysis set and individual data points excluded from the analysis will be provided. The final analysis of PK parameters will be calculated based on actual sample collection time, rather than scheduled times. In addition, the PK sparse exposure data from this study may be used in the development of population PK and PK/PD models. Pharmacokinetic plasma levels and parameters will be determined, listed, and summarized for the PK evaluable population in the Pharmacokinetic Analysis Plan (PKAP). Only samples with acceptable PK (as defined in the PKAP) will be included in the summary statistics, and a listing of individual data points that were excluded from the analysis will be presented. Plasma concentrations will be listed by for the PK Population. Summary statistics of Compound 1 concentrations will be reported by dose level, Day and Cycle. Details of this analysis will be provided in the PKAP. Possible relationships between PK parameters, PD variables, safety, and efficacy may be examined.

[0172] Biomarker Analyses:

[0173] Summary statistics will be computed for baseline biomarkers. The absolute and percent change from baseline will be determined. Summary statistics will be computed for each collection time point.

Example 2. A Phase 1A Dose Escalation Study of Compound 1 in Adult Subjects with Advanced and/or Metastatic Hormone Receptor (HR)-positive, HER2-negative Breast Cancer

[0174] This example describes initial results, as of a first cutoff date, from the Phase 1A dose escalation portion of the study described in Example 1.

Study Design

[0175] Overall study design is summarized in FIG. 1. All patients in the study were adults with ER+/HER2- recurrent, locally advanced or metastatic breast cancer with at least 1 prior hormonal regimen for metastatic disease (Table 1).

Table 1.

RECIST 1.1, Response Evaluation Criteria in Solid Tumors, version 1.1. Patient Population

[0176] As of a first cutoff date, 40 patients were treated in the study. Thirty-eight patients were postmenopausal women, one patient was a pre/perimenopausal women, and one patient was male. Thirty-five patients were white, one was African-American and four did not report race (Table 2).

Table 2. Demographics and Baseline Disease Characteristics

CDK = cyclin-dependent kinase; ctDNA = circulating tumor DNA; ECOG PS = Eastern Cooperative Oncology Group performance status. aOne patient in the 150 mg dose group was missing data as of the data cutoff date. ^bctDNA was not collected at baseline in 8 patients.

[0177] Of the 40 patients treated, 16 were still on treatment at the time of a first data cutoff, and 17 had discontinued treatment due to progressive disease (Table 3). Table 3. Patient Disposition

“Reasons for treatment discontinuation were: 17 (42.5%) progressive disease, 1 (2.5%) adverse event of febrile neutropenia, and 6 (15%) for other reasons (rising tumor markers [n=2], physician decision [n=l], patient decision n=l], transfer of care [n=l], HER2+ on post-treatment biopsy [n= 1]).

Pharmacokinetics

[0178] As shown in FIG. 2 and Table 4, Compound 1 was readily bioavailable with a median tmax ranging between 2 and 4 hours. Steady-state Compound 1 plasma concentrations exceeded the target efficacious average concentration for dose levels > 60 mg QD. Dose-proportional increases in Compound 1 exposures (mean Cmax and AUCo-24) were observed across all evaluated doses after single and multiple doses. Effective half-lives (ti/2) were between 51 and 73 h. Overall, Compound 1 displayed high oral bioavailability and steady-state plasma levels with minimal peak-to-trough variability.

Table 4.

Statistics presented: GeoMean (GeoCV%).

AUCo-24 = area under the concentration-time curve from 0 to 24 hours; c_avg = average plasma concentration; c_max = maximum plasma concentration; GeoMean = geometric mean; GeoCV % = geometric coefficient of variation; ti/2eff = effective half-life; t_max = time to maximum concentration.

“Median (min-max). ^b24-h Compound 1 imputed using the observed predose value for computation of AUCo-24- cn=4. ^dOne patient removed as unevaluable for PK. Safety

[0179] Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 at all dose levels (Table 5). No dose-limiting toxicities (DLTs) were observed and the maximum tolerated dose (MTD) was not reached. The most common TEAEs were fatigue, nausea, and constipation (Table 6). No clinically significant bradycardia, ocular toxicity, or diarrhea were observed. Six patients had dose reductions - two patients at 210 mg dose had reductions (one to 120 mg, one to 60 mg), and four patients at 300 mg dose had reductions (three to 120 mg and one to 60 mg).

Table 5. Treatment-Emergent Adverse Events (TEAEs) Occurring in >15% of Patients

G>3 = grade 3 and 4 events; TEAEs = treatment-emergent adverse events.

T50 mg cohort data were not mature as of the cutoff date and were not included. b Adverse events of interest that did not reach >15%.

Two patients at 90 mg and 3 patients at 300 mg experienced photopsia (flashing lights). All events were grade 1 except for 1 event at 300 mg which was grade 2. Ophthalmologic exams were conducted upon symptoms and no detriment in visual acuity or physical abnormalities were reported. There was no interruption in Compound 1 dosing due to photopsia.

Four patients experienced grade 1 asymptomatic bradycardia; one of these four was found to have prior history of asymptomatic bradycardia. One patient was in the 120 mg cohort; one patient was in the 210 mg cohort; and two patients were in the 300 mg cohort. There was no interruption in Compound 1 dosing due to bradycardia. Table 6. Adverse Events Attributed to Study Drug by Investigator Occurring in >15% of

Patients

G>3 = grade 3 and 4 events a150 mg cohort data were not mature as of the data cutoff date and are not included. ^bTwo patients had grade 3/4 neutropenic events attributed to study drug by the investigator that did not reach >15%: 1 patient experienced grade 4 neutropenia and grade 4 febrile neutropenia and 1 patient had grade 4 neutropenia. Neutropenia resolved within several weeks of discontinuing study drug.

Efficacy

[0180] FIG. 3 summarizes treatment duration and response in all patients (N=41) as of a first cutoff date in this study. Two confirmed partial responses (cPR) maintained for > 8 months were achieved as of the data cutoff date, each harboring an ESRI mutation (one in each of the 60 mg and 120 mg cohorts). A long duration of benefit was observed, with 8 patients on therapy > 6 months and two patients on therapy > 1 year.

[0181] FIG. 4 shows response of target lesion in patients with measurable disease (N=22). Robust target lesion reduction (up to 100%) was observed in response-eligible patients.

[0182] In the clinical benefit rate (CBR)-evaluable population, the CBR was 29% (7/24). CBR is CR + PR + SD > 24 weeks. The CBR-evaluable population includes patients with measurable and nonmeasurable disease who received at least one cycle of treatment, had at least one post-baseline tumor assessment, and enrolled > 24 weeks prior to the data cutoff date.

[0183] In the population evaluable for response, the overall response rate (ORR) was 9% (2/23). This population included patients with measurable disease who received at least one cycle of treatment and had at least one post-baseline tumor assessment.

Anticipated Recommended Phase 2 Dose (RP2D)

[0184] Based on these results, the anticipated RP2D was 60 mg to 120 mg. At 60 mg and above, exposures exceeded the predicted target efficacious average concentration based on preclinical models. In the cohorts within the anticipated RP2D range, the ORR was 17% and the CBR was 46%. Two patients with PD were observed in the anticipated RP2D range (Table 7).

Table 7.

CBR = clinical benefit rate; CR = complete response; ORR = overall response rate; PR = partial response; SD = stable disease. ^aORR and CBR were evaluated per RECIST version 1.1. ^bIncludes patients who received at least one cycle of treatment, were evaluable for a response, and enrolled >24 weeks prior to the data cutoff date. The data for 90 mg an 150 mg dose cohorts were not mature for CBR as of the data cutoff date.

Conclusions

[0185] At dose levels of 60 mg and above, Compound 1 demonstrated high and steady exposure levels that were above the predicted efficacious concentration based on preclinical models, supporting a once daily dosing regimen. No DLTs were observed and MTD was not reached. Most TEAEs were grades 1 or 2 at all dose levels.

[0186] Evidence of clinical benefit was observed in patients with ER+/HER2- metastatic breast cancer, including those with prior CDK4/6 inhibitor and fulvestrant therapy and those with ESRI mutations.

[0187] An anticipated dose range of 60 mg to 120 mg was identified for RP2D evaluation based on a favorable safety and tolerability profile. In the anticipated RP2D range, ORR was 17% and CBR was 46%.

Example 3. Case Study 1

[0188] A 41 -year-old female was administered 120 mg Compound 1 once daily as part of the study described in Example 2. Prior to Compound 1 treatment, the patient had peritoneal carcinomatosis and bone metastasis. The patient had previously been treated with a CDK4/6 inhibitor (palbociclib), endocrine therapies (anastrozole, leuprolide, tamoxifen, and fulvestrant) and chemotherapy (ACT and capecitabine). The patient harbored a ESRI mutation (Y537S). After Compound 1 treatment, the patient had a confirmed partial response maintained for > 9 months with normalization of lymph node lesion and resolution of peritoneal stranding and ascites (FIG. 5). Target lesions were reduced by 71%. Example 4. Case Study 2

[0189] A 61 -year-old female was administered 60 mg Compound 1 once daily as part of the study described in Example 2. Prior to Compound 1 treatment, the patient had multiple liver metastases. The patient had previously been treated with a CDK4/6 inhibitor (ribociclib), endocrine therapies (letrozole, anastrozole, exemestane, tamoxifen, and fulvestrant), and a mTOR inhibitor (everolimus). The patient harbored a ESRI mutation (Y537S). After Compound 1 treatment, the patient had a confirmed partial response maintained for > 8 months. As shown in FIG. 6, target lesions were reduced by 46%.

Example 5. A Phase I Dose Escalation and Dose Expansion and Phase II Monotherapy Open-label, First-in-Human, Multicenter Study of Compound 1 in Adult Subjects with Advanced and/or Metastatic Hormone Receptor (HR)-positive, HER2-negative Breast Cancer

[0190] The present example provides an exemplary study of dose escalation and expansion and related endpoints associated with administration of Compound 1. There are two parts of this example: Phase I: Dose Escalation and Expansion; and Phase II: Estimate and/or Identify an Objective Response Rate (ORR) of Compound 1.

[0191] This is a Phase I dose escalation and dose expansion and Phase II monotherapy openlabel, first-in-human study to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D), to characterize the safety and pharmacokinetic (PK) profile, and to estimate the preliminary anti-tumor activity of Compound 1 as a single agent in adult subjects with hormone receptor (HRj-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic or locally advanced breast cancer.

[0192] Treatment and study subject evaluation is performed in 28-day cycles. This study comprises 2 Phases: Phase I (Part A [Dose Escalation] and Part B [Dose Expansion]) and Phase II. Additionally, all subjects (Phase I and Phase II) will be eligible to participate in 1 of 2 substudies.

[0193] Phase I, Part A (Dose Escalation): This portion of the study evaluated the safety and PK of a range of doses of Compound 1 administered orally daily to subjects and determined the MTD and/or RP2D. Part A employed a rolling 6 dose escalation study design, whereby cohorts of 3 to 6 subjects were sequentially enrolled and monitored for DLTs during the first cycle of study treatment.

[0194] Phase I, Part B (Dose Expansion): At the end of Phase I, Part A, a comprehensive review of safety, tolerability, and PK data was performed to assess whether one Compound 1 dose can be identified as the RP2D. Part B will enroll approximately 30 subjects in the expansion phase at the RP2D, or in the event 2 dose levels are being considered for the RP2D, then up to approximately 30 subjects will be enrolled in each of the 2 dose levels.

[0195] Phase II: This portion of the study further explores the clinical activity, safety, and PK of Compound 1 at the RP2D and will estimate the preliminary anti-tumor activity. Subjects will be enrolled over 3 cohorts in Phase II: Cohort A will enroll subjects with measurable disease without evidence of CNS metastases (subjects participating in Phase I, Part B (Dose Expansion) at the RP2D may be included in this cohort), Cohort B will enroll approximately 15 subjects with non-measurable (evaluable) disease without evidence of CNS metastases; and Cohort C will enroll approximately 15 subjects with evaluable disease (measurable and non-measurable) with CNS metastases.

[0196] Sub-Studies: All subjects (Phase I and Phase II) will be eligible to participate in 1 of 2 sub-studies: Frequent ECG or Food Effect. Subjects may participate in either the Frequent ECG sub-study or the Food Effect sub-study but not both. Participation in a sub-study is optional.

Study Objectives

Phase I

[0197] Primary Objectives:

• To identify the MTD and/or RP2D of Compound 1 (Part A)

• To confirm the RP2D of Compound 1 (Part B)

• To assess the safety and tolerability of Compound 1 (Parts A and B)

• To assess the PK of Compound 1 (Parts A and B)

[0198] Secondary Objectives (Parts A and B):

• To estimate the Overall Response Rate (ORR) defined as the Complete Response (CR) + Partial Response (PR) rate of Compound 1

• To estimate the Clinical Benefit Rate (CBR) (CR + PR + Stable Disease [SD] >24 weeks) of Compound 1 To estimate Duration of Response (DoR) of Compound 1 in subjects who have a confirmed CR or PR

[0199] Exploratory Objectives (Parts A and B):

• To evaluate the pharmacodynamic effects of treatment with Compound 1 on biomarkers in tissue, plasma, and circulating tumor DNA (ctDNA)

• To evaluate the effect of Compound 1 on the QTc interval

• To evaluate the effect of food on Compound 1 PK

• To correlate biomarkers of ESRa and progesterone receptor expression with clinical activity of Compound 1.

Phase II

[0200] Primary Objectives

• To estimate the ORR of Compound 1 in subjects with HR+/HER2- metastatic or locally advanced breast cancer with no evidence of central nervous system (CNS) metastases who have progressed following at least 1 hormonal therapy regimen in the metastatic or locally advanced setting.

• To assess the safety and tolerability of Compound 1

• To assess the plasma PK of Compound 1

[0201] Secondary Objectives

• To estimate the CBR of Compound 1 in subjects with HR+/HER2- metastatic or locally advanced breast cancer with no evidence of CNS metastases who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic or locally advanced setting.

• To estimate the DoR, Progression-Free Survival (PFS), and time to progression of Compound 1 in subjects with with HR+/HER2- metastatic or locally advanced breast cancer with no evidence of CNS metastases who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic or locally advanced setting.

[0202] Exploratory Objectives

• To estimate the anti-tumor activity of Compound 1 in subjects with HR+/HER2- metastatic or locally advanced breast cancer who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic setting and have CNS disease. For subjects with brain metastatic disease enrolled in the study, assessment of response rate will be determined according to Response Evaluation Criteria in Solid Tumors Criteria (RECIST) 1.1 (which determines response in both the CNS and non-CNS compartments) and the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria (which addresses the CNS component)

• To estimate the ORR of Compound 1 in subjects with HR+/HER2- and mutESRl or wtESRl metastatic breast cancer with no evidence of CNS metastases who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic setting

• To estimate the CBR of Compound 1 in subjects with HR+/HER2- and mutESRl or wtESRl metastatic breast cancer with no evidence of CNS metastases who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic or locally advanced setting

• To estimate the DoR of Compound 1 in subjects with HR+/HER2- and mutESRl or wtESRl metastatic breast cancer with no evidence of CNS metastases who have progressed after receiving at least 1 hormonal treatment regimen in the metastatic or locally advanced setting

• To evaluate the pharmacodynamic effects of treatment with Compound 1 on biomarkers in tissue, plasma, and ctDNA

• To evaluate treatment duration and best response to therapy of Compound 1 as compared to duration and best response of the last documented hormonal anticancer therapy in subjects whose last therapy prior to entering the study was not an investigational agent

• To evaluate the effect of Compound 1 on the QTc interval

• To evaluate the effect of food on Compound 1 PK

• To assess biomarkers of ERa and progesterone receptor expression and proliferation pretreatment and during treatment with Compound 1.

Study Endpoints

[0203] The study endpoints of each of the two parts of the study are provided below.

Phase I

[0204] Primary Endpoints

• Incidence and nature of DLTs as defined in the protocol

MTD and/or RP2D of Compound 1 when used as a single agent • Incidence, nature, and severity of Treatment-Emergent Adverse Events (TEAEs) and serious adverse events (SAEs) according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0

• Plasma levels of Compound 1 at pre-defined intervals to establish PK parameters (includes maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), area under the curve (AUC), half-life (t* ), and Compound 1 trough concentration at steady state)

[0205] Secondary Endpoints:

• ORR by evaluation of tumor response assessments using RECIST 1.1 in subjects with measurable disease

• CBR, as defined by percent of subjects with CR + PR + SD for >24 weeks, by evaluation of tumor response assessments using RECIST 1.1

• DoR by evaluation of tumor response assessments using RECIST 1.1

[0206] Exploratory Endpoints:

• To explore candidate biomarkers in ctDNA pre- and post-therapy (such as mutESRl, PIK3CA variants, and others)

• Exploratory analyses of metabolites of Compound 1 in plasma may also be conducted, and if so, the results of those analyses will be reported separately by the Sponsor

• Baseline QTc and post-dose plasma concentration on Cycle 1 Day 1 (C1D1) and at steady state will be evaluated

• Plasma levels of Compound 1 at pre-defined intervals to establish PK parameters; includes Cmax, Cmin, Tmax, AUC, t* , and Compound 1 concentration at steady state in the fed state

• Quantitative change from baseline in ERa and progesterone receptor (percent and Allred score) and percent Ki67 in fresh biopsy samples obtained at C1D1, C3D1, and at the EOT visit.

• Quantitative ERa and progesterone receptor (percent and Allred score) in archival biopsy samples

Phase II

[0207] Primary Endpoints: • ORR by evaluation of tumor response assessments using RECIST 1.1 in subjects without evidence of CNS metastases who have measurable disease

• Incidence, nature, and severity of TEAEs and SAEs according to NCI-CTCAE version 5.0

• Plasma levels of Compound 1 at pre-defined intervals to establish PK parameters (includes Cmax, Cmin, Tmax, AUC, t* , and Compound 1 trough concentration at steady state)

[0208] Secondary Endpoints:

• CBR as defined by percent of subjects with a CR + PR + SD for >24 weeks, by evaluation of tumor response assessments using RECIST 1.1 in subjects without evidence of CNS metastases

• Duration of Response (DoR), time to progression, and progression free survival (PFS) by evaluation of time to progression in subjects without evidence of CNS metastases

[0209] Exploratory Endpoints:

• ORR by evaluation of tumor response assessments in subjects with CNS metastases using RECIST 1.1 (for disease in the CNS and non-CNS components) and RANO-BM (for the CNS component)

• Intracranial CBR (iCBR) defined as intracranial CR + intracranial PR + intracranial SD for >24 weeks by evaluation of tumor response assessments using RECIST 1.1 and RANO-BM will also be determined in subjects with CNS disease

• Evaluation of ORR, CBR, and DoR using RECIST 1.1 in subjects with mutESRl without evidence of CNS metastases

• Evaluation of ORR, CBR, and DoR using RECIST 1.1 in subjects with wtESRl without evidence of CNS metastases

• To explore candidate biomarkers in ctDNA pre- and post-therapy (such as mutESRl, PIK3CA variants and others)

• Quantitative change from baseline in ERa and progesterone receptor (percent and Allred score) and percent Ki67 in fresh biopsy samples obtained at CID 1, C3D1, and the EOT visit.

• Quantitative ERa and progesterone receptor (percent and Allred score) in biopsy samples obtained in archival samples. • Exploratory analyses of metabolites of Compound 1 in plasma may also be conducted, and if so, the results of those analyses will be reported separately by the Sponsor

• Treatment duration and best response on Compound 1 by evaluation of tumor response assessments using RECIST 1.1 in subjects with mutESRl or wtESRl metastatic breast cancer in comparison with last prior hormonal therapy

• Baseline QTc and post-dose plasma concentration on C1D1 and at steady state will be evaluated

• Plasma levels of Compound 1 at pre-defined intervals to establish PK parameters; includes Cmax, Cmin, Tmax, AUC, t* , and Compound 1 concentration at steady state in the fed state

Number of Subjects Planned

[0210] Phase I, Part A: Dose Escalation: Approximately 42 subjects will be enrolled. Part B: Dose Expansion: Approximately 60 subjects will be enrolled. To allow for replacement of subjects who are not evaluable, up to a total of approximately 102 subjects may participate in the Phase I portion of the study.

[0211] Phase II: Up to 88 evaluable subjects will be enrolled over 3 cohorts in the Phase II: Cohort A will enroll 50 subjects with measurable disease without evidence of CNS metastases (subjects in the expansion at the RP2D will be included in this cohort), Cohort B will enroll approximately 15 subjects with non-measurable (evaluable) disease without evidence of CNS metastases; and Cohort C will enroll approximately 15 subjects with CNS metastases. To allow for subject replacement up to a total of approximately 88 subjects may be enrolled in the Phase II portion of the study.

[0212] Sub-Studies: Of the 190 subjects planned for enrollment in the study (up to 102 subjects from Phase I and up to 88 subjects from Phase II), all subjects will have the opportunity to participate in the ECG sub-study or in the food effect sub-study, but not both.

Diagnosis and Inclusion/Exclusion Criteria

[0213] Individuals eligible to participate in the Phase I Dose Escalation Phase and the Expansion Phase and the Phase II portion of the study must meet all of the following criteria: Inclusion Criteria

1. Age > 18 years, including males and females Subject is willing and able to participate and comply with all trial requirements and to provide signed and dated informed consent prior to initiation of any trial procedures Subject has histologically or cytologically confirmed locally advanced or metastatic breast cancer for which standard curative measures do not exist Tumor must be HR-positive and HER2 negative as determined in the most recently obtained archival tumor tissue sample from a metastatic site (unless de novo diagnosis or no metastatic biopsy undertaken) using locally accepted criteria by the local pathology report. HR positive is defined as ER+/PR+, ER+/PR-, ER-/PR+. Subject must be willing to provide paraffin blocks or a minimum of 10 unstained slides of archival tumor tissues if available from the most recently obtained tumor biopsy The subject must have received at least 1 prior hormonal regimen for locally advanced or metastatic disease. Subject must have received at least 6 months of a prior continuous endocrine therapy for locally advanced or metastatic breast cancer Subject has a life expectancy >6 months in the opinion of the investigator Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 Male subjects must be willing to adhere to highly-effective contraception during the study and for 90 days following the last study drug administration. Highly-effective contraception methods must include one of the following criteria: a. Successful vasectomy b. For subjects who have not had a successful vasectomy, and are partners of women of childbearing potential, their partners adhere to any one of the following: i. Hormonal contraception + male subject’s use of a condom with spermicide ii. IUD (hormonal or non-hormonal) iii. Bilateral tubal ligation + male subject’s use of a condom with spermicide iv. Depo Provera + male subject’s use of a condom with spermicide Females of childbearing potential must be willing to adhere to highly-effective contraception during the study and for 90 days following the last study drug administration: a. Highly-effective contraception methods must include one of the following: i. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. ii. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. iii. Male partner sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject and the success of the vasectomy must be medically confirmed as per local practice. iv. Placement of a non-hormonal intrauterine device (IUD). b. Additionally, females of childbearing potential, must meet all of the following criteria: i. Not pregnant, as confirmed by a negative serum pregnancy test (P-human chorionic gonadotropin) before starting study treatment ii. Not breastfeeding c. A female subject is considered to be of childbearing potential unless she meets one of the following criteria: i. Is aged > 60 years ii. Has had a hysterectomy, bilateral tube ligation, or bilateral oophorectomy iii. Has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone levels) iv. Is menopausal (amenorrhea > 12 months) while off drugs that interfere with ovarian function Pre and per-menopausal female subjects must be willing to take a LHRH agonist > 2 weeks before the first study drug administration and for the duration of the study. Subjects must have not taken proton pump inhibitors (PPI) for 7 days prior to first study drug administration and agree to avoid taking PPI therapy for at least the first 2 cycles of therapy Subjects must have a corrected QT interval (QTcF) < 470 ms for females and <450 ms for males (as calculated by the Fridericia correction formula) Subjects must not have received prior endocrine therapy (including fulvestrant), CDK4/6 inhibitors, alpelisib, everolimus, or poly-ADP ribose polymerase (PARP) inhibitors within 2 weeks prior to the first administration of study drug Subjects must not have received prior chemotherapy within 2 weeks or investigational therapy within 4 weeks prior to the first administration of study drug or within 5 half lives of either chemotherapy of investigational agent (whichever is earlier). Subjects must not have received antibody therapy within 4 weeks prior to first administration of study drug. Prior radiotherapy must have been completed at least 2 weeks prior to start of Cycle 1 with recovery of any toxicity to < Grade 1 (except for alopecia) Subjects must have had at least 4 weeks from major surgery Subjects must have had any toxicities from prior therapy resolved or be < Grade 1 as defined by NCI-CTCAE, v 5.0 at the time of starting study treatment with the exception of alopecia Subjects have the following laboratory values (obtained < 28 days prior to first dose): a. Serum creatinine < upper limit of normal (ULN) or has an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m² according to the Modification of Diet in Renal Disease (MDRD) formula b. Total bilirubin < 1.5 x ULN unless prior history of Gilbert’s syndrome c. Aspartate transaminase and alanine transaminase < 2.5 x ULN, or < 5 x ULN if due to liver involvement by tumor d. Hemoglobin > 9.0 g/dL without requirement for red blood cell (RBC) transfusion within the last 4 weeks e. Platelets >100 x 10⁹ cells/L f. Absolute neutrophil count (ANC) >1.5 xlO⁹ cells/L (without the use of hematopoietic growth factors within the prior 3 weeks) g. Prothrombin time (PT) and international normalized ratio (INR) < 1.5 x ULN, activated partial thromboplastin time (PTT) <1.5 x ULN. If on chronic anticoagulation, the INR must be in the therapeutic range Additionally, for individuals eligible to participate in the Phase I, Part A (Dose Escalation) of the study:

21. The subject must have received no more than 2 prior chemotherapy regimens for locally advanced or metastatic disease

22. Subjects must have evaluable disease. Subjects with both measurable and non- measurable disease are eligible.

Additionally, for individuals eligible to participate in the Phase I, Part B (Dose Expansion) and Phase II:

23. Subjects must have measurable disease by RECIST 1.1 criteria

24. The subject must have received no more than 1 prior chemotherapy regimen for locally advanced or metastatic disease

25. The subject must have had at least one and no more than 4 prior hormonal based therapies for locally advanced, recurrent, or metastatic disease

26. Subjects with brain metastases are eligible for the study (Phase I Part A, Phase I Part B, and Phase II Cohort C) if the meet all of the following criteria: a. The subject’s brain metastases have been treated or do not require urgent local treatment at the time of study enrollment b. The subject has been off dexamethasone or is on a stable dose of dexamethasone of < 2 mg daily (or an alternate steroid dosed at a level equal to < 2 mg daily) for at least 2 weeks prior to first study drug administration

Phase II Cohort A:

27. Subjects must have measurable disease by RECIST 1.1 criteria

28. Subject must not have evidence of CNS metastases. (Imaging of the brain is NOT required if the subject does not have symptoms suggesting CNS disease)

Phase II Cohort B:

29. Subjects must have non-measurable and evaluable disease

30. Subject must not have evidence of CNS metastases. (Imaging of the brain is NOT required if the subject does not have symptoms suggesting CNS disease)

Additionally, for individuals eligible to participate in the Phase II Cohort C (CNS cohort)

31. The subject must have received no more than 3 prior chemotherapy regimens for locally advanced or metastatic disease 32. The subject must have had at least one prior hormone-based therapy for locally advanced, recurrent, or metastatic disease

33. Subjects must have evaluable disease. (Subjects with either measurable or non- measurable disease are eligible.

Exclusion Criteria

[0214] Individuals who meet any of the following exclusion criteria will not be eligible to participate in either the Phase I or Phase II part of the study:

1. Subjects with a prior or concurrent malignancy whose natural history or treatment may interfere with the safety or efficacy assessment of the investigational regimen as determined by the Investigator

2. Subjects with known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, congestive heart failure (New York Heart Association Functional Classification Class 2B-4) and uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg on anti-hypertensive medications)

3. Subjects with myocardial infarction or unstable angina within 6 months prior to the first administration of study drug

4. Subject with a history of cerebral vascular disease within 6 months prior to the first administration of study drug

5. Subject has an active infection that requires antimicrobial therapy

6. Subject has a history of leptomeningeal disease or spinal cord compression

7. Subject has a history of allergic reactions attributed to compounds of similar chemical composition to Compound 1

8. Subject has a history of a pulmonary embolism or deep venous thrombosis within the last 6 months or subject has an increased risk of thrombosis as determined by the investigator. (Subjects on chronic anticoagulation are allowed)

9. Medical history or ongoing gastrointestinal disorders that could affect absorption of Compound 1 (such as active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper GI surgery including gastric resection and including difficulties with swallowing capsules)

10. Subjects requiring therapy with strong CYP3A4 inhibitors and inducers 11. Subjects requiring medications with known risk of QT interval prolongation or increased risk of Torsades de Pointes

12. Subject has a known Human Immunodeficiency Virus (HIV) infection

13. Subject has a known clinically significant history of liver disease consistent with Child- Pugh Class B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis

14. Subject has clinically significant co-morbidities, such as uncontrolled pulmonary disease, CNS metastases that require treatment or steroid doses of > 2 mg, active infection, psychiatric disease, or any other condition that could impact the ability of the subject to participate in this study or otherwise has the potential to confound the study results

Study Treatment

[0215] Compound 1 will be supplied in tamper-resistant high density polyethylene (HDPE) bottles as capsules containing 15 mg or 60 mg dose strengths which the pharmacist or study staff will supply the appropriate dose for each dose cohort.

Dosing Regimen:

[0216] The starting dose is 30 mg once daily. Compound 1 will be administered orally once daily at approximately the same time of the day on an empty stomach. Subjects should be fasting for 2 hours prior to taking Compound 1 and for 1 hour post Compound 1 administration. For the first cycles of therapy, subjects should take Compound 1 in the morning to allow for PK assessments. After the pre-dose PK sample is collected on C3D1, subjects may take Compound 1 at a time of day of their choosing, but should take the drug at approximately the same time each day. Cycles are repeated every 28 days. In cases where a subject misses his/her normal dosing time, the subject may still take the dose within 12 hours of the regular dosing time. Subjects should not take 2 consecutive daily doses within 12 hours of each other.

[0217] On days of in-clinic visits, Compound 1 will be administered to the subject by staff at the clinic (the subject should be counseled not to take their Compound 1 dose at home on the day of the clinic visit).

[0218] Subjects participating in the Food Effect sub-study should fast for at least 10 hours before Compound 1 administration in C2D1 and C2D15 and remain fasting until after the PK sample scheduled for 4 hours after dosing is obtained. Dose Levels:

[0219] Dose escalation for Phase I, Part A will be per the table below. Dose escalation will follow a rolling 6 design. See Skolnik, et al., J. of Clin. Oncology, 26(2), 190-195 (2008).

[0220] The available safety and PK data will be reviewed, and intermediary dose levels may be tested. Up to a maximum dose of 360 mg once a day will be evaluated.

Phase I - Part A Dose Escalation: Dose levels Compound 1

*Intermediate dose levels will be tested.

Dose Escalation Plan

Phase I, Part A

[0221] In Part A (Dose Escalation), cohorts of 3 to 6 subjects will be enrolled at each Compound 1 dose level and each subject will participate in only 1 cohort. Subjects at each dose level will be treated and observed for DLT through the end of the first cycle.

[0222] The rolling 6 dose escalation rules noted below will be employed, considering DLTs observed in Cycle 1. Cohorts of 3 to 6 subjects will be treated at each dose level. In the rolling 6 design, up to 6 subjects may be concurrently enrolled at each dose level of the study. The decision to escalate to the next highest dose level is made by the investigators participating in the Phase I study and representatives of the sponsor at a cohort review meeting after at least 3 subjects have completed Cycle 1. Decisions as to whether to enroll a new subject onto the current, next highest, or next lowest dose level are made based on the number of DLTs and the review of AEs. Dose level assignment is based on the number of subjects currently enrolled in the cohort, the number of DLTs observed, the number of subjects at risk for developing a DLT (ie, subjects enrolled but who were not yet evaluable for toxicity), and the available PK results. If 2 or more DLTs at a given dose level are observed, the dose level will be de-escalated. Intermediate dose levels will be tested. Intra-subject dose escalation is not permitted during Part A (Dose Escalation).

Maximum Tolerated Dose Determination and Cohort Expansion

Definition of Dose Limiting Toxicity

[0223] A Dose Limiting Toxicity (DLT) is defined as any of the following TEAEs that occur despite optimal medical management, graded using NCLCTCAE v5.0 during Cycle 1; except those that are clearly and incontrovertibly due to disease progression or extraneous causes:

• Any death not clearly due to the underlying disease or extraneous causes

• Grade >3 non-hematologic toxicity (unless otherwise noted below)

• Grade >3 nausea and/or vomiting and/or Grade 3 diarrhea not resolving within 72 h with optimal treatment

• Grade 3 neutropenia accompanied with fever and/or infection

• Grade 3 thrombocytopenia associated with bleeding

• Grade >4 hematologic toxicity • AST or ALT > 3x the ULN and a total bilirubin > 2x times the ULN without initial findings of cholestasis (elevated serum alkaline phosphatase) and no other reason for the increase in transaminases and total bilirubin

• AST or ALT > 8x ULN or AST or ALT > 5x ULN for >14 days

• ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

• Grade >3 blurred vision or retinopathy

• Grade >3 fatigue that does NOT resolve to Grade < 1 within 7 days

• Grade >2 TEAEs that result in omission of treatment for >7 days during Cycle 1 or delay of Cycle 2 for >7 days

• Multiple concurrent adverse events (AEs) in a single subject leading to DLT will be considered a single DLT

[0224] Subjects must receive at least 75% (21 days) of planned Compound 1 doses in Cycle 1 in order to be evaluated for determination of DLTs. Subjects who withdraw from study before receiving 75% of the planned doses in the first cycle of treatment for reasons unrelated to study drug toxicity will be considered to have inadequate data to support dose escalation. Subjects who receive less than 75% of the study drug due to the occurrence of a DLT are considered DLT evaluable and will not be replaced. (Subjects receiving less than 75% of the planned dose in Cycle 1 without a DLT will be evaluated in the overall safety analysis but not for the purposes of dose escalation.)

Definition of MTD:

[0225] For purposes of defining the MTD and/or expansion phase recommended dose of Compound 1, subjects will be evaluated according to the actual starting dose of Compound 1 during the first treatment cycle. For most subjects, this will be the dose cohort to which they were assigned. Subjects who receive at least 75% (21 days) of the planned doses in Cycle 1 will be considered to have sufficient safety data/follow-up to support dose escalation. In such cases, replacement subjects may be enrolled to receive the same starting dose of Compound 1 as the subjects who withdraw prematurely. [0226] The MTD is defined as the highest feasible dose tested in which fewer than 33% of subjects experienced DLT attributable to the study drug, when at least 6 subjects were treated at that dose and were assessable for toxicity.

Determination of RP2D:

[0227] Following Phase la dose escalation of Compound 1 from 30 mg to 300 mg QD, a recommended phase 2 dose (RP2D) range was defined of 60 to 120 mg QD. Sixty patients are planned for Phase lb enrollment, with 30 patients at each dose level (60 and 120 mg). At 60 mg and 120 mg, Compound 1 demonstrated high oral bioavailability and dose proportional exposure. At 120 mg, Compound 1 consistently exceeded the predicted efficacy plasma concentration thresholds from preclinical models. Safety data from 37 patients enrolled in Phase lb indicated no clinically meaningful difference in the frequency of TEAEs between the 2 dose levels (60 mg, 120 mg) as the most common TEAEs (>10%) were nausea (28%, 21%), vomiting (17%, 16%), fatigue (17%, 5%), and headache (11%, 11%), respectively. Most events were Grade 1 or 2, with the exception of two Grade 3 events at 60 mg (diarrhea and anemia). There were no dose reductions or dose discontinuations due to an AE. Based on safety and pharmacokinetic data from this study, 120 mg Compound 1 QD has been selected as the RP2D.

[0228] Since the RP2D has been determined, active subjects enrolled on the Phase I part of the study may be treated at the RP2D with approval of the Medical Monitor if the investigator or designee considers this in the best interest of the subject after discussion with the Medical Monitor.

Dose Modifications for Phase I and Phase II:

[0229] All AEs should be assessed according to the CTCAE, v5.0. In event of multiple toxicities, dose delays and modifications should occur in accordance with the highest Grade AEs observed.

[0230] Subjects who experience a DLT or any of the following AEs in Cycle 2 and beyond will have study drug treatment interrupted. Dose modification guidelines will include dose reductions as follows: the first dose reduction will be approximately 20% to 30%, the second dose reduction is approximately 40% to 50%, and the third dose reduction is approximately 70% to 80%. Dose reductions below 15 mg daily are not allowed. Dose modifications will only be made for TEAEs that are not clearly due to disease progression or extraneous causes.

Concomitant Medications

[0231] All prescription and over-the-counter medications taken by a subject within 30 days before the first study drug administration will be recorded.

[0232] Proton pump inhibitors should be avoided and are prohibited during the first 2 cycles of therapy. After that, PPI may be used only if other methods of symptom control have been ineffective. The Medical Monitor should be notified in PPI are started. The use of H2 blockers is strongly discouraged. If the subject experiences symptoms of gastric acid reflux that are not relieved with conservative measures (small meals, no eating after 6 PM, avoiding foods that stimulate stomach acid such as caffeine, alcohol, tomatoes, spicy foods). The PI or designee may prescribe H2 blockers to be taken once or twice a day provided they are taken at least 2 h prior to (or post) the Compound 1 dose; however, 4 hours is preferred.

[0233] No other cancer therapies or investigational agents are permitted during the entire duration of the study treatment.

[0234] Based on the in vitro drug-drug interaction profile of Compound 1, the types of concomitant medications to avoid or to use with caution:

[0235] Subjects should avoid medications with known risk of QT interval prolongation or increased risk of Torsades de Pointes. An exemplary list of these medications is provided below:

[0236] Subjects should avoid strong CYP3A4 inhibitors or inducers, if possible. However, their use is this study is not exclusionary. An exemplary list of strong CYP3A1 inhibitors and inducers is provided below:

[0237] P-gp, BCRP, CYP2C8, and CYP2C9 substrates with narrow therapeutic index should be used with caution. An exemplary list of these substrates is provided below:

[0238] Pre- and perimenopausal women must take an LHRH agonist of physician’s choice.

[0239] Medications for nausea, vomiting, diarrhea, and constipation may be given according to the standard of care guidelines at the discretion of the PI or designee. Granisetron (or other) is preferred over ondansetron due to the potential prolongation of QT interval with ondansetron.

[0240] Bisphosphonates or other bone modifying agents are allowed provided the subject has been on these agents for at least 4 weeks prior to Cycle 1.

[0241] Subjects who have febrile neutropenia (FN) should receive antibiotics per standard of care. Granulocyte colony stimulating factor (G-CSF) may be used at the PI or designee’s discretion.

[0242] Medications considered necessary for the subject’s safety and well-being may be given at the discretion of the investigator. Any concomitant medications added or discontinued during the study should be recorded.

Duration of Treatment

[0243] In the absence of unacceptable Compound 1 treatment-related toxicity or disease progression, subjects may receive Compound 1 treatment for up to 1 year and beyond 1 year with the agreement of the PI or designee and the Sponsor.

[0244] Treatment will continue until any 1 of the following occurs:

• SAE or AE that require dose discontinuation

• Progressive disease as determined by RECIST 1.1. (Tumor marker elevations in the absence of unequivocal radiologic progression of target or non-target lesions is not considered disease progression. Per RECIST 1.1, disease progression requires an overall disease burden increase based on the change in non-measurable disease that is comparable in magnitude to the increase that would be required to declare PD for measurable disease: i.e., an increase in tumor burden representing an additional 73% increase in ‘volume,’ which is equivalent to a 20% increase in diameter in a measurable lesion.)

• Initiation of non-protocol anticancer therapy

• Illness or condition that may interfere with the subject’s participation or require treatment discontinuation

• Treating PI or designee’s determination that continuation of protocol therapy is not in the subject’s best interests

• Pregnancy

• Noncompliance

• Voluntary withdrawal of consent

• Sponsor termination of the study

Criteria for Evaluation

[0245] Safety:

[0246] Safety will be assessed by periodic physical examinations, 12-lead electrocardiograms (ECGs), clinical laboratory assessments, and monitoring of AEs. 12-lead ECGs will be evaluated at baseline (Screening) and at prespecified timepoints during treatment and at the end of treatment. Additional clinical laboratory assessments and 12-ECGs will also be obtained when clinically indicated. AEs will be graded using NCI-CTCAE version 5.0 criteria.

[0247] Site teleconferences between the Sponsor and all participating sites will be held during the dose escalation phase to discuss any suspected AEs/DLTs that have occurred in each cohort. The Safety Committee will include Pls participating in the study, the Medical Monitor, and the Sponsor’s Medical Director. Study drug-related toxicities from the current cohort will be reviewed during the site teleconferences before escalating to the next dose level.

[0248] PK and ECG determinations:

[0249] The PK profile will be assessed by determining the plasma levels of Compound 1 at intervals. In addition to the scheduled samples, an unscheduled PK blood sample should be drawn as soon as possible after a SAE and following a dose reduction of Compound 1. Following a dose reduction, the pre-dose sample will be collected at the next clinic visit that is least 1 week after the subject has taken Compound 1 at a reduced dose. [0250] All subjects will have ECGs in triplicate at multiple timepoints.

[0251] Subjects should be supine for 10 minutes before obtaining the ECG and 2 minutes should elapse between each ECG. The ECG should be obtained immediately prior to PK blood draws and prior to assessment of blood pressure and other vital signs.

[0252] Pharmacodynamics:

[0253] Tumor samples and blood will be collected for pharmacodynamic assessments. ER, PR, and Ki67 by immunochemistry will be evaluated in tumor biopsies and mutESRl and other biomarkers of interests in ctDNA from blood collections. ER and PR will be assessed by percent and scored using the Allred method. In addition, for ER, PR and Ki67 the absolute and percent change from baseline will be evaluated.

[0254] Predictive Markers of Compound 1 Activity

[0255] Biomarkers that may predict Compound 1 activity will be evaluated in archival tumor tissues. These include quantitative levels of ER and PR by immunohistochemistry (percent cells positive and Allred score), phosphoinositide 3-kinase alpha catalytic subunit (PIK3CA), phosphatase variants and potentially other biomarkers, e.g., Ki-67, ESRI, ERBB2, KRAS, AKT, and TP53.

[0256] Efficacy:

[0257] Radiographic and/or physical assessments of the malignancy will be made at Screening/baseline (within 28 days prior to the first study drug administration) and after every 2 cycles of treatment. Subjects who have been determined to have obtained a clinical benefit from Compound 1 may decrease the frequency of radiographic and physical assessments of malignancy to every 3 months after radiographic assessment following the completion of 8 cycles of therapy. Overall response (CR and PR) as determined by the subject’s best tumor response, DoR, time to progression, and PFS will be assessed using RECIST 1.1. For subjects with brain metastatic disease enrolled in the study, assessment of response rate in the non-CNS and CNS compartments will be defined according to RECIST 1.1 and RANO-BM criteria. Additional imaging studies and tumor measurements will be performed in subjects obtaining a PR or CR on a second examination > 4 weeks after initial response determination. CBR will be determined as follows: CR + PR + subjects with SD for > 24 weeks. iCBR will be determined as follows: intracranial CR + intracranial PR + subjects with intracranial SD for > 24 weeks in the CNS. Statistical Methods

[0258] Safety Analyses:

[0259] Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, DLTs, laboratory values, electrocardiogram results, vital signs, and ECOG PS. Safety data analysis will be conducted on all subjects receiving at least 1 full or partial dose of Compound 1. DLT summary will be conducted on DLT evaluable subjects, defined as subjects in the dose escalation portion of the study receiving at least 75% of Compound 1 doses or experience a DLT in Cycle 1. All treatment-emergent AEs regardless of attribution will be summarized by cohort, as follows:

• All DLTs (regardless of grade)

• All AEs (regardless of grade or attribution)

• All Grade 3/4/5 AEs

• All drug-related AEs (regardless of grade)

• All AEs leading to study drug or study discontinuations

• All SAEs, including deaths

• All AEs of special interest (regardless of grade)

[0260] A separate listing of all on-study deaths will be presented.

[0261] Efficacy Analyses:

[0262] An analysis of ORR will be conducted for subjects with measurable disease enrolled in the study who have completed at least 1 cycle of Compound 1 and have a post-treatment tumor assessment. The number and percentage of subjects experiencing an overall response (CR + PR) will be summarized. The DoR will be summarized descriptively using the Kaplan-Meier method. The DoR is defined as the number of days from the start date of PR or CR (whichever response is achieved first) to the first date that progressive disease is objectively documented. CBR will be summarized.

[0263] Subjects without measurable disease will not be included in the determination of ORR; however, they will be included in safety, secondary, and exploratory analyses where appropriate.

[0264] Subjects with CNS metastases will be analyzed in a separate cohort. ORR in subjects with CNS metastases will be performed using both RECIST 1.1 (for disease in the CNS and non- CNS components) and RANO-BM (for the CNS component). iCBR defined as intracranial CR +, intracranial PR + subjects with intracranial SD for >24 weeks in the CNS will also be determined.

[0265] The ORR in the expansion phase will also be examined by mutation status (mutESRl, wtESRl). The respective mutation status cohort may be expanded further if the ORR indicates favorable risk/safety ratio for these subjects with metastatic or locally advanced breast cancer for which standard curative measures do not exist.

[0266] Pharmacokinetic Analyses:

[0267] Pharmacokinetic parameters will be determined for the PK Analysis Set using standard compartmental or non-compartmental methods. A listing of subjects excluded from the analysis set and individual data points excluded from the analysis will be provided. The final analysis of PK parameters will be calculated based on actual sample collection time, rather than scheduled times. In addition, the PK sparse exposure data from this study may be used in the development of population PK and PK/PD models. Pharmacokinetic plasma levels and parameters will be determined, listed, and summarized for the PK evaluable population in the Pharmacokinetic Analysis Plan (PKAP). Only samples with acceptable PK (as defined in the PKAP) will be included in the summary statistics, and a listing of individual data points that were excluded from the analysis will be presented. Plasma concentrations will be listed by for the PK Population. Summary statistics of Compound 1 concentrations will be reported by dose level, Day and Cycle. Details of this analysis will be provided in the PKAP. Possible relationships between PK parameters, PD variables, safety, and efficacy may be examined.

[0268] Biomarker Analyses:

[0269] Summary statistics will be computed for baseline biomarkers. The absolute and percent change from baseline will be determined. Summary statistics will be computed for each collection time point.

Example 6. A Phase 1A Dose Escalation Study of Compound 1 in Adult Subjects with Advanced and/or Metastatic Hormone Receptor (HR)-positive, HER2-negative Breast Cancer

[0270] This example describes results, as of a second or third cutoff date, from the Phase 1A dose escalation portion of the study described in Example 1 and Example 5.

Patient Population [0271] As of a second cutoff date, 42 patients were treated in Phase 1A of the study. Patient characteristics for Phase 1A and Phase IB of the study are summarized in Table 8. (Phase IB of the study is discussed in Example 7 below.)

Table 8. Demographics and Baseline Disease Characteristics

CDK = cyclin-dependent kinase; ctDNA = circulating tumor DNA; ECOG PS = Eastern Cooperative Oncology Group performance status.

Pharmacokinetics

[0272] Compound 1 demonstrated high oral bioavailability and steady-state plasma levels with minimal peak-to-trough variability. FIG. 7 shows a graph of Compound 1 mean plasma concentration profiles from C2D1 for different doses of Compound 1. As shown in FIG. 7, the R2PD (120 mg) exceeded the model-predicted, physiologically relevant efficacy threshold. The mean terminal ti/2 was about 8 days, which supports once daily dosing of Compound 1. Safety

[0273] As of a second cutoff date, most treatment-emergent adverse events (TEAEs) were grade 1 or 2 at all dose levels (Table 9). No dose-limiting toxicities (DLTs) were observed and the maximum tolerated dose (MTD) was not reached. No clinically significant bradycardia, ocular toxicity, or diarrhea were observed.

Table 9. TEAEs Occurring in > 15% of Patients

Efficacy

[0274] Efficacy was observed in heavily pre-treated patients, with two confirmed responses at 60 mg and 120 mg doses. FIG. 8 summarizes treatment duration and response in all patients (N=42) as of a third cutoff date in this study. Confirmed partial response (PR) for greater than or equal to 1 year was observed in 2 patients. Six patients remained on treatment for greater than or equal to 1 year, and 9 patients remained on treatment for greater than or equal to 24 weeks. Table 10 summarizes ORR and CBR observed in this study. Table 10

^a ORR: CR+PR, measurable disease, one cycle Compound 1, one post-baseline tumor assessment. ^b CBR: CR+PR+SD >24 weeks, measurable or non-measurable disease, one cycle Compound 1, one post-baseline tumor assessment.

[0275] FIG. 9 summarizes best response of target lesion in patients with measurable disease (N=25), as of a third data cutoff.

Example 7. A Phase IB Dose Expansion Study of Compound 1 in Adult Subjects with Advanced and/or Metastatic Hormone Receptor (HR)-positive, HER2-negative Breast Cancer

[0276] This example describes results, as of a second or third cutoff date, from the Phase IB dose expansion portion of the study described in Example 1 and Example 5.

Patient Population

[0277] As of a second cutoff date, 37 patients were treated in Phase IB of the study. Patient characteristics for Phase 1A and Phase IB of the study are summarized in Table 8 above.

[0278] As of a third cutoff date, a total of 50 patients were treated in Phase IB of the study (N=25 for each cohort).

Pharmacokinetics

[0279] Pharmacokinetic analyses demonstrated dose-proportional exposure of Compound 1, high oral bioavailability, and steady-state plasma levels with minimal peak-to-trough variability.

Safety

[0280] The majority of reported adverse events were Grade 1 or 2 at both dose levels, and the most common treatment-emergent adverse events occurring in >10% of patients were nausea, vomiting, fatigue, and headache, which were similar across both doses. [0281] As of a second cutoff date, no discontinuations or dose reductions due to AE were observed at either 60 mg or 120 mg dose. Two dose interruptions due to AE were observed at 60 mg and 120 mg doses (Grade 2 increased LFTs (unrelated), and Grade 2 fatigue/depression). TEAEs occurring in > 10% of patients are summarized in Table 11.

Table 11

* No Grade 4 events. ** Grade 3 diarrhea assessed as not related to study drug; Grade 3 anemia related.

[0282] As of a third cutoff date, two cases of Grade 4 and one case of Grade 3 neutropenia had been observed in patients in the 120 mg cohort of the Phase lb expansion. One patient with Grade 4 neutropenia paused treatment for one week, restarted at a lower dose and subsequently had an unconfirmed partial response at the first scan. A second patient had Grade 4 febrile neutropenia with no evidence of infection. The patient discontinued treatment and remains off- study. Concurrent with disease progression at 8 weeks, a third patient had Grade 3 neutropenia, which has since resolved.

Efficacy

[0283] Early anti-tumor activity was observed, with a total of 4 partial responses in 31 efficacy-evaluable patients in the Phase lb expansion as of a third cutoff date (1 confirmed partial response at 60 mg and 3 unconfirmed partial responses, pending confirmation at a subsequent scan, at 120 mg).

[0284] FIG. 10 summarizes treatment duration and response in all patients (N=42) as of a third cutoff date in this study. Of 31 evaluable subjects, 1 had confirmed PR at 60 mg, and 3 had unconfirmed PR at 120 mg.

[0285] FIG. 11 summarizes best response of patients (N=31), as of a third cutoff date. Example 8. Phase lb Results from a Dose Escalation and Dose Expansion Study of Compound 1, an Oral CERAN, in Subjects with Advanced and/or Metastatic Estrogen Receptor (ER)-Positive, HER2-Negative Breast Cancer

[0286] This example describes results, as of a fourth cutoff date, from the Phase IB dose expansion portion of the study described in Example 1 and Example 5.

Patient Population

[0287] As of a fourth cutoff date, a total of 56 patients were treated. Patient demographics and baseline disease characteristics are summarized in Table 12. In particular, 84% of patients had visceral disease at baseline; 57% of patients had 2 or more prior lines of endocrine therapy in an advanced setting; 34% of patients received prior chemotherapy in an advanced setting; 16% of patients received an investigational SERD in an advanced setting; and 58% of patients had mutant ESRI .

Table 12

[0288] Of the 56 patients, 19 were still on treatment at the time of a fourth cutoff date, and 28 had discontinued therapy due to radiographic disease progression. Table 13 summarizes patient disposition as of a fourth cutoff date.

Table 13

Pharmacokinetics

[0289] Compound 1 is characterized by a high oral bioavailability and a relatively fast absorption. Steady-state plasma levels showed minimal peak-to-trough variability, allowing complete inhibition of estrogen receptor for the full dosing interval. The RP2D (120 mg QD) exceeded the predicted efficacious threshold based on estradiol dependent preclinical models. A mean terminal half-life (T1/2) of 8 days supported a once daily dosing regimen.

[0290] Combined pharmacokinetic parameters of Compound 1, as of a fifth cutoff date, from Phase la and Phase lb studies described in Example 1 and Example 5 are shown in FIG. 12 and summarized in Table 14. Table 14

a Median (Min-Max)

Safety

[0291] Most TEAEs were Grade 1 or 2 across both dose levels (60 mg and 120 mg). The most common TEAEs at the 120 mg dose level were nausea, fatigue, vomiting, headache, constipation, and decreased neutrophil. Three patients had a dose reduction due to an adverse event; all three were in the 120 mg cohort. Two patients, both in the 120 mg cohort, had a dose discontinuation due to an adverse event.

[0292] Treatment-emergent adverse events occurring in > 10% of patients are summarized in Table 15.

Table 15

[0293] Adverse events attributed to Compound 1 by investigator occurring in > 10% of patients are summarized in Table 16. Table 16

* Grade 3 anemia at 60 mg; and Grade 3 INR ratio increased and WBC count decreased at 120 mg not included in table. ** Grade 4 events included neutrophil count decreased and neutropenia.

Efficacy

[0294] Two confirmed partial responses were achieved as of a fourth cutoff date - one in the 60 mg cohort, and one in the 120 mg cohort. In the clinical benefit rate (CBR)-evaluable population, the CBR was 26.9%. (CBR is CR + PR + SD > 24 weeks. The CBR-evaluable population included patients with measurable disease who received at least 1 cycle of treatment, had at least 1 post-baseline tumor assessment, and was enrolled > 24 weeks prior to the data cutoff date.) In the population evaluable for response, the overall response rate (ORR) was 4.1%. (The population evaluable for response included patients with measurable disease who received at least 1 cycle of treatment and had at least 1 post-baseline tumor assessment.)

[0295] Efficacy response by cohort for 60 mg and 120 mg doses is summarized in Table 17.

Table 17

a ORR and CBR were evaluated per RECIST version 1.1. b Includes patients who received at least one cycle of treatment, were evaluable for a response, and were enrolled > 24 weeks prior to the data cutoff date.

[0296] Table 18 summarizes efficacy response by cohort for 60 mg and 120 mg doses in patients with an ESRI mutation. Table 18

^a ORR and CBR were evaluated per RECIST version 1.1. ^b Includes patients who received at least one cycle of treatment, were evaluable for a response, and were enrolled > 24 weeks prior to the data cutoff date.

[0297] FIG. 13 summarizes overall tumor response in the Phase lb study. FIG. 14 shows target lesion evaluation by sum of the longest diameter in the Phase lb study.

Claims

1. A method of treating a disease, disorder, or condition in a subject comprising administering a composition comprising Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof, wherein from about 30 mg to about 360 mg of Compound 1 are administered to the subject once daily.

2. The method of claim 1, wherein an amount of Compound 1 administered to the subject daily is from about 30 mg to about 120 mg.

3. The method of claim 1, wherein an amount of Compound 1 administered to the subject daily is from about 60 mg to about 120 mg.

4. The method of claim 1, wherein an amount of Compound 1 administered to the subject daily is about 120 mg.

5. The method of claim 1, wherein an amount of Compound 1 administered to the subject daily is about 90 mg.

6. The method of claim 1, wherein an amount of Compound 1 administered to the subject daily is about 60 mg.

7. The method of claim 1, wherein an amount of Compound 1 administered to the subject daily is about 30 mg.

8. The method of any one of claims 1-7, wherein the composition is administered to the subject one daily for one or more 28 day cycles.

9. The method of any one of claims 1-8, wherein the composition is administered to the subject once daily for two, three, four, or five 28 day cycles.

10. The method of any one of claims 1-9, wherein the disease, disorder, or condition is a cancer.

11. The method of claim 10, wherein the cancer is a breast cancer.

12. A method of treating a disease, disorder, or condition in a subject comprising administering Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof, according to a regimen established to achieve one or more of the following characteristics when administered to a population of comparable subjects:

(i) a mean Cmax from about 135 ng/mL to about 1410 ng/mL;

(ii) a median t_max from about 2 h to about 4 h;

(iii) a mean Cavg from about 80 ng/mL to about 1070 ng/mL;

(iv) a mean AUCo-24 from about 1950 ng*h/mL to about 26000 ng*hr/mL; or

(v) a mean effective ti/2 from about 50 h to about 75 h.

13. The method of claim 12, wherein an amount of Compound 1 administered to the subject daily is from about 30 mg to about 360 mg.

14. The method of claim 12, wherein an amount of Compound 1 administered to the subject daily is from about 30 mg to about 120 mg.

15. The method of claim 12, wherein an amount of Compound 1 administered to the subject daily is from about 60 mg to about 120 mg.

16. The method of claim 12, wherein an amount of Compound 1 administered to the subject daily is about 120 mg.

17. The method of claim 12, wherein an amount of Compound 1 administered to the subject daily is about 90 mg.

18. The method of claim 12, wherein an amount of Compound 1 administered to the subject daily is about 60 mg.

19. The method of claim 12, wherein an amount of Compound 1 administered to the subject daily is about 30 mg.

20. The method of any one of claims 12-19, wherein Compound 1 is administered once daily.

21. The method of any one of claims 1-20, wherein an average plasma concentration (Cavg) of Compound 1 in the subject post administration is from about 80 ng/mL to about 1070 ng/mL.

22. The method of any one of claims 1-21, wherein an average plasma concentration (Cavg) of Compound 1 in the subject post administration is from about 210 ng/mL to about 410 ng/mL.

23. The method of any one of claims 1-22, wherein an average plasma concentration (Cavg) of Compound 1 in the subject post administration is from about 100 ng/mL to about 200 ng/mL.

24. The method of any one of claims 1-23, wherein a maximum plasma concentration (Cmax) of Compound 1 in the subject post administration is from about 135 ng/mL to about 1410 ng/mL.

25. The method of any one of claims 1-24, wherein a maximum plasma concentration (Cmax) of Compound 1 in the subject post administration is from about 290 ng/mL to about 620 ng/mL.

26. The method of any one of claims 1-24, wherein a maximum plasma concentration in the subject post administration of Compound 1 is from about 200 ng/mL to about 400 ng/mL.

27. The method of any one of claims 1-22, wherein a maximum plasma concentration (Cmax) of Compound 1 in the subject post administration is from about 30 ng/mL to about 300 ng/mL.

28. The method of any one of claims 1-27, wherein an AUCo-24 in the subject post administration of Compound 1 is from about 1950 ng*h/mL to about 26000 ng*hr/mL.

29. The method of any one of claims 1-28, wherein an AUCo-24 in the subject post administration of Compound 1 is from about 5000 ng*h/mL to about 10000 ng*hr/mL.

30. The method of any one of claims 1-28, wherein an AUC in the subject post administration of Compound 1 is from about 2000 ng*h/mL to about 4000 ng*h/mL.

31. The method of any one of claims 12-30, wherein the disease, disorder, or condition is a cancer.

32. The method of claim 31, wherein the cancer is a breast cancer.

33. The method of any one of claims 1-32, wherein Compound 1 is administered in combination with an anti-cancer agent.

34. The method of claim 33, wherein the anti-cancer agent is a CDK 4/6 inhibitor, a PI3Kalpha inhibitor, or an mTOR inhibitor.

35. The method of any one of claims 1-34, wherein the subject has previously received endocrine therapy.

36. The method of claim 35, wherein the subject’s disease has progressed while receiving endocrine therapy.

37. A method of treating a disease, disorder, or condition in a subject comprising administering a composition comprising Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof, wherein presence of one or more biomarkers selected from Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53 has previously been detected in a biological sample derived from the subject.

38. The method of any one of claims 1-37, wherein the biological sample is a tissue sample.

39. The method of claims 38, wherein the tissue sample is derived from a tumor.

40. The method of any one of claims 37-39, wherein the biomarker is detected by analysis of circulating tumor DNA (ctDNA).

41. A method of treating a disease, disorder, or condition in a subject comprising;

(i) analyzing circulating tumor DNA of a biological sample derived from the subject to detect the presence of one or more biomarkers selected from Ki-67, ER, PR, ESRI, ERBB2, PIK3CA, KRAS, AKT, and TP53; and

(ii) administering a composition comprising Compound 1

Compound 1 or a pharmaceutically acceptable salt thereof to the subject.

42. The method of any one of claims 37-41, wherein the disease, disorder, or condition is a cancer.

43. The method of claim 42, wherein the cancer is a breast cancer.

44. The method of any one of claims 1-43, wherein Compound 1 is administered in a unit dosage form.

45. The method of claim 44, wherein the unit dosage form is a capsule or tablet.

46. The method of any one of claims 1-45, wherein the subject has ER+/HER2- recurrent, locally advanced, or metastatic breast cancer.

47. The method of any one of claims 1-46, wherein the subject has previously received one or two prior chemotherapy regimens for locally advanced or metastatic disease.

48. The method of any one of claims 1-47, wherein the subject has received one prior chemotherapy regimen for locally advanced or metastatic disease.

49. The method of any one of claims 1-48, wherein the subject has previously received no more than four endocrine therapies.

50. The method of any one of claims 1-49, wherein the subject is harboring a ESRI mutation (e.g., Y537S).

51. The method of claim 50, wherein the ESRI mutation has been detected by liquid biopsy.