WO2024076633A1 - Méthodes de traitement de troubles médiés par le récepteur des œstrogènes - Google Patents

Méthodes de traitement de troubles médiés par le récepteur des œstrogènes Download PDF

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WO2024076633A1
WO2024076633A1 PCT/US2023/034466 US2023034466W WO2024076633A1 WO 2024076633 A1 WO2024076633 A1 WO 2024076633A1 US 2023034466 W US2023034466 W US 2023034466W WO 2024076633 A1 WO2024076633 A1 WO 2024076633A1
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Prior art keywords
compound
alpelisib
administered
pharmaceutically acceptable
subject
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PCT/US2023/034466
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English (en)
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Pamela M. KLEIN
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Olema Pharmaceuticals, Inc.
Novartis Ag
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Application filed by Olema Pharmaceuticals, Inc., Novartis Ag filed Critical Olema Pharmaceuticals, Inc.
Publication of WO2024076633A1 publication Critical patent/WO2024076633A1/fr

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  • the present disclosure provides, among other things, methods of treating, stabilizing, or lessening the severity or progression of estrogen receptor-mediated diseases, disorders, and conditions via administration of an orally bioavailable estrogen receptor antagonist and an orally bioavailable PI3KCA inhibitor.
  • the present disclosure provides a method of treating an estrogen receptor-mediated disease in a subject comprising administering to the subject a composition comprising Compound 1
  • the present disclosure provides a kit comprising a composition comprising Compound 1
  • the present disclosure provides, among other things, methods of treating estrogen receptor-mediated diseases in a subject comprising administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, in combination with a composition comprising alpelisib or a pharmaceutically acceptable salt thereof.
  • the present disclosure encompasses an insight that certain synergies may be achieved when combining Compound 1 and alpelisib when treating an estrogen receptor-mediated disease relative to administration of Compound 1 or alpelisib administered in isolation.
  • 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.
  • “about” refers to ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1% of a referenced value.
  • 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.
  • 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.).
  • 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
  • phenomenon e.g., heat, electric current or field, magnetic force or field, etc.
  • 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.
  • 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).
  • an “antagonist” may be referred to as an “inhibitor”.
  • 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.
  • a particular entity e.g., polypeptide, genetic signature, metabolite, microbe, etc.
  • 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.
  • 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.
  • 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.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample is or comprises biological tissue or fluid.
  • 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.
  • a biological sample is or comprises cells obtained from an individual.
  • obtained cells are or include cells from an individual from whom the sample is obtained.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof.
  • 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.
  • Combination therapy refers to those situations in which a subject is concomitantly exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents).
  • the two or more regimens may be administered concomitantly; 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.
  • “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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • a monomeric residue in a polymer e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide
  • a residue in an appropriate reference polymer may be identified as “corresponding to” a residue in an appropriate reference polymer.
  • 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.
  • sequence alignment strategies including software programs such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH/GL SEARCH, Genoogle, HMMER, HHpred/HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, 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.
  • software programs such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH/GL SEARCH, Genoogle, HMMER, HHpred/HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBL
  • 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.
  • an active agent e.g., a therapeutic or diagnostic agent
  • each such unit contains a predetermined quantity of active agent.
  • 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).
  • Dosing regimen or 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.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.).
  • oral administration and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.
  • 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 intrastemal injection and infusion.
  • a patient 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.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions
  • composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • 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.).
  • 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.
  • 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.
  • compositions or vehicles such as a liquid or solid fdler, 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.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com 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
  • compositions 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).
  • 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.
  • 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.
  • pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxa
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • 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.
  • 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.
  • reference describes a standard or control relative to which a comparison is performed.
  • 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.
  • a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest.
  • a reference or control is a historical reference or control, optionally embodied in a tangible medium.
  • a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment.
  • small molecule means a low molecular weight organic and/or inorganic compound.
  • a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size.
  • a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD.
  • 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.
  • 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.
  • a small molecule does not include a polymeric moiety.
  • a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide).
  • a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide).
  • 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.
  • a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent).
  • a small molecule is biologically active.
  • a small molecule is detectable (e.g., comprises at least one detectable moiety).
  • a small molecule is a therapeutic agent.
  • 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. [0035] 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.
  • small molecule compounds have structures that permit isotopic substitution (e.g., 2 H or 3 H for H; U C, 13 C or 14 C for 12 C; 13 N or 13 N for 14 N; 17 O or 18 O for 16 O; 36 C1 for 35/37 Cl; 18 F for 19 F; 131 I for 127 I; etc).
  • such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.
  • reference to a particular small molecule compound may relate to a specific form of that compound.
  • a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
  • 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.
  • a reference preparation of interest e.g., in a primary sample from a source of interest such as a biological or environmental source
  • 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.
  • Therapeutic agent in general refers to any agent that elicits a desired pharmacological effect when administered to an organism.
  • an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population.
  • the appropriate population may be a population of model organisms.
  • an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc.
  • 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.
  • 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.
  • a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
  • Treat refers 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.
  • the compounds of the invention 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.
  • the present disclosure provides, among other things, a method of treating estrogen receptor-mediated diseases, disorders, and conditions comprising administering to a patient in need thereof, Compound 1
  • Compound 1 and alpelisib are administered to a patient as separate compositions, each comprising one or more suitable pharmaceutically acceptable excipients.
  • the present disclosure encompasses an insight that particular synergies may be achieved when administering Compound 1 and alpelisib together to a patient suffering from an estrogen receptor-mediated disease, disorder, or condition.
  • the presently claimed methods may exhibit benefits over currently available methods of treatment such as fulvestrant, as both Compound 1 and alpelisib are orally bioavailable, and can be administered to a patient in any suitable form, including as a capsule or tablet or the like.
  • 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.
  • 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, lher. 89:44, 2011).
  • tumors e.g., breast tumors
  • therapies targeting the ER are standard of care for many patients with ER + tumors (see, for example, Cardoso et al Annals One.
  • an estrogen receptor-mediated disease is a cancer.
  • a cancer is breast cancer.
  • a cancer e.g., a breast cancer
  • has metastasized to another organ e.g., the brain, bones, lungs, and/or liver.
  • an organ having metastases is the brain of the subject.
  • an organ having metastases is a bone of the subject.
  • an organ having metastases is a lung of the subject.
  • an organ having metastases is the liver of the subject.
  • a subject is suffering from HR+/HER2- metastatic breast cancer.
  • a subject is suffering from cancer that has metastasized to another organ (e g., brain, lung, liver, and/or bone).
  • a subject is suffering from histologically or cytologically confirmed advanced or metastatic breast cancer (e.g., for which standard curative measures do not exist).
  • a subject suffering from a disease described herein has previously been administered an endocrine therapy.
  • a subject has received at least 6 months of a prior continuous endocrine therapy for locally advanced or metastatic breast cancer.
  • a subject has received no more than 2 prior hormonal regimens for advanced or metastatic disease.
  • a subject suffering from a disease described herein has previously been administered chemotherapy (e.g., chemotherapy for locally advanced or metastatic disease). In some embodiments, a subject has previously been administered no more than one chemotherapy regimen for locally advanced or metastatic breast cancer. [0053] 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.
  • chemotherapy e.g., chemotherapy for locally advanced or metastatic disease.
  • a subject has previously been administered no more than one chemotherapy regimen for locally advanced or metastatic breast cancer.
  • a subject has previously received at least one of a CDK4/6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.
  • a subject has been determined to harbor a PIK3CA mutation, e.g., a subject who is receiving a combination of Compound 1 and alpelisib.
  • the presence of a PIK3CA mutation is determined using an FDA-approved diagnostic test.
  • the presence of a PIK3CA mutation is determined from a metastatic tissue specimen or from plasma (e.g., ctDNA).
  • a complete estrogen receptor antagonist is characterized by complete antagonism of the estrogen receptor with no or minimal residual estrogen receptor agonist activity.
  • 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.
  • 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.
  • AF1 and AF2 activating function 1
  • AF2 activating function 2
  • Compound 1 overcomes the shortcomings of fulvestrant, and is an orally bioavailable Complete Estrogen Receptor ANtagonist (“CERAN”).
  • CERAN Complete Estrogen Receptor ANtagonist
  • 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.
  • 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.
  • Compound 1, as a CERAN both completely inactivates ER and degrades ER, as well as completely inactivating ER by inactivating both the activation function 1 (AF1) and activation function 2 (AF2) transcriptional activation functions.
  • AF1 activation function 1
  • AF2 activation function 2
  • Compound 1 robustly degrades the estrogen receptor in ER+ cell lines.
  • Previous therapies such as traditional selective estrogen receptor degraders (SERDs), which only degrade ER, or selective estrogen receptor modulators (SERMs) which have mixed agonist and antagonist effects, fail to achieve the complete estrogen receptor antagonism achieved by Compound 1.
  • SESDs selective estrogen receptor degraders
  • SERMs selective estrogen receptor modulators
  • 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.
  • a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, further comprises one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • Solid compositions of a similar type may also be employed as fdlers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings (i.e. buffering agents) and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • 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 30 mg to about 120 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.
  • 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 1 is administered to the subject in an amount that is about 60 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is about 90 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is about 120 mg.
  • 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 30 mg to about 120 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is about 60 mg to about 120 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is from about 15 mg to about 100 mg QD.
  • 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 subj ect 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.
  • Compound 1 is administered to the subject in a unit dosage form.
  • a unit dosage form is a capsule or tablet.
  • a unit dosage form comprises about 15 mg to about 120 mg of Compound 1.
  • a unit dosage form comprises about 15 mg to about 100 mg of Compound 1.
  • a unit dosage form comprises about 60 mg to about 120 mg of Compound 1.
  • 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.
  • a unit dosage form comprises about 15 mg of Compound 1.
  • 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.
  • 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 30 mg to about 120 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 60 mg to about 120 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is in an amount that is from about 15 mg to about 100 mg QD.
  • 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. 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.
  • 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 an agent (e.g., Compound 1) is not administered to the subject.
  • a dose holiday is one day, one week, or one 28-day cycle.
  • 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.
  • Alpelisib is an inhibitor of phosphatidylinositol-3 -kinase (PI3K) with inhibitory activity predominantly against PI3Ka.
  • PI3K phosphatidylinositol-3 -kinase
  • Alpelisib is also known by the following name: (2S)-A 1 -[4-methyl-5-[2-(2,2,2-trifluoro-l,l- dimethylethyl)-4-pyridinyl]-2-thiazolyl]-l,2-pyrrolidinedicarboxamide.
  • Alpelisib is approved in combination with fulvestrant for treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA- mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • PIK3CA-mutated advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.
  • Alpelisib is also indicated for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA Related Overgrowth Spectrum (PROS) who require systemic therapy.
  • the complete prescribing information for alpelisib is found in the labels for PIQRAY®, located at www.accessdata.fda.gov/drugsatfda_docs/label/2022/212526s0061bl.pdf, and VIJOICE®, located at www.accessdata.fda.gov/drugsatfda docs/label/2022/215039s0001bledt.pdf, each of which is incorporated herein by reference in its entirety.
  • Alpelisib is an inhibitor of phosphatidylinositol-3 -kinase (PI3K) with inhibitory activity predominantly against PI3Ka.
  • Gain-of-function mutations in the gene encoding the catalytic a-subunit of PI3K (PIK3CA) lead to activation of PI3Ka and Akt-signaling, cellular transformation and the generation of tumors in in vitro and in vivo models.
  • PI3K phosphatidylinositol-3 -kinase
  • PIK3CA catalytic a-subunit of PI3K
  • alpelisib inhibited the phosphorylation of PI3K downstream targets, including Akt and showed activity in cell lines harboring a PIK3CA mutation.
  • alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer.
  • PI3K inhibition by alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells.
  • ER estrogen receptor
  • the combination of alpelisib and fulvestrant demonstrated increased antitumor activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.
  • a composition comprising alpelisib, or a pharmaceutically acceptable salt thereof, is provided and/or utilized in any suitable pharmaceutical composition or dosage form.
  • compositions comprising alpelisib, or a pharmaceutically acceptable salt thereof further comprises one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • alpelisib or a pharmaceutically acceptable salt thereof is provided and/or utilized in a film-coated tablet for oral administration.
  • a tablet comprising alpelisib or a pharmaceutically acceptable salt thereof also comprises one or more of hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, or sodium starch glycolate.
  • a tablet comprising alpelisib or a pharmaceutically acceptable salt thereof is coated with a film-coating that comprises one or more of hypromellose, iron oxide black, iron oxide yellow, iron oxide red, macrogol/polyethylene glycol (PEG) 4000, talc, and titanium dioxide.
  • alpelisib refers to alpelisib 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 alpelisib means the amount of alpelisib in free base form. Accordingly, alpelisib may be provided and/or utilized as, e.g., a salt form of alpelisib such that the amount of the salt (or other form) is an amount that corresponds to the “free base equivalent” of alpelisib.
  • alpelisib is administered to the subject in an amount that is from about to 50 mg to about 400 mg. In some embodiments, alpelisib is administered to the subject in an amount that is from about to 250 mg to about 350 mg. In some embodiments, alpelisib is administered to the subject in an amount that is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg. In some embodiments, alpelisib is administered to the subject in an amount that is about 300 mg. In some embodiments, alpelisib is administered to the subject in an amount that is about 250 mg. In some embodiments, alpelisib is administered to the subject in an amount that is about 200 mg.
  • alpelisib is administered to the subject in an amount that is about 50 mg to about 400 mg once per day (QD). In some embodiments, alpelisib is administered to the subject in an amount that is about 250 mg to about 350 mg once per day (QD). In some embodiments, alpelisib is administered to the subject in an amount that is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg once per day (QD). In some embodiments, alpelisib is administered to the subject in an amount that is about 300 mg QD. In some embodiments, alpelisib is administered to the subject in an amount that is about 250 mg QD. In some embodiments, alpelisib is administered to the subject in an amount that is about 200 mg QD.
  • alpelisib is administered to the subject in a unit dosage form.
  • a unit dosage form is a capsule or tablet.
  • a unit dosage form comprises about 50 mg to about 250 mg of alpelisib.
  • a unit dosage form comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg of alpelisib.
  • a unit dosage form comprises about 50 mg of alpelisib.
  • a unit dosage form comprises about 150 mg of alpelisib.
  • a unit dosage form comprises about 200 mg of alpelisib.
  • a unit dosage form is a capsule.
  • a unit dosage form is a tablet.
  • a total daily dose of alpelisib administered to the subject is in an amount that is about 50 mg to about 400 mg. In some embodiments, a total daily dose of alpelisib administered to the subject is about 250 mg to about 350 mg. In some embodiments, a total daily dose of alpelisib administered to the subject is in an amount that is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg. In some embodiments, a total daily dose of alpelisib administered to the subject is about 300 mg. In some embodiments, a total daily dose of alpelisib administered to the subject is about 250 mg. In some embodiments, a total daily dose of alpelisib administered to the subject is about 200 mg.
  • alpelisib is administered to the subject once daily on each day of a 28-day cycle.
  • alpelisib is administered to a subject in a fed state (e.g., administered with food about 1 hour after administration of Compound 1 without food).
  • the present disclosure encompasses the recognition that 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 Compound 1, or a pharmaceutically acceptable salt thereof in combination with alpelisib, or pharmaceutically acceptable salts thereof.
  • an ER- associated disorder e.g., a cancer or breast cancer
  • the present disclosure provides combination therapy comprising administration of Compound 1 and alpelisib.
  • the present disclosure encompasses an insight that certain synergies may be achieved when combining Compound 1 and alpelisib when treating an estrogen receptor-mediated disease relative to administration of Compound 1 or alpelisib administered in isolation.
  • the present disclosure provides a method of treating a disease, disorder, or condition comprising administering once daily to a subject about 15 mg to about 360 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about to 50 mg to about 400 mg of alpelisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering once daily to a subject about 30 mg to about 120 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 300 mg alpelisib, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating a disease, disorder, or condition comprising administering once daily to a subject about 30 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 300 mg alpelisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering once daily to a subject about 60 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 300 mg alpelisib, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating a disease, disorder, or condition comprising administering once daily to a subject about 90 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 300 mg alpelisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering once daily to a subject about 120 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 300 mg alpelisib, or a pharmaceutically acceptable salt thereof.
  • Compound 1 and alpelisib are each administered daily for a 28 day cycle. In some embodiments, Compound 1 and alpelisib are administered for one, two, three, four, five, or more 28-day cycles.
  • administration of Compound 1 and alpelisib can be administered concomitantly or separately.
  • Compound 1 and alpelisib are administered concomitantly.
  • Compound 1 and alpelisib are administered at approximately the same time each day (e.g., alpelisib is administered, e.g., with food, within approx. 1 hour of Compound 1 administration, e.g., without food.).
  • alpelisib is administered prior to administration of Compound 1.
  • alpelisib is administered after administration of Compound 1.
  • the present disclosure provides a method comprising administering Compound 1 or a pharmaceutically acceptable salt thereof to a subject who has received or is receiving alpelisib (e.g., according to a regimen provided herein). In some embodiments, the present disclosure provides a method comprising administering alpelisib to a subject who has received or is receiving Compound 1 (e.g., according to a regimen provided herein).
  • the present disclosure provides an improvement in a method of treating a disease, disorder, or condition comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, and alpelisib in combination, the improvement comprises administering from about 30 mg to about 120 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement further comprises administering about 300 mg of alpelisib, or a pharmaceutically acceptable salt thereof. In some embodiments, an improvement comprises administering 30 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, an improvement comprises administering 60 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, an improvement comprises administering 90 mg Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, an improvement comprises administering 120 mg Compound 1, or a pharmaceutically acceptable salt thereof. Kits
  • kits comprising one or more compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof, and one or more compositions comprising alpelisib, or a pharmaceutically acceptable salt thereof.
  • a kit comprises a composition that comprises about 30 mg to about 360 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition that comprises about 50 mg to about 400 mg of alpelisib, or a pharmaceutically acceptable salt thereof.
  • a kit comprises a composition that comprises about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition that comprises about 300 mg of alpelisib, or a pharmaceutically acceptable salt thereof.
  • a kit comprises a composition that comprises about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition that comprises about 300 mg of alpelisib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises a composition that comprises about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition that comprises about 300 mg of alpelisib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises a composition that comprises about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition that comprises about 300 mg of alpelisib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit further comprises packaging material that comprises a label which indicates that Compound 1 and alpelisib can be used for treating an estrogen-receptor mediated disease, disorder, or condition.
  • Example 1 A Phase lb Open-Label Multicenter Study of Compound 1 in Combination with the PI3K Inhibitor Alpelisib in Adult Subjects with Advanced and/or Metastatic HR Positive, HERZ Negative Breast Cancer
  • the present example provides a Phase lb open-label, 2-part study of Compound 1 in combination with alpelisib.
  • the study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and/or recommended Phase 2 dose (RP2D); and to characterize the safety and pharmacokinetic (PK) profde of Compound 1 in combination with alpelisib in adult subjects with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Subjects will receive treatment and will be evaluated in 28-day cycles.
  • DLT dose-limiting toxicity
  • MTD maximum tolerated dose
  • RP2D Phase 2 dose
  • PK pharmacokinetic
  • the present example comprises two parts:
  • Part 1 Dose Escalation: This part will evaluate the safety and pharmacokinetics of a range of doses of Compound 1 administered orally (PO) once daily (QD) to subjects in combination with 300 mg of alpelisib administered PO QD and to determine the RP2D.
  • the dose escalation study design will include cohorts of 3 to 6 evaluable subjects who are sequentially enrolled and monitored for DLTs during the first cycle of study treatment. At the cohort safety review, PK and safety events will be reviewed and the DLT observation may be extended to 2 cycles.
  • Part 2 Dose Expansion: This part of the study will further evaluate the safety and pharmacology of Compound 1 at the RP2D in combination with alpelisib and provide an exploratory estimate of anti-tumor activity of the combinations.
  • DLT dose-limiting toxicity
  • MTD maximum tolerated dose
  • RP2D RP2D
  • DoR duration of response
  • Plasma levels of Compound 1 (and potential metabolites) and alpelisib at pre-defined intervals to establish PK parameters including maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), area under the curve (AUC), half-life (t 1/2), and Compound 1 trough concentration at steady state.
  • Plasma levels of Compound 1 (and potential metabolites) and alpelisib at pre-defined intervals to establish PK parameters including maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), area under the curve (AUC), half-life (tl/2), and Compound 1 trough concentration at steady state.
  • CBR as defined by percent of subjects with a CR + PR + SD for > 24 weeks in subjects without evidence of CNS metastases • DoR, time to progression, and progression free survival (PFS) in subjects without evidence of CNS metastases
  • HR+/HER2- disease as determined in the most recently obtained archival tumor tissue sample from a metastatic site, using locally accepted criteria by the local pathology report.
  • Evaluable disease measurable and non-measurable.
  • a. Measurable disease i.e., at least 1 measurable lesion as per RECIST 1. 1 (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).
  • Highly-effective contraception methods include: 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. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by followup hormone level assessment. iii.
  • male partner sterilization (at least 6 months prior to screening).
  • 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.
  • IUD intrauterine device
  • 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: i. Is aged > 60 years ii.
  • 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. Depo Provera + male subject’s use of a condom with spermicide
  • PPI proton pump inhibitor
  • Subjects must not have received prior endocrine or targeted therapy ⁇ 2 weeks prior to the first study drug dose.
  • Subjects must not have received prior fulvestrant, chemotherapy, antibody therapy, targeted therapy, or investigational therapy ⁇ 4 weeks prior to the first study drug dose.
  • Any toxi cities from prior therapy must have resolved to ⁇ Grade 1 or Baseline, as defined by the NCI CTCAE v5.0 prior to the first study drug dose, with the exception of alopecia.
  • Subjects with brain metastases are eligible for the study if they meet all the following criteria: a. Brain metastases have been treated, or do not require treatment at the time of study enrollment, or are unlikely to require treatment during the study. 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 4 weeks prior to first study drug administration.
  • Standard 12-lead ECG values defined as the mean of the triplicate ECGs: a. QTcF at Screening ⁇ 470 msec for females and ⁇ 450 msec for males. b. Mean resting heart rate of 50 to 90 beats per minute (bpm) (determined from ECG).
  • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following: a. Myocardial infarction, angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to first study drug dose. b. Documented cardiomyopathy. c. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome or risk factors for Torsades de Pointes (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia; history of cardiac failure; or history of clinically significant/symptomatic bradycardia. d.
  • TdP Torsades de Pointes
  • Clinically significant cardiac arrhythmias e.g., ventricular tachycardia
  • complete left bundle branch block e.g., high-grade atrioventricular block (e.g., bifascicular block, Mobitz type II, and third degree atrioventricular block).
  • atrioventricular block e.g., bifascicular block, Mobitz type II, and third degree atrioventricular block.
  • GI gastrointestinal
  • HIV human immunodeficiency virus
  • 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.
  • active viral or other hepatitis e.g., hepatitis B or hepatitis C virus
  • current alcohol abuse e.g., alcohol abuse, or cirrhosis.
  • Type I or uncontrolled type 2 diabetes 16.
  • BCRP breast cancer resistance protein
  • CYP cytochrome P450
  • Part 1 Dose Escalation: Approximately 9 to 18 subjects are planned to be enrolled; the exact number of subjects to be enrolled is dependent on the dose levels at which DLTs are seen. Subjects who discontinue from Part 1 (Dose Escalation) of the study before completing Cycle 1 (C 1) for reasons other than DLT are to be replaced.
  • Part 2 Dose Expansion: Twelve subjects are to be enrolled in the Dose Expansion Part of the study. Subjects who discontinue from Part 2 (Dose Expansion) of the study before completing at least 2 cycles of therapy and at least 1 post-baseline disease response assessment are to be replaced.
  • Subjects are to take Compound 1 capsules PO QD at approximately the same time of day on an empty stomach. Subjects should be fasted for 2 hours before Compound 1 administration and remain fasting, with the exception of the water allowed to take the study drug, until 1 hour after dosing. Cycles are repeated every 4 weeks (28 days) with continuous Compound 1 dosing.
  • a 3+3 dose escalation will be followed, considering DLT observation in Cycle 1. Cohorts of 3 to 6 subjects will be treated at each dose level. Three subjects may be concurrently enrolled in each dose level of the study. Decisions to enroll a new subject onto the current, next highest, or next lowest dose level are made based on available data at the time of new subject enrollment. If 2 or more DLTs at a given dose level are observed, the dose level will be deescalated. The decision to escalate to the next highest dose level is made by the participating investigators and representatives of the sponsor at a cohort review meeting after at least 3 subjects have completed Cycle 1. Intra-subject dose escalation is not permitted.
  • DLT protocol - defined TEAEs graded by the investigator per the NCI CTCAE v5.0 and that are considered by the investigator to be at least possibly related to Compound 1.
  • TEAEs meeting the definition of a DLT are described separately.
  • PK and safety events will be reviewed and the DLT observation may be extended to 2 cycles).
  • Subjects must receive at least 75% (at least 21 of 28 doses) of planned Compound 1 doses in Cl to be evaluated for determination of DLT. Subjects receiving less than 75% of the planned dose for reasons other than DLT will be replaced. (Subjects receiving ⁇ 75% of the planned dose in Cl will be evaluated in the overall safety analysis but not for the purposes of dose escalation.) In such cases, replacement subjects may be enrolled to receive the same starting dose of Compound 1 as the subjects who withdrew prematurely.
  • the MTD is defined as the highest feasible dose tested in which ⁇ 33% (i.e., ⁇ 1 of 6) subjects experienced a DLT.
  • At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of study drug is required for inclusion in the analysis of a specific safety parameter.
  • a baseline measurement is also required.
  • Safety Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, DLTs, laboratory values, ECG results, and vital signs.
  • Pharmacokinetics Pharmacokinetic parameters will be determined for each analyte (Compound 1 and alpelisib) in the PK Analysis Set using standard compartmental or noncompartmental methods.
  • Pharmacodynamics Pharmacodynamic assessment will be made by evaluating ctDNA pre- and post-treatment. ctDNA will be evaluated for ESRI mutations and other pathways significant to ER activity.
  • 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. After the C8 radiographic assessment, subjects who have been determined to have obtained a clinical benefit from study treatment may decrease the frequency of radiographic and physical assessments of malignancy to every 3 months. ORR and CBR, as determined by the subject’s best tumor response, duration of response, and time to progression will be assessed by the investigator using RECIST vl.l. 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.
  • Safety Analyses The safety data from Part 1 (Dose Escalation) will be summarized by dose cohort. Safety data also will be summarized for Part 2 (Dose Expansion). Safety will be assessed through summaries of AEs, laboratory test results, vital signs, and ECOG PS. [0124] Adverse events will be classified by system organ class and preferred term using MedDRA with severities classified using the CTCAE 5.0 criteria. All collected AE data will be listed. All SAEs will also be listed. All TEAEs regardless of attribution will be summarized by cohort. The changes in hematology, chemistry, and other laboratory values will be summarized descriptively for each scheduled protocol assessment time point.
  • the duration of objective response will be calculated for subjects who achieve CR or PR.
  • the duration of objective response 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. Disease progression will be determined by the investigator using RECIST vl.l.
  • Pharmacokinetic parameters will be determined for each analyte (Compound 1 and alpelisib) in the PK Analysis Set using standard compartmental or noncompartmental methods. Analyte concentrations will be summarized using appropriate descriptive statistics (e.g., N, arithmetic mean, standard deviation, minimum, median, maximum, coefficient of variation [CV] %, geometric mean and CV associated to the geometric mean) for each cohort per cycle and day.
  • Biomarker Analyses Descriptive statistics will be primarily used to summarize the biomarker data generated in this study. For continuous variables, the number of subjects with nonmissing data, mean, either the standard error or standard deviation, median, 25th percentile (first quartile), 75th percentile (third quartile), minimum, and maximum will be presented. For discrete data, the frequency and percent distribution will be presented.

Abstract

La présente invention concerne des méthodes de traitement d'une maladie, d'un trouble ou d'un état pathologique dont la médiation est assurée par un récepteur des œstrogènes chez un sujet, comprenant l'administration au sujet d'une composition comprenant un composé (1) ou un sel pharmaceutiquement acceptable de celui-ci en combinaison avec de l'alpelisib, ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2023/034466 2022-10-05 2023-10-04 Méthodes de traitement de troubles médiés par le récepteur des œstrogènes WO2024076633A1 (fr)

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US63/413,467 2022-10-05

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