WO2024015506A1 - Methods of treating estrogen receptor-mediated disorders - Google Patents

Methods of treating estrogen receptor-mediated disorders Download PDF

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Publication number
WO2024015506A1
WO2024015506A1 PCT/US2023/027615 US2023027615W WO2024015506A1 WO 2024015506 A1 WO2024015506 A1 WO 2024015506A1 US 2023027615 W US2023027615 W US 2023027615W WO 2024015506 A1 WO2024015506 A1 WO 2024015506A1
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Prior art keywords
compound
palbociclib
administered
subject
dose
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PCT/US2023/027615
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French (fr)
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WO2024015506A8 (en
Inventor
Julia Ann LAWRENCE
Pamela M. KLEIN
Justin Thomas HOFFMAN
Julia Perkins SMITH
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Olema Pharmaceuticals, Inc.
Pfizer Inc.
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Application filed by Olema Pharmaceuticals, Inc., Pfizer Inc. filed Critical Olema Pharmaceuticals, Inc.
Publication of WO2024015506A1 publication Critical patent/WO2024015506A1/en
Publication of WO2024015506A8 publication Critical patent/WO2024015506A8/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

  • 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.
  • 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
  • Palbociclib or a pharmaceutically acceptable salt thereof optionally wherein the kit comprises a label indicating that Compound 1 and palbociclib are useful for the treatment of estrogen receptor mediated-diseases, disorders, and conditions.
  • FIG. 1 is an illustration of a mechanism of action of Compound 1 in the inhibition of cancer cell proliferation.
  • FIG. 2 shows the clinical study design of an open-label, phase lb/2 dose escalation and dose expansion study.
  • FIG. 3 is a graph showing the steady state AUC0-24 (area under the concentration time curve from 0 to 24h) and steady state Cmax (maximum concentration) of palbociclib as a single agent and in combination with a range of Compound 1 doses. Data are GeoMean ⁇ GeoSD.
  • FIG. 4 is a graph showing the steady state AUC0-24 (area under the concentration time curve from 0 to 24h) and steady state Cma ⁇ (maximum concentration) of Compound 1 as a single agent and in combination with 125 mg palbociclib over a range of Compound 1 doses. Data are GeoMean ⁇ GeoSD.
  • FIG. 5 is a graph showing the duration of treatment for patients in the study at the time of a second data cutoff (see Example 3).
  • 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 palbociclib, or a pharmaceutically acceptable salt thereof.
  • the present disclosure encompasses an insight that certain synergies are achieved when combining Compound 1 and palbociclib when treating an estrogen receptor-mediated disease relative to administration of Compound 1 or palbociclib when 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 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.
  • 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.).
  • 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.
  • 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.
  • Dosage form or unit dosage form are examples of dosage form or unit dosage form.
  • 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).
  • 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.
  • 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.
  • 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.
  • a patient or subject displays one or more symptoms of a disorder or condition.
  • a patient or subject has been diagnosed with one or more disorders
  • a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • Pharmaceutical 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/or 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 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.
  • 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;
  • compositions comprising: [0030] pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt 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/or 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, 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, palm
  • 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.
  • small molecule compounds have structures that can exist in one or more steroisomeric forms.
  • 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.
  • small molecule compounds have structures that can exist in one or more tautomeric forms.
  • 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 15 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 disclosure 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
  • 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 ER0 signaling has been reported to be able to achieve tumor suppressor effects; see, for example, Nilsson & Gustafson Clin. Pharmacol. Ther. 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 ER+/HER2- recurrent, locally advanced, or 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 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 one endocrine therapies. 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.
  • a disease described herein e.g., a tumor, such as an ER+/HER2- tumor
  • a subject suffering from a disease described herein has previously been administered chemotherapy (e.g., chemotherapy for locally advanced or metastatic disease).
  • chemotherapy e.g., chemotherapy for locally advanced or metastatic disease.
  • a subject has previously been administered no more than one chemotherapy regimen.
  • a subject has previously been administered one chemotherapy regimen.
  • a subject has previously been administered one or two chemotherapy regimens.
  • a subject has previously received at least one of a CDK4/6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.
  • the present disclosure teaches particular usefulness of a compound (e.g., Compound 1) that is a complete estrogen receptor antagonist.
  • a “complete estrogen receptor antagonist,” as that term is used herein, is characterized by complete antagonism of the estrogen receptor with no or minimal residual estrogen receptor agonist activity.
  • 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.
  • agent e.g., a small molecule compound
  • 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
  • fulvestrant is the only approved therapy that has each characteristic of a complete estrogen receptor antagonist. But fulvestrant suffers from numerous shortcomings, including poor oral bioavailability, and an inability to cross the blood brain barrier.
  • a complete estrogen receptor antagonist is Compound 1
  • Compound 1 or a pharmaceutically acceptable salt thereof.
  • 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 l is a small molecule Complete Estrogen Receptor Antagonist (CERAN).
  • CERAN Complete Estrogen Receptor Antagonist
  • 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.
  • SERMs selective estrogen receptor modulators
  • Compound 1 completely inactivates 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 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 fillers 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 15 mg to about 360 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about 30 mg to about 360 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about 30 mg to about 300 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about 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 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 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.
  • Compound 1 is administered to the subject in a unit dosage form.
  • 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 60 mg to about 120 mg. In some embodiments, a total daily dose of Compound 1 administered to the subj ect 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 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.
  • 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 a compound (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.
  • Palbociclib is a selective inhibitor of cyclin-dependent kinases CDK4 and CDK6, and has formula:
  • Palbociclib is approved for treatment of hormone receptor positive (e.g., HR+ or ER+) human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant.
  • hormone receptor positive e.g., HR+ or ER+
  • HER2 human epidermal growth factor receptor 2
  • Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin DI and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation.
  • palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle.
  • ER estrogen receptor
  • Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma (Rb) protein phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest compared to treatment with each drug alone.
  • Rb retinoblastoma
  • a composition comprising palbociclib, 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.
  • inert diluent such as sucrose, lactose or starch.
  • SUBSTITUTE SHEET 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.
  • additional substances other than inert diluents e.g., lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • 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 fillers 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.
  • a composition comprising palbociclib further comprises one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells.
  • palbociclib refers to palbociclib 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 palbociclib means the amount of palbociclib in free base form. Accordingly, palbociclib may be provided and/or utilized as, e.g., a salt form of palbociclib such that the amount of the salt (or other form) is an amount that corresponds to the “free base equivalent” of palbociclib.
  • palbociclib is administered to the subject in an amount that is from about 50 mg to about 150 mg. In some embodiments, palbociclib is administered to the subject in an amount that is from about 75 mg to about 125 mg. In some embodiments, palbociclib is administered to the subject in an amount that is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg. In some embodiments, palbociclib 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, palbociclib is administered to the subject in an amount that is about 75 mg. In some embodiments, palbociclib is administered to the subject in an amount that is about 100 mg. In some embodiments, palbociclib is administered to the subject in an amount that is about 125 mg.
  • palbociclib is administered to the subject in an amount that is about 50 mg to about 150 mg per day (QD). In some embodiments, palbociclib is administered to the subject in an amount that is about 75 mg to about 125 mg per day (QD). In some embodiments, palbociclib is administered to the subject in an amount that is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg QD. In some embodiments, palbociclib is administered to the subject in an amount that is about 75 mg QD. In some embodiments, palbociclib is administered to the subject in an amount that is about 100 mg QD. In some embodiments, palbociclib is administered to the subject in an amount that is about 125 mg QD.
  • a unit dosage form is a capsule or tablet.
  • a unit dosage form comprises about 50 mg to about 150 mg of palbociclib.
  • a unit dosage form comprises about 75 mg to about 125 mg of palbociclib.
  • a unit dosage form comprises about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of palbociclib.
  • a unit dosage form comprises about 75 mg of palbociclib.
  • a unit dosage form comprises about 100 mg of palbociclib. In some embodiments, a unit dosage form comprises about 125 mg of palbociclib. 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 palbociclib administered to the subject is in an amount that is about 50 mg to about 150 mg per day (QD). In some embodiments, a total daily dose of palbociclib administered to the subject is about 75 mg to about 125 mg. In some embodiments, a total daily dose of palbociclib administered to the subject is in an amount that is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg QD. In some embodiments, a total daily dose of palbociclib administered to the subject is about 75 mg. In some embodiments, a total daily dose of palbociclib administered to the subject is about 100 mg. In some embodiments, a total daily dose of palbociclib administered to the subject is about 125 mg.
  • palbociclib is administered to the subject once daily for 21 days of a 28-day cycle (i.e., once daily for 21-days followed by a 7-day dose holiday).
  • 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 palbociclib, or a pharmaceutically acceptable salt thereof.
  • an ER- associated disorder e.g., a cancer or breast cancer
  • the present disclosure encompasses the surprising synergies achieved by the combination of Compound 1 and palbociclib.
  • the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject about 30 mg to about 300 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 50 mg to about 150 mg of palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition with a composition comprising about 60 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating a disease, disorder, or condition with a composition comprising about 90 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition with a composition comprising about 120 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered daily for a 28 day cycle, and palbociclib is administered daily for 21 days of the 28-day cycle (i.e., the same 28 day cycle). In some embodiments, Compound 1 and palbociclib are administered for one, two, three, four, five, or more 28-day cycles.
  • Compound 1 and palbociclib can be administered concomitantly or separately.
  • Compound 1 and palbociclib are administered concomitantly.
  • palbociclib is administered prior to administration of Compound 1.
  • palbociclib 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 palbociclib (e.g., according to a regimen provided herein). In some embodiments, the present disclosure provides a method comprising administering palbociclib to a subject who has received or is receiving Compound 1 (e.g., according to a regimen provided herein).
  • kits comprising one or more compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof, and one or more compositions comprising palbociclib, or a pharmaceutically acceptable salt thereof.
  • a kit comprises a composition that comprises about 30 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition that comprises about 50 mg to about 150 mg of palbociclib, 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 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof.
  • 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 125 mg of palbociclib, 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 125 mg of palbociclib, 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 palbociclib can be used for treating an estrogen-receptor mediated disease, disorder, or condition (e.g., breast cancer).
  • a method of treating an estrogen receptor mediated disease, disorder, or condition in a subject comprising administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, in combination with a composition comprising palbociclib, or a pharmaceutically acceptable salt thereof.
  • Embodiment 13 wherein the cancer has metastasized to the brain, bone, lungs, or liver. 15. The method of any one of Embodiments 1-14, wherein the subject has previously received at least one of a CDK4/6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.
  • a kit comprising a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising palbociclib, or a pharmaceutically acceptable salt thereof.
  • kits of Embodiment 16 wherein the composition that comprises Compound 1 comprises about 30 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • kits of Embodiment 16 or 17, wherein the composition that comprises palbociclib comprises about 50 mg to about 150 mg of palbociclib, or a pharmaceutically acceptable salt thereof.
  • kit of any one of Embodiments 16-18 wherein the kit comprises about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • kit comprises about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof.
  • kits of Embodiment 23, wherein the estrogen receptor-mediated disease, disorder, or condition is a cancer.
  • Example 1 A Phase 1 Dose Escalation and Dose Expansion Open-label, Multicenter, Study of Compound 1 in Combination with the CDK4/6 Inhibitor Palbociclib in Adult Subjects with Advanced or Metastatic HR-positive, HER2-negative Breast Cancer
  • the present example provides a phase 1 dose escalation and dose expansion open-label study to determine the maximum tolerated dose (MTD), and/or recommended phase 2 dose (RP2D) of Compound 1 in combination with palbociclib; characterize the safety and pharmacokinetic (PK) profde of the combination; and to estimate the preliminary anti-tumor activity of Compound 1 in combination with the cyclin dependent kinase (CDK) 4/6 inhibitor palbociclib in adult subjects with hormone receptor-positive (HR+/ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC). Treatment and study subject evaluation will be performed in 28-day cycles.
  • MTD maximum tolerated dose
  • R2D phase 2 dose
  • the present example comprises two parts:
  • Part 1 Dose Escalation: This portion of the study will evaluate the safety and PK of a range of doses of Compound 1 administered orally (PO) to subjects in combination with palbociclib 125 mg PO, and to determine the RP2D of Compound 1. Part 1 will employ a dose escalation study design, whereby cohorts of 3 to 6 subjects will be sequentially enrolled and monitored for dose limiting toxi cities (DLTs) during the first cycle of study treatment.
  • DLTs dose limiting toxi cities
  • Part 2 Dose Expansion: This portion of the study further explores the safety and PK of Compound 1 at the RP2D in combination with palbociclib. Clinical activity of Compound 1 at the RP2D in combination with palbociclib will also be explored.
  • Plasma levels of Compound 1 and palbociclib 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 and palbociclib concentrations at steady state.
  • Biomarkers in ctDNA pre- and post-treatment with of Compound 1 when administered in combination with palbociclib such as mutESRl, phosphoinositide 3-kinase alpha catalytic subunit [PIK3CA] variants, and others).
  • CBR Clinical benefit rate
  • Biomarkers in ctDNA pre- and post-treatment with Compound 1 at the RP2D when administered in combination with palbociclib such as mutESRl, PIK3CA variants, and others.
  • 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.
  • Effective forms of birth control include barrier methods used in conjunction with a spermicidal cream or jelly, 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.
  • a female subject is considered to be of childbearing potential unless she:
  • Pre- or peri -menopausal female subjects must be willing to take a luteinizing horm one- releasing hormone (LHRH) agonist >2 weeks before first study drug administration and for the duration of the study. 11.
  • LHRH one- releasing hormone
  • PPI proton pump inhibitor
  • Subjects must not have received prior endocrine or targeted therapy ⁇ 2 weeks prior to the first administration of study drug (including fulvestrant, alpelisib, everolimus, CDK4/6 inhibitors, phosphoinositol-3 -kinase [PI3K] inhibitors, or poly ADP -ribose polymerase [PARP] inhibitors).
  • study drug including fulvestrant, alpelisib, everolimus, CDK4/6 inhibitors, phosphoinositol-3 -kinase [PI3K] inhibitors, or poly ADP -ribose polymerase [PARP] inhibitors.
  • 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.
  • Serum creatinine ⁇ the upper limit of normal (ULN) or, if higher than the normal range, calculated creatinine clearance (CrCl) must be >50 mL/min (e.g., by Cockcroft-Gault formula). Actual body weight must be used for CrCl, unless body mass index (BMI) >30 kg/m2, in which case, lean body weight must be used; b. Total bilirubin ⁇ 1.5 x ULN unless prior history of Gilbert’s syndrome; c.
  • AST Aspartate transaminase
  • ALT alanine transaminase
  • d Hemoglobin >9.0 g/dL without requirement for red blood cell (RBC) transfusion within the last 4 weeks
  • e Platelet count >100 x 109 cells/L
  • f Absolute neutrophil count (ANC) >1.5 x 109 cells/L (without the use of hematopoietic growth factors within the prior 3 weeks)
  • ANC Absolute neutrophil count
  • 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.
  • ventricular arrhythmia requiring therapy
  • congestive heart failure New York Heart Association Functional Classification Class 2B-4
  • uncontrolled hypertension defined as systolic blood pressure >150 mm Hg and/or diastolic blood pressure >100 mm Hg while on anti-hypertensive medications.
  • GI gastrointestinal
  • HIV human immunodeficiency virus
  • liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (eg, hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis.
  • active viral or other hepatitis eg, hepatitis B or hepatitis C virus
  • current alcohol abuse e.g., hepatitis B or hepatitis C virus
  • Subject has clinically significant co-morbidities, such as 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.
  • Part 1 Dose Escalation: Approximately 12 to 18 evaluable subjects are planned to be enrolled in Part 1; 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 before completing Cycle 1 (Cl) for reasons other than DLT are to be replaced.
  • Part 2 Dose Expansion: Approximately 12 to 18 evaluable subjects are to be enrolled in Part 2. Subjects who discontinue from Part 2 before completing at least 2 cycles of therapy and at least 1 post-baseline disease response assessment are to be replaced.
  • 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 use to make up the appropriate dose for each dose cohort.
  • HDPE high-density polyethylene
  • Palbociclib will be supplied in boxes of 21 tablets. Each box contains 3 blister cards each with 7 tablets. Dose strengths are 125 mg, 100 mg, and 75 mg. [0101] Subjects are to take Compound 1 capsules PO once daily (QD) in the morning at approximately the same time of day on an empty stomach. Subject should be fasted for 2 hours before Compound 1 administration and remain fasting, with the exception of the water allowed for taking the study drug, until 1 hour after dosing. 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).
  • Compound 1 capsules should be swallowed with water (approximately 8 ounces or 240 mL) without chewing or sucking the capsule.
  • Compound 1 will be administered in combination with palbociclib. Subjects should take their palbociclib dose at the same time each day with administration of Compound 1. Subjects should take their palbociclib dose at the same time each day, with or without food, as per the instructions in the package insert. Compound 1 should be taken first, on an empty stomach, followed by palbociclib (without food). If a subject prefers to take palbociclib with food, palbociclib dosing must then occur at least 1 hour after Compound 1 dosing. After C3D15, when PK assessments have been completed, Compound 1 and palbociclib can be taken at different times of the day (e.g., Compound 1 will be taken in the morning and palbociclib will be taken in the evening).
  • palbociclib Dose modifications of palbociclib will be per the instructions in the package insert. If palbociclib doses are required to be held, they will not be replaced thus maintaining the treatment schedule of daily dosing for the first 21 days in a 28-day cycle.
  • the starting dose of palbociclib will be per the package insert at 125 mg PO daily for 21 days (i.e., the first 21 days in every 28 day cycle). If palbociclib doses are required to be held, they will not be replaced, thus maintaining the treatment schedule of daily dosing for the first 21 days in a 28-day cycle.
  • Palbociclib tablets should be swallowed whole, and not chewed, crushed, or split before swallowing.
  • the DLT observation period is Cycle 1 (Cl). Cohorts of 3 subjects will be treated at each dose level. In the 3 + 3 design, 3 subjects will be concurrently enrolled at each dose level in the study. If 0 of 3 subjects develop a DLT, then subjects will be enrolled in the next highest dose level. If 1 of 3 subjects develops a DLT, 3 additional subjects will be enrolled at that dose level. If 2 or more of 6 subjects develop a DLT then the MTD has been exceeded and subjects will be enrolled at the next lowest dose level. The decision to escalate to the next highest dose level will made by the Investigators participating in the phase 1 study and representatives of the Sponsor at a cohort review meeting after all subjects enrolled in that cohort have completed Cycle 1. Intra-patient dose escalation is not permitted.
  • a DLT is defined as the occurrence of any of the following TEAEs graded by the Investigator per the NCI CTCAE v5.0 during Cl, except those that are clearly due to disease progression (PD) or extraneous causes:
  • AST or ALT >3 x ULN and a total bilirubin >2 x 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 >8 x ULN or AST or ALT >5 x ULN for >14 days.
  • Subjects must receive at least 75% (at least 21 of 28 doses) of planned Compound 1 doses and 75% of palbociclib doses (at least 16 of 21 doses) in Cl in order to be evaluated for determination of DLT.
  • Subjects receiving less than 75% of the planned dose of either drug 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.
  • subjects will be evaluated according to the actual starting dose of Compound 1 during Cl. For most subjects, this will be the dose cohort to which they were assigned. Subjects who receive at least 75% (at least 21 of 28 doses) of the planned doses in Cl will be considered to have sufficient safety data/follow-up to support dose escalation. 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. In such cases, replacement subjects may be enrolled to receive the same starting dose of Compound 1 as the subjects who withdraw prematurely.
  • the MTD is defined as the highest feasible dose tested in which ⁇ 33% (i.e., ⁇ 1 of 6) subjects experienced a DLT attributable to the study drug, when at least 6 subjects were treated at that dose and were assessable for toxicity.
  • the RP2D will be determined after review of all the available safety and PK data.
  • 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. To assess change from baseline, a baseline measurement is also required.
  • Palbociclib 125 mg QD will be administered for 21 days in 28-day cycles. Subjects should take their Compound 1 and palbociclib dose at the same time each day. Subjects will take palbociclib and Compound 1 in a fasted state (subject should be fasting for at least 2 hours before and remain fasting, with the exception of the water allowed to take the study drug, until 1 hour after dosing).
  • Palbociclib is a commercially available kinase inhibitor indicated for the treatment of adult subjects with HR+/HER2- advanced or MBC in combination either with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men, or fulvestrant in subjects with disease progression following endocrine therapy.
  • Palbociclib is supplied as 125 mg, 100 mg, and 75 mg tablets.
  • Safety will be assessed by periodic physical examinations, 12-lead ECGs, clinical laboratory assessments, and monitoring of AEs.
  • Biomarkers that may predict Compound 1 and palbociclib activity will be evaluated in archival tumor tissues. These include quantitative levels of ER and progesterone receptor (PR) by immunohistochemistry (percent cells positive and Allred score), phosphoinositide 3 -kinase alpha catalytic subunit (PI3KCA), phosphatase variants, and potentially other biomarkers. Biomarkers of interests in ctDNA will be measured at baseline and over time including mutESRl that may be pharmacodynamic and predictive markers of Compound 1 and palbociclib activity.
  • PR progesterone receptor
  • PI3KCA phosphoinositide 3 -kinase alpha catalytic subunit
  • phosphatase variants and potentially other biomarkers.
  • Biomarkers of interests in ctDNA will be measured at baseline and over time including mutESRl that may be pharmacodynamic and predictive markers of Compound 1 and palbociclib 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 8 weeks starting from the first day of study treatment (i.e., after 2 cycles of treatment).
  • Subjects who have been determined to have obtained a clinical benefit from study treatment as determined by the treating Investigator may decrease the frequency of radiographic and physical assessments of malignancy to every 12 weeks after the 32-week (8-month, and typically 8 cycles of treatment) radiographic assessment.
  • ORR and CBR, as determined by the subject’s best tumor response, DOR, and time to progression will be assessed by the Investigator using RECIST 1.1. 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 to confirm the response.
  • Safety Analyses Safety data analysis will be conducted on all subjects receiving at least 1 dose of the study drug. Summarization of DLTs will be conducted on DLT evaluable subjects. The safety data from the dose-escalation phase will be summarized by dose cohort. Safety will be assessed through summaries of AEs, laboratory test results, vital signs, and ECOG PS. AEs will be classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) with severities classified using the NCI CTCAE criteria.
  • SOC system organ class
  • MedDRA Medical Dictionary for Regulatory Activities
  • Efficacy Analyses The number and percentage of subjects experiencing an objective response (CR + PR) will be summarized. The duration of objective response will be summarized descriptively using the Kaplan-Meier method. The DOR is defined as time from first documentation of tumor response to PD. CBR also will be summarized.
  • PK parameters including AUC, Cmax, Cmin, Tmax, and tl/2 will be determined. Comparisons across dose levels will be made to assess proportionality. In addition, comparison between single dose and multi-dose PK parameters will be made for assessment of steady-state drug accumulation.
  • Compound 1 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER-driven transcriptional activity.
  • CDK4/6 inhibitors in combination with endocrine therapy have improved progression free survival and overall survival for patients with metastatic breast cancer (MBC) in the first and second line settings.
  • MBC metastatic breast cancer
  • Compound 1 potently inactivates both wildtype ER and mutant forms of ER. The latter confers ligand independent activity and is a mechanism of resistance to standard of care endocrine therapies.
  • Compound 1 in combination with palbociclib demonstrated synergistic activity in models of wild-type ER and those containing ESRI activating mutations, and in models of brain metastasis.
  • a Phase 1/2 monotherapy study of Compound 1 is ongoing in MBC subjects who have received 1 or more prior endocrine therapies. Monotherapy is well tolerated with a RP2D of 120 mg QD. The aim of this combination study is to define the maximum tolerated dose (MTD), safety, tolerability, and pharmacokinetics (PK) of Compound 1 in combination with palbociclib.
  • MTD maximum tolerated dose
  • PK pharmacokinetics
  • Key eligibility criteria include patients with MBC or locally advanced breast cancer who have received no more than 1 prior line of endocrine therapy (prior CDK4/6 inhibitors and one line of chemotherapy are permitted) and measurable or non-measurable disease.
  • cohorts are sequentially enrolled and patients receive escalating doses of Compound 1 orally QD continuously in combination with 125 mg of palbociclib orally for 21 of 28 days. Patients will be evaluated for dose limiting toxicities (DLTs) if >75% of both treatments were administered within the first treatment 28-day treatment cycle.
  • Blood is collected for PK on cycle 1 day 1, 2 and cycle 2 day 15, 16 for Compound 1 and cycle 1 day 15 for palbociclib.
  • PK profiles, exposure parameters, and drug-drug interactions (DDIs) are assessed. Patients are monitored for adverse events (AE), and tumor assessments (RECIST 1.1) are conducted every two cycles.
  • AE adverse events
  • RECIST 1.1 tumor assessments
  • Results As of a first cutoff date, nine patients have been enrolled into dose levels 30 mg, 60 mg, and 90 mg of Compound 1 in combination with palbociclib. There were no DLTs at the 30, 60, or 90 mg dose level. The most common Grade 1/2 treatment emergent adverse events (TEAE), which occurred in 2 patients, were nausea, gastroesophageal reflux, vomiting, and fatigue. Grade 3 neutropenia occurred in 4 patients. No Grade 4 events were observed. Compound 1 was highly bioavailable and showed dose proportional exposure in combination with palbociclib. The single and multiple dose exposure of Compound 1 was consistent with that observed in the monotherapy study, indicating an absence of effect of palbociclib on Compound 1 PK. 90 mg steady-state evaluation is ongoing. Palbociclib concentrations at steady state did not demonstrate a meaningful difference from published exposure parameters for the three dose levels evaluated, indicating an absence of DDL
  • Example 3 A Phase lb/2 Study of Compound 1 in Combination with Palbociclib in Patients with Advanced or Metastatic Estrogen Receptor (ER)-Positive, HER2-Negative Breast Cancer
  • the present example describes results, such as pharmacokinetic, drug-drug interaction, safety, and anti -turn or activity data, from a Phase lb/2 study of Compound 1 in combination with palbociclib, as described in Example 1.
  • Compound 1 is a complete ER antagonist (CERAN) and selective ER degrader (SERD), which blocks both the AF1 and AF2 transcriptional activation domains of the ER (FIG. 1) (Alemany C, et al. Presented at AACR-NCI-EORTC. October 7-10, 2021).
  • Compound 1 has demonstrated activity in both ESRI wild-type and ESRI mutant pre-clinical models. Results from an ongoing phase 1/2 study with Compound 1 as monotherapy demonstrated acceptable safety, good tolerability, and a pharmacokinetics profile supportive of once-daily oral dosing in patients with HR+/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or MBC.
  • the present example describes an open-label phase lb/2 dose-escalation and doseexpansion study (FIG. 2).
  • Eligible patients were women (regardless of menopausal status) or men with HR+, HER2- advanced or metastatic breast cancer.
  • Eligible patients had zero or one prior endocrine therapy (with or without CDK4/6 inhibitor) for locally advanced or metastatic disease.
  • One prior line of chemotherapy for advanced or metastatic disease was allowed.
  • Eligible patients had evaluable (measurable or non-measurable) disease by RECIST 1.1 criteria.
  • a One patient received chemotherapy, endocrine therapy and olaprib.
  • b ctDNA from 18 patients was available at the time of data cutoff for ESRI mutation evaluation.
  • CDK cyclin-dependent kinase
  • ctDNA circulating tumor DNA
  • ECOG Eastern Cooperative Oncology Group.
  • neutropenia was assessed as related to palbociclib and unrelated to Compound 1.
  • neutropenia was assessed as related to palbociclib and possibly related to Compound 1.
  • 6 patients had dose reductions of palbociclib due to neutropenia.
  • No patients had dose reductions of Compound 1 for neutropenia.
  • Neutropenia was reversible in all patients and the timing was consistent with palbociclib-related neutropenia.
  • Palbociclib did not affect Compound 1 PK; the rate and extent of absorption and half-life were consistent with single agent Compound 1 (Table 4 and FIG. 4).
  • Compound 1 was readily bioavailable and demonstrated doseproportional exposure and a long half-life.
  • Steady-state plasma levels showed minimal peak-to- trough variability, enabling consistent steady state target coverage.
  • Plasma samples for Compound 1 assessment were collected on Cl day (D) 1 (C1D1), C1D2/D8/D15, C2D15/D16, C3D1/D15, C5D1, C7D1, and C9D1.
  • D Cl day
  • C1D1 C1D2/D8/D15
  • C2D15/D16 C3D1/D15
  • C5D1, C7D1, and C9D1 C5D1, C7D1, and C9D1.
  • C1D15, C2D15, and C3D15 AUC0-24, area under the concentration time curve from 0 to 24 h; Cavg, average concentration; C max , maximum concentration; Cmin, minimum concentration; Tmax, time to maximum concentration.

Abstract

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

Description

METHODS OF TREATING ESTROGEN RECEPTOR-MEDIATED DISORDERS
RELATED APPLICATIONS
[0001J This application claims priority to and benefit of U.S. Application No. 63/389,062, filed July 14, 2022, and U.S. Provisional Application No. 63/465,292, filed May 10, 2023, 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). Endocrine therapy is often the first line of treatment for advanced stage estrogen receptor positive cancer. However, most patients develop resistance to endocrine therapy over time. Fulvestrant, a selective estrogen receptor degrader has clinical activity in some patients who demonstrate resistance to aromatase inhibitors due to ESRI mutations but is administered by intramuscular injection due to limited oral 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 in a subject comprising administering to the subject a composition comprising Compound 1
Figure imgf000002_0001
Compound 1 or a pharmaceutically acceptable salt thereof, in combination with a composition comprising palbociclib
Figure imgf000003_0001
Palbociclib or a pharmaceutically acceptable salt thereof.
[0004] In some embodiments, the present disclosure provides a kit comprising a composition comprising Compound 1
Figure imgf000003_0002
Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising palbociclib:
Figure imgf000003_0003
Palbociclib or a pharmaceutically acceptable salt thereof, optionally wherein the kit comprises a label indicating that Compound 1 and palbociclib are useful for the treatment of estrogen receptor mediated-diseases, disorders, and conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1 is an illustration of a mechanism of action of Compound 1 in the inhibition of cancer cell proliferation.
[0006] FIG. 2 shows the clinical study design of an open-label, phase lb/2 dose escalation and dose expansion study.
[0007] FIG. 3 is a graph showing the steady state AUC0-24 (area under the concentration time curve from 0 to 24h) and steady state Cmax (maximum concentration) of palbociclib as a single agent and in combination with a range of Compound 1 doses. Data are GeoMean±GeoSD.
2
SUBSTITUTE SHEET ( RULE 26) [0008] FIG. 4 is a graph showing the steady state AUC0-24 (area under the concentration time curve from 0 to 24h) and steady state Cma\ (maximum concentration) of Compound 1 as a single agent and in combination with 125 mg palbociclib over a range of Compound 1 doses. Data are GeoMean±GeoSD.
[0009] FIG. 5 is a graph showing the duration of treatment for patients in the study at the time of a second data cutoff (see Example 3).
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0010] 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 palbociclib, or a pharmaceutically acceptable salt thereof. In particular, the present disclosure encompasses an insight that certain synergies are achieved when combining Compound 1 and palbociclib when treating an estrogen receptor-mediated disease relative to administration of Compound 1 or palbociclib when administered in isolation.
Definitions
[0011] 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 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.
[0012] 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.
[0013] 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.). [0014] 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”.
[0015] 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.
[0016] 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.
[0017] Combination therapy . As used herein, the term “combination therapy” refers to those situations in which a subject is concomitantly exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents). In some embodiments, 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. 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).
[0018] 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.
[0019] 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 190th 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/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. [0020] 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.
[0021] 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).
[0022] 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.
[0023] 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.).
[0024] 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. [0025] 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.
[0026] 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. [0027] 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.
[0028] 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/or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[0029] 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 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’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides; and other nontoxic compatible substances employed in pharmaceutical formulations.
[0030] 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/or 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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; UC, 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.
[0040] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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).
[0046] The compounds of the disclosure, 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
[0047] 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 ER0 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.
[0048] Among other things, presence or development of certain ER mutations has been reported to impact effectiveness of various ER-targeted therapies (see, for example, Jeselsohn et al Nature Rev. Clin. One. 12, 573, 2015; Gelsomino et al. Breast Cancer Res. Treat 157:253, 2016; Toy et al. 2013 ). Some particularly problematic mutations are those that “activate” one or more aspects of ER expression and/or function; some activating mutations have been reported that can render the ER ligand-independent (i.e., constitutively active). For example, particular mutations in the ER ligand binding domain, including D538G and Y537S, have been demonstrated to constitutively activate the ER; other mutations including deletions and/or fusions that remove the ligand binding domain, can have similar effects (see, for example, Li et al. Cell Repts 4: 1116, 2013; Veeraraghavan et al Breast Cancer Research and Treatment 158, 219-232, 2016; Veeraraghavan, et al. Nature Comms 5:4577, 2014/ Some reports have indicated that as many as 50% of women with metastatic breast cancer may have activating ER mutations detectible in circulating tumor DNA.
SUBSTITUTE SHEET ( RULE 26) [0049] 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.
[0050] 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 (e.g., the brain, bones, lungs, and/or liver). 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.
[0051] 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, and/or bone).
[0052] 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 one endocrine therapies. 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.
[0053] In some embodiments, a subject suffering from a disease described herein has previously been administered chemotherapy (e.g., chemotherapy for locally advanced or metastatic disease). In some embodiments, a subject has previously been administered no more than one chemotherapy regimen. 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.
[0054] 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.
Complete Estrogen Receptor Antagonists
[0055] 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. [0056] 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.
[0057] Currently, fulvestrant is the only approved therapy that has each characteristic of a complete estrogen receptor antagonist. But fulvestrant suffers from numerous shortcomings, including poor oral bioavailability, and an inability to cross the blood brain barrier.
[0058] In some embodiments, a complete estrogen receptor antagonist is Compound 1
Figure imgf000018_0001
Compound 1 or a pharmaceutically acceptable salt thereof. [0059] 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.
[0060] Compound l 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.
[0061] 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.
[0062] In some embodiments, a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, further comprises one or more pharmaceutically acceptable carriers or excipients. For example, pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[0063] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and/or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
[0064] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings (i.e. buffering agents) and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [0065] In some embodiments, Compound 1 is administered to the subject in an amount that is from about 15 mg to about 360 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about 30 mg to about 360 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about 30 mg to about 300 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about 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 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.
[0066] 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.
[0067] In some embodiments, Compound 1 is administered to the subject in a unit dosage form. In some embodiments, 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.
[0068] 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 subj ect 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.
[0069] 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 a compound (e.g., Compound 1) is not administered to the subject. In some embodiments, a dose holiday is one day, one week, or one 28-day cycle. In some embodiments, Compound 1 is administered once daily for one or more 28-day cycles, followed by a dose holiday, and then resumption of administration of Compound 1 once daily at the same dose level prior to the dose holiday.
CDK4/6 Inhibitors
[0070] Palbociclib is a selective inhibitor of cyclin-dependent kinases CDK4 and CDK6, and has formula:
Figure imgf000023_0001
(otherwise known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-l-yl)pyri din-2 - yl]amino}pyrido[2,3-d]pyrimidin7(8H)-one). Palbociclib is approved for treatment of hormone receptor positive (e.g., HR+ or ER+) human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant. The complete prescribing information for palbociclib is found in the label for IBRANCE®, located at www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s0081bl.pdf, which is incorporated herein by reference in its entirety.
[0071] Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin DI and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma (Rb) protein phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest compared to treatment with each drug alone.
[0072] In some embodiments, a composition comprising palbociclib, or a pharmaceutically acceptable salt thereof, further comprises one or more pharmaceutically acceptable carriers or excipients. For example, 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. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms
22
SUBSTITUTE SHEET ( RULE 26) may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[0073] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and/or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
[0074] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings (i.e. buffering agents) and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [0075] In some embodiments, a composition comprising palbociclib further comprises one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells. [0076] Unless otherwise indicated, as used herein “palbociclib” refers to palbociclib 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 palbociclib means the amount of palbociclib in free base form. Accordingly, palbociclib may be provided and/or utilized as, e.g., a salt form of palbociclib such that the amount of the salt (or other form) is an amount that corresponds to the “free base equivalent” of palbociclib.
[0077] In some embodiments, palbociclib is administered to the subject in an amount that is from about 50 mg to about 150 mg. In some embodiments, palbociclib is administered to the subject in an amount that is from about 75 mg to about 125 mg. In some embodiments, palbociclib is administered to the subject in an amount that is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg. In some embodiments, palbociclib 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, palbociclib is administered to the subject in an amount that is about 75 mg. In some embodiments, palbociclib is administered to the subject in an amount that is about 100 mg. In some embodiments, palbociclib is administered to the subject in an amount that is about 125 mg.
[0078] In some embodiments, palbociclib is administered to the subject in an amount that is about 50 mg to about 150 mg per day (QD). In some embodiments, palbociclib is administered to the subject in an amount that is about 75 mg to about 125 mg per day (QD). In some embodiments, palbociclib is administered to the subject in an amount that is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg QD. In some embodiments, palbociclib is administered to the subject in an amount that is about 75 mg QD. In some embodiments, palbociclib is administered to the subject in an amount that is about 100 mg QD. In some embodiments, palbociclib is administered to the subject in an amount that is about 125 mg QD.
[0079] In some embodiments, palbociclib 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 50 mg to about 150 mg of palbociclib. In some embodiments, a unit dosage form comprises about 75 mg to about 125 mg of palbociclib. In some embodiments, a unit dosage form comprises about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg of palbociclib. In some embodiments, a unit dosage form comprises about 75 mg of palbociclib. In some embodiments, a unit dosage form comprises about 100 mg of palbociclib. In some embodiments, a unit dosage form comprises about 125 mg of palbociclib. In some embodiments, a unit dosage form is a capsule. In some embodiments, a unit dosage form is a tablet.
[0080] In some embodiments, a total daily dose of palbociclib administered to the subject is in an amount that is about 50 mg to about 150 mg per day (QD). In some embodiments, a total daily dose of palbociclib administered to the subject is about 75 mg to about 125 mg. In some embodiments, a total daily dose of palbociclib administered to the subject is in an amount that is about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, or about 125 mg QD. In some embodiments, a total daily dose of palbociclib administered to the subject is about 75 mg. In some embodiments, a total daily dose of palbociclib administered to the subject is about 100 mg. In some embodiments, a total daily dose of palbociclib administered to the subject is about 125 mg.
[0081] In some embodiments, palbociclib is administered to the subject once daily for 21 days of a 28-day cycle (i.e., once daily for 21-days followed by a 7-day dose holiday).
Combination Therapies
[0082] 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 palbociclib, or a pharmaceutically acceptable salt thereof.
[0083] The present disclosure encompasses the surprising synergies achieved by the combination of Compound 1 and palbociclib.
[0084] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject about 30 mg to about 300 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 50 mg to about 150 mg of palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition with a composition comprising about 60 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition with a composition comprising about 90 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition with a composition comprising about 120 mg Compound 1, or a pharmaceutically acceptable salt thereof, in combination with about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered daily for a 28 day cycle, and palbociclib is administered daily for 21 days of the 28-day cycle (i.e., the same 28 day cycle). In some embodiments, Compound 1 and palbociclib are administered for one, two, three, four, five, or more 28-day cycles.
[0085] It is understood that Compound 1 and palbociclib can be administered concomitantly or separately. For example, in some embodiments, Compound 1 and palbociclib are administered concomitantly. In some embodiments, palbociclib is administered prior to administration of Compound 1. In some embodiments, palbociclib is administered after administration of Compound 1.
[0086] In some embodiments, 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 palbociclib (e.g., according to a regimen provided herein). In some embodiments, the present disclosure provides a method comprising administering palbociclib to a subject who has received or is receiving Compound 1 (e.g., according to a regimen provided herein).
Kits
[0087] In some embodiments, the present disclosure provides a kit comprising one or more compositions comprising Compound 1, or a pharmaceutically acceptable salt thereof, and one or more compositions comprising palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, a kit comprises a composition that comprises about 30 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition that comprises about 50 mg to about 150 mg of palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, 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 125 mg of palbociclib, 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 125 mg of palbociclib, 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 125 mg of palbociclib, 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 palbociclib can be used for treating an estrogen-receptor mediated disease, disorder, or condition (e.g., breast cancer).
Exemplary Embodiments
1. A method of treating an estrogen receptor mediated disease, disorder, or condition in a subject comprising administering a composition comprising Compound 1
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof, in combination with a composition comprising palbociclib, or a pharmaceutically acceptable salt thereof.
2. The method of Embodiment 1, wherein Compound 1 is administered in an amount that is about 30 mg to about 300 mg.
3. The method of Embodiment 1 or 2, wherein palbociclib is administered in an amount that is about 50 mg to about 150 mg.
4. The method of any one of Embodiments 1-3, wherein Compound 1 is administered in an amount that is about 60 mg. 5. The method of any one of Embodiments 1-3, wherein Compound 1 is administered in an amount that is about 90 mg.
6. The method of any one of Embodiments 1-3, wherein Compound 1 is administered in an amount that is about 120 mg.
7. The method of any one of Embodiments 1-6, wherein palbociclib is administered in an amount that is about 125 mg.
8. The method of any one of Embodiments 1-7, wherein Compound 1 is administered once daily.
9. The method of any one of Embodiments 1-8, wherein palbociclib is administered once daily for 21 days, followed by a 7-day dose holiday.
10. The method of any one of Embodiments 1-9, wherein Compound 1 and palbociclib are administered concomitantly.
11. The method of any one of Embodiments 1-10, wherein the estrogen receptor-mediated disease, disorder, or condition is a cancer.
12. The method of Embodiment 11, wherein the cancer is breast cancer.
13. The method of Embodiment 11 or 12, wherein the cancer has metastasized to another organ.
14. The method of Embodiment 13, wherein the cancer has metastasized to the brain, bone, lungs, or liver. 15. The method of any one of Embodiments 1-14, wherein the subject has previously received at least one of a CDK4/6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.
16. A kit comprising a composition comprising Compound 1
Figure imgf000030_0001
or a pharmaceutically acceptable salt thereof, and a composition comprising palbociclib, or a pharmaceutically acceptable salt thereof.
17. The kit of Embodiment 16, wherein the composition that comprises Compound 1 comprises about 30 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
18. The kit of Embodiment 16 or 17, wherein the composition that comprises palbociclib comprises about 50 mg to about 150 mg of palbociclib, or a pharmaceutically acceptable salt thereof.
19. The kit of any one of Embodiments 16-18, wherein the kit comprises about 60 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
20. The kit of any one of Embodiments 16-18, wherein the kit comprises about 90 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
21. The kit of any one of Embodiments 16-18, wherein the kit comprises about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof. 22. The kit of any one of Embodiments 16-21, wherein the kit comprises about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof.
23. The kit of any one of Embodiments 16-22, wherein the kit further comprises packaging material that comprises a label which indicates that Compound 1 and palbociclib can be used for treating an estrogen-receptor mediated disease, disorder, or condition.
24. The kit of Embodiment 23, wherein the estrogen receptor-mediated disease, disorder, or condition is a cancer.
EXAMPLES
Example 1. A Phase 1 Dose Escalation and Dose Expansion Open-label, Multicenter, Study of Compound 1 in Combination with the CDK4/6 Inhibitor Palbociclib in Adult Subjects with Advanced or Metastatic HR-positive, HER2-negative Breast Cancer
[0088] The present example provides a phase 1 dose escalation and dose expansion open-label study to determine the maximum tolerated dose (MTD), and/or recommended phase 2 dose (RP2D) of Compound 1 in combination with palbociclib; characterize the safety and pharmacokinetic (PK) profde of the combination; and to estimate the preliminary anti-tumor activity of Compound 1 in combination with the cyclin dependent kinase (CDK) 4/6 inhibitor palbociclib in adult subjects with hormone receptor-positive (HR+/ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC). Treatment and study subject evaluation will be performed in 28-day cycles.
[0089] The present example comprises two parts:
[0090] Part 1 (Dose Escalation): This portion of the study will evaluate the safety and PK of a range of doses of Compound 1 administered orally (PO) to subjects in combination with palbociclib 125 mg PO, and to determine the RP2D of Compound 1. Part 1 will employ a dose escalation study design, whereby cohorts of 3 to 6 subjects will be sequentially enrolled and monitored for dose limiting toxi cities (DLTs) during the first cycle of study treatment.
[0091] Part 2 (Dose Expansion): This portion of the study further explores the safety and PK of Compound 1 at the RP2D in combination with palbociclib. Clinical activity of Compound 1 at the RP2D in combination with palbociclib will also be explored.
[0092] The objectives of the study are as described below for Part 1 (Dose Escalation). Primary Objectives
• To estimate the MTD and/or RP2D of Compound 1 when administered in combination with palbociclib.
• To assess the safety and tolerability of Compound 1 when administered in combination with palbociclib.
• To assess the PK of Compound 1 and palbociclib when administered in combination Exploratory Objectives
• To preliminarily assess the anti-tumor activity (objective response rate [ORR], defined as complete response [CR] + partial response [PR], clinical benefit rate [CBR], defined as CR + PR + stable disease [SD] for >24 weeks, and duration of response [DOR]) of Compound 1 when administered in combination with palbociclib in subjects with HR+/HER2- and wild type estrogen receptor 1 (wtESRl) or mutation in estrogen receptor 1 (mutESRl) MBC.
• To explore the effect of Compound 1 when administered in combination with palbociclib on the corrected QT interval (QTc) from electrocardiograms (ECGs) at baseline in comparison to those performed at various time points during the study.
• To evaluate the pharmacodynamic effects of treatment of Compound 1 when administered in combination with palbociclib on biomarkers in circulating tumor deoxyribonucleic acid (ctDNA).
[0093] The objectives of the study are as described below for Part 2 (Dose Expansion).
Primary Objectives
• To assess the safety and tolerability of Compound 1 at the RP2D when administered in combination with palbociclib.
• To assess the PK of Compound 1 at the RP2D when administered in combination with palbociclib.
Exploratory Objectives
• To conduct a preliminary assessment of the antitumor activity, based on the ORR, CBR, and DOR, of Compound 1 at the RP2D when administered in combination with palbociclib in subjects with HR+/HER2- and wtESRl and mutESRl MBC. • To explore the effect of Compound 1 at the RP2D when administered in combination with palbociclib on QTc from ECGs at baseline and to those performed at various time points during the study.
• To evaluate the pharmacodynamic effects of treatment with Compound 1 at the RP2D when administered in combination with palbociclib on biomarkers in ctDNA.
[0094] The endpoints of the study for Part 1 (Dose Escalation) are: Primary Endpoints
• Incidence of DETs during Cycle 1.
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0).
• Plasma levels of Compound 1 and palbociclib 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 and palbociclib concentrations at steady state.
Exploratory Endpoints
• ORR and CBR of Compound 1 when administered in combination with palbociclib, as assessed by the Investigator using the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST vl. l) in subj ects with HR+/HER2- and wtESRl ormutESRl MBC.
• DOR of Compound 1 when administered in combination with palbociclib in subjects with HR+/HER2-and wtESRl or mutESRl MBC.
• QTc at baseline, at the maximum plasma concentration on Cycle 1, Day 1 (C1D1), and at steady state will be evaluated by cohort.
• Biomarkers in ctDNA pre- and post-treatment with of Compound 1 when administered in combination with palbociclib (such as mutESRl, phosphoinositide 3-kinase alpha catalytic subunit [PIK3CA] variants, and others).
• Plasma levels of metabolites of Compound 1 at predefined intervals.
[0095] The endpoints of the study for Part 2 (Dose Expansion) are: Primary Endpoints
• Incidence of AEs and SAEs, as assessed using the NCI CTCAE v 5.0. • Overall response rate (ORR), as determined by the Investigator using RECIST vl. l, in subjects with HR+/HER2- and wtESRl or mutESRl MBC.
• Plasma levels of Compound 1 and palbociclib at pre-defined intervals to establish PK parameters (including Cmax, Cmin, Tmax, AUC, and tl/2) and Compound 1 and palbociclib concentrations at steady state.
Exploratory Endpoints
• Clinical benefit rate (CBR), as determined by the Investigator using RECIST vl.l, in subjects with HR+/HER2- and wtESRl or mutESRl MBC.
• DOR in subjects with HR+/HER2- and wtESRl or mutESRl MBC.
• In previously treated subjects, response to and duration of response to Compound 1 at the RP2D when administered in combination with palbociclib compared with the last prior systemic anti-cancer therapy.
• QTc at baseline, at the maximum plasma concentration on C1D1, and at steady state will be evaluated by cohort.
• Biomarkers in ctDNA pre- and post-treatment with Compound 1 at the RP2D when administered in combination with palbociclib (such as mutESRl, PIK3CA variants, and others).
• Plasma levels of Compound 1 metabolites at pre-defined intervals.
Inclusion Criteria
1. Female or male aged >18 years.
2. Willing and able to participate and comply with all study requirements and to provide signed and dated informed consent prior to initiation of any study procedures.
3. Histologically- or cytologically-confirmed locally advanced or MBC for which standard curative measures do not exist.
4. 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.
5. Willing to provide paraffin blocks or a minimum of 10 unstained slides of available archival tumor tissues from the most recently obtained tumor biopsy.
6. Received no more than 1 prior hormonal regimen for locally advanced or metastatic disease. (Hormonal regimens in combination with CDK4/6 inhibitors are allowed). able disease (measurable and non-measurable). expectancy >6 months, as judged by the Investigator. rn Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. ling to adhere to the following: a. If male, agrees 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, 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. b. If a female of childbearing potential, meets all of the following criteria:
• Not pregnant.
• Not breastfeeding.
• 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, 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.
A female subject is considered to be of childbearing 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) while off drugs that interfere with ovarian function.
• Pre- or peri -menopausal female subjects must be willing to take a luteinizing horm one- releasing hormone (LHRH) agonist >2 weeks before first study drug administration and for the duration of the study. 11. No proton pump inhibitor (PPI) use for 7 days prior to first study drug administration and agrees to refrain from PPI therapy for the duration of the study.
12. Has a corrected QT interval <470 ms for females and <450 ms for males (as calculated by the Fridericia correction formula [QTcF]).
13. Subjects must not have received prior endocrine or targeted therapy <2 weeks prior to the first administration of study drug (including fulvestrant, alpelisib, everolimus, CDK4/6 inhibitors, phosphoinositol-3 -kinase [PI3K] inhibitors, or poly ADP -ribose polymerase [PARP] inhibitors).
14. No chemotherapy, antibody therapy, or investigational therapy <4 weeks prior to the first study drug dose.
15. Prior radiotherapy must have been completed at least 2 weeks prior to start of Cycle 1 with recovery of toxicity <Grade 1 (except for alopecia).
16. At least 4 weeks prior to administration of the first dose of study drug from major surgery with recovery.
17. 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.
18. Has the following laboratory values within 28 days before the first study drug dose: a. Serum creatinine < the upper limit of normal (ULN) or, if higher than the normal range, calculated creatinine clearance (CrCl) must be >50 mL/min (e.g., by Cockcroft-Gault formula). Actual body weight must be used for CrCl, unless body mass index (BMI) >30 kg/m2, in which case, lean body weight must be used; b. Total bilirubin <1.5 x ULN unless prior history of Gilbert’s syndrome; c. Aspartate transaminase (AST) and alanine transaminase (ALT) <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. Platelet count >100 x 109 cells/L; f. Absolute neutrophil count (ANC) >1.5 x 109 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 (aPTT) < 1.5 x ULN. If on chronic anticoagulation, the PT and aPTT must be in the therapeutic range 19. The subject must have received no more than 1 prior chemotherapy regimen for locally advanced or metastatic disease.
20. 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.
Exclusion Criteria
1. 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 medical monitor.
2. Primary hormonal refractory disease as defined by progression in <6 months of a prior continuous endocrine therapy for locally advanced or MBC, progression during adjuvant hormonal therapy, or within 12 months of stopping adjuvant hormonal therapy.
3. 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 mm Hg and/or diastolic blood pressure >100 mm Hg while on anti-hypertensive medications).
4. Myocardial infarction or unstable angina within 6 months prior to the first administration of study drug.
5. History of cerebral vascular disease within 6 months prior to the first administration of study drug.
6. Active infection that requires antimicrobial therapy or is clinically significant.
7. History of leptomeningeal disease or spinal cord compression.
8. History of allergic reactions attributed to compounds of similar chemical composition to Compound 1 or palbociclib.
9. Requires concomitant use of strong cytochrome P450 (CYP) 3A4 inhibitors or inducers.
10. Requires medications with known risk of QT interval prolongation or increased risk of Torsades de Pointes 11. 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.)
12. History of pneumonitis or interstitial lung disease (ILD).
13. Medical history or ongoing gastrointestinal (GI) disorders that could affect absorption of Compound 1 or palbociclib (such as active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper GI surgery, including gastric resection, and including difficulty swallowing capsules).
14. Known human immunodeficiency virus (HIV) infection.
15. Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (eg, hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis.
16. Subject has clinically significant co-morbidities, such as 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.
[0096] The number of subjects planned for each part are provided below:
[0097] Part 1 (Dose Escalation): Approximately 12 to 18 evaluable subjects are planned to be enrolled in Part 1; 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 before completing Cycle 1 (Cl) for reasons other than DLT are to be replaced.
[0098] Part 2 (Dose Expansion): Approximately 12 to 18 evaluable subjects are to be enrolled in Part 2. Subjects who discontinue from Part 2 before completing at least 2 cycles of therapy and at least 1 post-baseline disease response assessment are to be replaced.
Study Treatment
[0099] 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 use to make up the appropriate dose for each dose cohort.
[0100] Palbociclib will be supplied in boxes of 21 tablets. Each box contains 3 blister cards each with 7 tablets. Dose strengths are 125 mg, 100 mg, and 75 mg. [0101] Subjects are to take Compound 1 capsules PO once daily (QD) in the morning at approximately the same time of day on an empty stomach. Subject should be fasted for 2 hours before Compound 1 administration and remain fasting, with the exception of the water allowed for taking the study drug, until 1 hour after dosing. 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). If a subject vomits after taking Compound 1, the dose should NOT be re-administered that day and standard anti-emetic measures should be taken prior to the next daily dose. Cycles are repeated every 4 weeks (28 days). [0102] Compound 1 capsules should be swallowed with water (approximately 8 ounces or 240 mL) without chewing or sucking the capsule.
[0103] Compound 1 will be administered in combination with palbociclib. Subjects should take their palbociclib dose at the same time each day with administration of Compound 1. Subjects should take their palbociclib dose at the same time each day, with or without food, as per the instructions in the package insert. Compound 1 should be taken first, on an empty stomach, followed by palbociclib (without food). If a subject prefers to take palbociclib with food, palbociclib dosing must then occur at least 1 hour after Compound 1 dosing. After C3D15, when PK assessments have been completed, Compound 1 and palbociclib can be taken at different times of the day (e.g., Compound 1 will be taken in the morning and palbociclib will be taken in the evening). Dose modifications of palbociclib will be per the instructions in the package insert. If palbociclib doses are required to be held, they will not be replaced thus maintaining the treatment schedule of daily dosing for the first 21 days in a 28-day cycle. The starting dose of palbociclib will be per the package insert at 125 mg PO daily for 21 days (i.e., the first 21 days in every 28 day cycle). If palbociclib doses are required to be held, they will not be replaced, thus maintaining the treatment schedule of daily dosing for the first 21 days in a 28-day cycle.
[0104] Palbociclib tablets should be swallowed whole, and not chewed, crushed, or split before swallowing.
[0105] 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). [0106] If the subj ect vomits after taking palbociclib, this should be documented in the subj ect’ s source document or dosing diary, and palbociclib should not be re-administered that day (ie, dosing can resume at the time of the next scheduled daily dose).
[0107] Dose escalation of Compound 1 will be as per the dosing table below and will follow a 3+3 design. See Storer BE., Biometrics, 1989;45(3):925-937. Part 1 (Dose Escalation) levels are provided in the table below for Compound 1
Figure imgf000040_0001
[0108] The available safety and PK data will be reviewed, and intermediary dose levels may be tested. Dose escalation to a maximum Compound 1 dose of 210 mg QD is planned.
[0109] Part 1 Dose Escalation Rules: The following 3 + 3 dose-escalation rules noted below will be followed. The DLT observation period is Cycle 1 (Cl). Cohorts of 3 subjects will be treated at each dose level. In the 3 + 3 design, 3 subjects will be concurrently enrolled at each dose level in the study. If 0 of 3 subjects develop a DLT, then subjects will be enrolled in the next highest dose level. If 1 of 3 subjects develops a DLT, 3 additional subjects will be enrolled at that dose level. If 2 or more of 6 subjects develop a DLT then the MTD has been exceeded and subjects will be enrolled at the next lowest dose level. The decision to escalate to the next highest dose level will made by the Investigators participating in the phase 1 study and representatives of the Sponsor at a cohort review meeting after all subjects enrolled in that cohort have completed Cycle 1. Intra-patient dose escalation is not permitted.
Maximum Tolerated Dose Determination and Cohort Expansion
Figure imgf000041_0001
Definition of DLT
[0110] A DLT is defined as the occurrence of any of the following TEAEs graded by the Investigator per the NCI CTCAE v5.0 during Cl, except those that are clearly due to disease progression (PD) or extraneous causes:
• Any TEAE with a fatal outcome (ie, Grade 5 TEAE) not clearly due to the underlying disease or extraneous causes.
• Grade >3 neutropenia accompanied with fever and/or infection.
• Grade 3 thrombocytopenia associated with bleeding.
• Grade 4 hematologic toxicity, with the exception of neutropenia.
• >Grade 3 nausea and/or vomiting and/or diarrhea not resolving within 72 hours with optimal treatment.
• AST or ALT >3 x ULN and a total bilirubin >2 x 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 >8 x ULN or AST or ALT >5 x ULN for >14 days. • ALT or AST >3 x 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 3 non-hematologic toxicity.
• >Grade 2 TEAEs resulting in study drug interruption for >7 days during C 1 or delay of C2 for >7 days.
[0111] Multiple concurrent TEAEs in an individual subj ect meeting the definition of DLT will be considered a single DLT.
[0112] Subjects must receive at least 75% (at least 21 of 28 doses) of planned Compound 1 doses and 75% of palbociclib doses (at least 16 of 21 doses) in Cl in order to be evaluated for determination of DLT. Subjects receiving less than 75% of the planned dose of either drug 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.
Definition of MTD or RP2D
[0113] For purposes of defining the MTD and/or RP2D of Compound 1 in combination with palbociclib, subjects will be evaluated according to the actual starting dose of Compound 1 during Cl. For most subjects, this will be the dose cohort to which they were assigned. Subjects who receive at least 75% (at least 21 of 28 doses) of the planned doses in Cl will be considered to have sufficient safety data/follow-up to support dose escalation. 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. In such cases, replacement subjects may be enrolled to receive the same starting dose of Compound 1 as the subjects who withdraw prematurely.
[0114] The MTD is defined as the highest feasible dose tested in which <33% (i.e., <1 of 6) subjects experienced a DLT attributable to the study drug, when at least 6 subjects were treated at that dose and were assessable for toxicity.
[0115] The RP2D will be determined after review of all the available safety and PK data. [0116] 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. To assess change from baseline, a baseline measurement is also required.
Duration of Treatment
[0117] In the absence of unacceptable treatment-related toxicity or disease progression, subjects may receive study treatment for up to 1 year and beyond 1 year with the agreement of the Investigator and the Sponsor. Subjects who discontinue Compound 1 must also discontinue palbociclib within the context of this protocol.
[0118] Treatment will continue until any 1 of the following occurs:
• SAE or adverse event (AE) that require dose discontinuation as described in the table, Dose Modification or Treatment Delay for Compound 1 -related TEAEs.
• PD, as determined by RECIST 1.1.
• Initiation of non-protocol anti-cancer therapy.
• Illness or condition that may interfere with the subj ect’ s participation or require treatment discontinuation.
• Investigator’s determination that continuation of protocol therapy is not in the subject’s best interests.
• Pregnancy.
• Non-compliance.
• Voluntary withdrawal of consent.
• Sponsor termination of the study.
Reference Therapies, Dose, Route, and Regimen
Palbociclib
[0119] Palbociclib 125 mg QD will be administered for 21 days in 28-day cycles. Subjects should take their Compound 1 and palbociclib dose at the same time each day. Subjects will take palbociclib and Compound 1 in a fasted state (subject should be fasting for at least 2 hours before and remain fasting, with the exception of the water allowed to take the study drug, until 1 hour after dosing). [0120] Palbociclib (IBRANCE®) is a commercially available kinase inhibitor indicated for the treatment of adult subjects with HR+/HER2- advanced or MBC in combination either with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men, or fulvestrant in subjects with disease progression following endocrine therapy.
[0121] Palbociclib is supplied as 125 mg, 100 mg, and 75 mg tablets.
Criteria for Evaluation
[0122] Safety: Safety will be assessed by periodic physical examinations, 12-lead ECGs, clinical laboratory assessments, and monitoring of AEs.
[0123] 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 with each cohort. Participating Investigators and the Sponsor’s Medical Monitor will review study drug-related toxicities from the current cohort during the site teleconferences before escalating to the next dose. [0124] Pharmacokinetics: The PK profde will be assessed by determining the plasma levels of Compound 1 and palbociclib at the intervals indicated in the Schedule of Events.
[0125] Predictive and Pharmacodynamic Markers of Compound 1 Activity: Biomarkers that may predict Compound 1 and palbociclib activity will be evaluated in archival tumor tissues. These include quantitative levels of ER and progesterone receptor (PR) by immunohistochemistry (percent cells positive and Allred score), phosphoinositide 3 -kinase alpha catalytic subunit (PI3KCA), phosphatase variants, and potentially other biomarkers. Biomarkers of interests in ctDNA will be measured at baseline and over time including mutESRl that may be pharmacodynamic and predictive markers of Compound 1 and palbociclib activity.
[0126] Efficacy: 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 8 weeks starting from the first day of study treatment (i.e., after 2 cycles of treatment). Subjects who have been determined to have obtained a clinical benefit from study treatment as determined by the treating Investigator may decrease the frequency of radiographic and physical assessments of malignancy to every 12 weeks after the 32-week (8-month, and typically 8 cycles of treatment) radiographic assessment. ORR and CBR, as determined by the subject’s best tumor response, DOR, and time to progression will be assessed by the Investigator using RECIST 1.1. 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 to confirm the response.
Statistical Methods
[0127] Safety Analyses: Safety data analysis will be conducted on all subjects receiving at least 1 dose of the study drug. Summarization of DLTs will be conducted on DLT evaluable subjects. The safety data from the dose-escalation phase will be summarized by dose cohort. Safety will be assessed through summaries of AEs, laboratory test results, vital signs, and ECOG PS. AEs will be classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) with severities classified using the NCI CTCAE criteria.
[0128] All collected AE data will be listed. Separately, all SAEs will also be listed. All TEAEs regardless of attribution will be summarized by cohort, as follows:
• All DLTs (regardless of grade).
• All TEAEs (regardless of grade or attribution).
• All Grade 3/4/5 TEAEs.
• All drug-related TEAEs (regardless of grade).
• All TEAEs leading to study drug or study discontinuations.
• All SAEs, including deaths.
• All TEAEs of special interest (regardless of grade).
[0129] Efficacy Analyses: The number and percentage of subjects experiencing an objective response (CR + PR) will be summarized. The duration of objective response will be summarized descriptively using the Kaplan-Meier method. The DOR is defined as time from first documentation of tumor response to PD. CBR also will be summarized.
[0130] Pharmacokinetic Analyses: PK parameters, including AUC, Cmax, Cmin, Tmax, and tl/2 will be determined. Comparisons across dose levels will be made to assess proportionality. In addition, comparison between single dose and multi-dose PK parameters will be made for assessment of steady-state drug accumulation.
[0131] Pharmacodynamic/Biomarker Analyses: 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: Data From a Phase lb Escalation Study of Compound 1 in Combination with Palbociclib in Patients with Advanced and/or Metastatic Estrogen Receptor (ER)-Positive, HER2-Negative Breast Cancer
[0132] Compound 1 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER-driven transcriptional activity. CDK4/6 inhibitors in combination with endocrine therapy have improved progression free survival and overall survival for patients with metastatic breast cancer (MBC) in the first and second line settings. However, most patients will progress and newer combinations such as with Compound 1 may provide improved clinical outcome. Compound 1 potently inactivates both wildtype ER and mutant forms of ER. The latter confers ligand independent activity and is a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, Compound 1 in combination with palbociclib demonstrated synergistic activity in models of wild-type ER and those containing ESRI activating mutations, and in models of brain metastasis. A Phase 1/2 monotherapy study of Compound 1 is ongoing in MBC subjects who have received 1 or more prior endocrine therapies. Monotherapy is well tolerated with a RP2D of 120 mg QD. The aim of this combination study is to define the maximum tolerated dose (MTD), safety, tolerability, and pharmacokinetics (PK) of Compound 1 in combination with palbociclib.
[0133] Methods: Key eligibility criteria include patients with MBC or locally advanced breast cancer who have received no more than 1 prior line of endocrine therapy (prior CDK4/6 inhibitors and one line of chemotherapy are permitted) and measurable or non-measurable disease. Using a 3+3 design, cohorts are sequentially enrolled and patients receive escalating doses of Compound 1 orally QD continuously in combination with 125 mg of palbociclib orally for 21 of 28 days. Patients will be evaluated for dose limiting toxicities (DLTs) if >75% of both treatments were administered within the first treatment 28-day treatment cycle. Blood is collected for PK on cycle 1 day 1, 2 and cycle 2 day 15, 16 for Compound 1 and cycle 1 day 15 for palbociclib. PK profiles, exposure parameters, and drug-drug interactions (DDIs) are assessed. Patients are monitored for adverse events (AE), and tumor assessments (RECIST 1.1) are conducted every two cycles.
[0134] Results: As of a first cutoff date, nine patients have been enrolled into dose levels 30 mg, 60 mg, and 90 mg of Compound 1 in combination with palbociclib. There were no DLTs at the 30, 60, or 90 mg dose level. The most common Grade 1/2 treatment emergent adverse events (TEAE), which occurred in 2 patients, were nausea, gastroesophageal reflux, vomiting, and fatigue. Grade 3 neutropenia occurred in 4 patients. No Grade 4 events were observed. Compound 1 was highly bioavailable and showed dose proportional exposure in combination with palbociclib. The single and multiple dose exposure of Compound 1 was consistent with that observed in the monotherapy study, indicating an absence of effect of palbociclib on Compound 1 PK. 90 mg steady-state evaluation is ongoing. Palbociclib concentrations at steady state did not demonstrate a meaningful difference from published exposure parameters for the three dose levels evaluated, indicating an absence of DDL
[0135] Conclusions: In the first three cohorts of Compound 1 and palbociclib, the combination was well tolerated and no DLTs occurred. There were no clinically significant DDIs observed between Compound 1 and palbociclib at the doses evaluated and exposure of each drug was consistent with observed monotherapy exposure levels. Dose escalation of Compound 1 in combination with palbociclib continues with enrollment to Compound 1 at 120 mg followed by dose expansion.
Example 3: A Phase lb/2 Study of Compound 1 in Combination with Palbociclib in Patients with Advanced or Metastatic Estrogen Receptor (ER)-Positive, HER2-Negative Breast Cancer
[0136] The present example describes results, such as pharmacokinetic, drug-drug interaction, safety, and anti -turn or activity data, from a Phase lb/2 study of Compound 1 in combination with palbociclib, as described in Example 1.
Introduction
[0137] Addition of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors to endocrine therapy has improved outcomes in patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (MBC) and is the current standard of care for first-line treatment (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer. V2.2023). Resistance to this first-line treatment eventually develops with mutations in estrogen receptor 1 (ESRI) constituting the most common mechanism (Rasha F, et al. Mol Cell Endocrinol. 2021;532:111322). The ability to suppress the activity of both wild-type and ESRI mutant estrogen receptors (ER) represents the potential to significantly improve upon current standard of care. Compound 1 is a complete ER antagonist (CERAN) and selective ER degrader (SERD), which blocks both the AF1 and AF2 transcriptional activation domains of the ER (FIG. 1) (Alemany C, et al. Presented at AACR-NCI-EORTC. October 7-10, 2021). Compound 1 has demonstrated activity in both ESRI wild-type and ESRI mutant pre-clinical models. Results from an ongoing phase 1/2 study with Compound 1 as monotherapy demonstrated acceptable safety, good tolerability, and a pharmacokinetics profile supportive of once-daily oral dosing in patients with HR+/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or MBC. Obj ective tumor responses and prolonged disease stabilizations were demonstrated in these heavily pretreated patients (Hamilton E, et al. Presented at EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium. October 26-29, 2022. Poster number 101). Previous data from the open-label, phase 1/2 study with Compound 1 in combination with the CDK4/6 inhibitor palbociclib in patients with HR+/HER2-negative MBC established the recommended phase 2 dose (RP2D) (Chan A, et al. Presented at San Antonio Breast Cancer Conference. Dec 6-10, 2022. Poster number 101). The present example provides additional pharmacokinetic (PK), DDI, safety, and anti -turn or activity data from this study, with longer follow-up and an additional 17 patients enrolled in the dose-expansion cohort.
Methods
[0138] The present example describes an open-label phase lb/2 dose-escalation and doseexpansion study (FIG. 2). Eligible patients were women (regardless of menopausal status) or men with HR+, HER2- advanced or metastatic breast cancer. Eligible patients had zero or one prior endocrine therapy (with or without CDK4/6 inhibitor) for locally advanced or metastatic disease. One prior line of chemotherapy for advanced or metastatic disease was allowed. Eligible patients had evaluable (measurable or non-measurable) disease by RECIST 1.1 criteria.
Results
Patient Population
[0139] As of a second cutoff date, 29 patients were enrolled in the study (Table 1). The doseescalation part of the study included three patients in each of four dose cohorts: Compound 1 at 30 mg, 60 mg, 90 mg, and 120 mg once daily on every day of a 28-day treatment cycle, plus palbociclib 125 mg once daily on days 1-21 of each 28 day treatment cycle (Table 2). Seventeen patients have been enrolled in the dose-expansion part of the study receiving Compound 1 120 mg plus palbociclib 125 mg, with total planned enrollment of ~45 patients. 24 (83%) patients had received prior endocrine therapy for advanced disease. 20 (69%) patients had received prior treatment with CDK4/6 inhibitors for advanced disease (palbociclib, n=14; ribociclib, n=5; both palbociclib and ribociclib, n=l).
Table 1: Patient Demographics and Disease Characteristics
Figure imgf000049_0001
Data are n (%) or n/N (%) unless otherwise specified. aOne patient received chemotherapy, endocrine therapy and olaprib. b ctDNA from 18 patients was available at the time of data cutoff for ESRI mutation evaluation. CDK, cyclin-dependent kinase; ctDNA, circulating tumor DNA; ECOG, Eastern Cooperative Oncology Group.
Table 2: Patient Disposition
Figure imgf000049_0002
Figure imgf000050_0001
Data are shown in n or n (%).
Safety
[0140] No DLTs were observed during the dose escalation portion of the study. As of a second data cutoff date, most treatment-emergent adverse events (TEAEs) were grade 1 or 2 (Table 3). There were no dose-related increases in incidence or severity of TEAEs. There were no treatment- related fatal events. No patients discontinued treatment due to TEAEs. The most common TEAEs (>20% of patients) included neutropenia, gastrointestinal events (nausea, vomiting, constipation, diarrhea, gastroesophageal reflux disease), and thrombocytopenia (Table 3).
Table 3: Treatment-emergent Adverse Events Reported in >20% of Patients
Figure imgf000050_0002
Data shown are n or n (%).
GERD, gastroesophageal reflux disease.
[0141] Five serious adverse events occurred: grade 2 malignant pleural effusion (n=l), grade 3 colitis (n=l), grade 4 neutropenia (n=2), and grade 5 multiple organ dysfunction syndrome (n=l). Except for neutropenia in 1 subject considered related to Compound 1 and palbociclib, all other serious adverse events were considered by the investigator as not related to Compound 1. Grade 3 or 4 neutropenia was reported in 16 (55%) patients. 14 (48%) patients had grade 3 neutropenia, all occurring during the first treatment cycle and all assessed as related to palbociclib in all patients and possibly related to Compound 1 in 6 patients. 2 (7%) patients had grade 4 neutropenia, both starting at week 4. In one patient neutropenia was assessed as related to palbociclib and unrelated to Compound 1. In the other patient, neutropenia was assessed as related to palbociclib and possibly related to Compound 1. 6 patients had dose reductions of palbociclib due to neutropenia. No patients had dose reductions of Compound 1 for neutropenia. Neutropenia was reversible in all patients and the timing was consistent with palbociclib-related neutropenia.
Pharmacokinetics
[0142] There were no drug-drug interactions (DDIs) between palbociclib and Compound 1 in the dose range of Compound 1 30 to 120 mg and palbociclib 125 mg. Compound 1 did not affect palbociclib (125 mg) exposure when compared with published concentrations for single-agent palbociclib (FIG. 3) (Pfizer Inc. Pfizer Canada ULC. 2021. Available at: https://www.pfizer.ca/files/Ibrance_PM_EN_243405_15-Jul-2021.pdf (accessed 30 March 2023).). The geometric mean parameters of palbociclib for each of the combination dose levels were within the geometric mean ± GeoSD of the reference data. Palbociclib did not affect Compound 1 PK; the rate and extent of absorption and half-life were consistent with single agent Compound 1 (Table 4 and FIG. 4). Compound 1 was readily bioavailable and demonstrated doseproportional exposure and a long half-life. Steady-state plasma levels showed minimal peak-to- trough variability, enabling consistent steady state target coverage.
Table 4: Compound 1 PK in Combination with Palbociclib (125 mg) at Steady State
Figure imgf000051_0001
Data shown are GeoMean (GeoCV%) or Median (minimum-maximum). Plasma samples for Compound 1 assessment were collected on Cl day (D) 1 (C1D1), C1D2/D8/D15, C2D15/D16, C3D1/D15, C5D1, C7D1, and C9D1. For palbociclib, they were collected on C1D15, C2D15, and C3D15. AUC0-24, area under the concentration time curve from 0 to 24 h; Cavg, average concentration; Cmax, maximum concentration; Cmin, minimum concentration; Tmax, time to maximum concentration.
Efficacy
[0143] Partial responses were observed in five patients (one confirmed; four unconfirmed) (FIG. 5). Stable disease was observed in 9 patients. 4 patients had stable disease for > 24 weeks. Clinical benefit rate was 41.7% (5/12 patients). 17 (59%) patients remained on treatment as of a second cutoff date. The longest duration of treatment was 56 weeks and ongoing. Attorney Docket No. 2012034-0258
Conclusions
[0144] The combination of Compound 1 30-120 mg with palbociclib 125 mg was shown to be safe and well-tolerated. No new safety signals were identified. There were no dose-related increases in the incidence, severity, or timing of adverse events. The incidence and severity of adverse events were consistent with the expected safety profile of palbociclib plus endocrine therapy and were similar, including neutropenia, to those reported with palbociclib plus letrozole in the PALOMA 2 study (Ibrance Package Insert. Pfizer Inc. 2019, Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s0081bl.pdf (Accessed April 28, 2023)): all grades neutropenia 80%, G3 neutropenia in 56% and G4 neutropenia in 10%. Tumor responses and prolonged disease stabilization were observed in this group of patients, including in patients who were previously exposed to CDK4/6 inhibitors. No DDI between Compound 1 and palbociclib was observed: there was no induced metabolism or increase in exposure of palbociclib when administered in combination with Compound 1; when administered in combination with palbociclib, Compound 1 exposure was consistent with the observed exposure of Compound 1 monotherapy.
[0145] The embodiments of the disclosure described above are intended to be merely exemplary, numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.
SUBSTITUTE SHEET ( RULE 26)

Claims

1. A method of treating an estrogen receptor mediated disease, disorder, or condition in a subject comprising administering a composition comprising Compound 1
Figure imgf000053_0001
or a pharmaceutically acceptable salt thereof, in combination with a composition comprising palbociclib, or a pharmaceutically acceptable salt thereof, wherein Compound 1 is administered in an amount that is about 30 mg to about 300 mg and palbociclib is administered in an amount that is about 50 mg to about 150 mg.
2. The method of claim 1, wherein Compound 1 is administered in an amount that is about
60 mg.
3. The method of claim 1, wherein Compound 1 is administered in an amount that is about
90 mg.
4. The method of claim 1, wherein Compound 1 is administered in an amount that is about
120 mg.
5. The method of any one of claims 1-4, wherein palbociclib is administered in an amount that is about 125 mg.
6. The method of any one of claims 1-5, wherein Compound 1 is administered once daily.
7. The method of any one of claims 1 -6, wherein palbociclib is administered once daily for 21 days, followed by a 7-day dose holiday.
8. The method of any one of claims 1-7, wherein Compound 1 and palbociclib are administered concomitantly.
9. The method of any one of claims 1-8, wherein the estrogen receptor-mediated disease, disorder, or condition is a cancer.
10. The method of claim 9, wherein the cancer is breast cancer.
11. The method of claims 9 or 10, wherein the cancer has metastasized to another organ.
12. The method of claim 11, wherein the cancer has metastasized to the brain, bone, lungs, or liver.
13. The method of any one of claims 1-12, wherein the subject has previously received at least one of a CDK4/6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.
14. A kit comprising a composition comprising Compound 1
Figure imgf000054_0001
or a pharmaceutically acceptable salt thereof, and a composition comprising palbociclib, or a pharmaceutically acceptable salt thereof, wherein the composition that comprises Compound 1 comprises about 30 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt thereof, and the composition that comprises palbociclib comprises about 50 mg to about 150 mg of palbociclib, or a pharmaceutically acceptable salt thereof.
15. The kit of claim 14, wherein the kit comprises about 60 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
16. The kit of claim 14, wherein the kit comprises about 90 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
17. The kit of claim 14, wherein the kit comprises about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
18. The kit of any one of claims 14-17, wherein the kit comprises about 125 mg of palbociclib, or a pharmaceutically acceptable salt thereof.
19. The kit of any one of claims 14-18, wherein the kit further comprises packaging material that comprises a label which indicates that Compound 1 and palbociclib can be used for treating an estrogen-receptor mediated disease, disorder, or condition.
20. The kit of claim 19, wherein the estrogen receptor-mediated disease, disorder, or condition is a cancer.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016097072A1 (en) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
WO2019144132A1 (en) * 2018-01-22 2019-07-25 Radius Pharmaceuticals, Inc. Estrogen receptor-modulating compounds
WO2020037203A2 (en) * 2018-08-17 2020-02-20 Genentech, Inc. Diagnostic and therapeutic methods for the treatment of breast cancer
WO2021007146A1 (en) * 2019-07-07 2021-01-14 Olema Pharmaceuticals, Inc. Regimens of estrogen receptor antagonists
WO2021178846A1 (en) * 2020-03-06 2021-09-10 Olema Pharmaceuticals, Inc. Methods of treating estrogen receptor-associated diseases

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016097072A1 (en) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
WO2019144132A1 (en) * 2018-01-22 2019-07-25 Radius Pharmaceuticals, Inc. Estrogen receptor-modulating compounds
WO2020037203A2 (en) * 2018-08-17 2020-02-20 Genentech, Inc. Diagnostic and therapeutic methods for the treatment of breast cancer
WO2021007146A1 (en) * 2019-07-07 2021-01-14 Olema Pharmaceuticals, Inc. Regimens of estrogen receptor antagonists
WO2021178846A1 (en) * 2020-03-06 2021-09-10 Olema Pharmaceuticals, Inc. Methods of treating estrogen receptor-associated diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FANNING SEAN W, GREENE GEOFFREY L: "Next-Generation ERα Inhibitors for Endocrine-Resistant ER+ Breast Cancer", ENDOCRINOLOGY, vol. 160, no. 4, 1 April 2019 (2019-04-01), pages 759 - 769, XP093132363, ISSN: 1945-7170, DOI: 10.1210/en.2018-01095 *

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