WO2023172909A1 - Compositions comprenant des anti-progestines et des modulateurs sélectifs des récepteurs des oestrogènes et leurs procédés d'utilisation - Google Patents

Compositions comprenant des anti-progestines et des modulateurs sélectifs des récepteurs des oestrogènes et leurs procédés d'utilisation Download PDF

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WO2023172909A1
WO2023172909A1 PCT/US2023/063858 US2023063858W WO2023172909A1 WO 2023172909 A1 WO2023172909 A1 WO 2023172909A1 US 2023063858 W US2023063858 W US 2023063858W WO 2023172909 A1 WO2023172909 A1 WO 2023172909A1
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cancer
progestin
administered
onapristone
estrogen receptor
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PCT/US2023/063858
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English (en)
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Martin Lehr
Evan DICK
Tarek SAHMOUD
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Context Biopharma Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • a pharmaceutical composition comprises an anti-progestin, or a pharmaceutically acceptable salt or solvate thereof; and a selective estrogen receptor modulator, or a pharmaceutically acceptable salt or solvate thereof.
  • Estrogen receptor or "ER” as used interchangeably herein refers to a receptor that isactivated by the hormone estrogen and is a member of the nuclear hormone family of intracellular receptors. There are two different isoforms of estrogen receptor, referred to as a (also referred to as “ERa”) and P (also referred to as “ERb”). ERa and ERb genes are encoded by ESRI and ESR2 gene, respectively. Hormone-activated estrogen receptors form dimers and may form homodimers or heterodimers. Both ERs are widely expressed in different tissue types.
  • Elacestrant surprisingly has the ability to degrade the estrogenreceptor. Both in vitro and in vivo studies have since shown that the antagonist activity of this ligand correlates with estrogen receptor degradation in a dose dependent manner. Elacestrant also inhibits estrogen dependent growth of breast cancer xenograft tumors and may be used totreat breast cancer, such as tamoxifen resistant breast cancer.
  • SERMs such as tamoxifen have low brain penetration and have exhibited efficacy in anecdotal cases of BCBM that are detailed in the literature
  • the SERD activity of elacestrant becomes key to the therapeutic potential of this compound for treatment of BCBM, as SERDs have been found to be effective in breast cancers that are resistant to SERM or aromatase inhibitor therapy.
  • Onapristone is an anti-progestin drug and progesterone receptor antagonist which was originally developed for potential contraceptive use and the use in benign gynecological disorders such as the treatment of uterine leiomyomas.
  • ONA binds to the progesterone receptor (PR), preventing the PR from binding to DNA and thereby inhibiting or eliminating PR-induced DNA transcription.
  • PR progesterone receptor
  • progesterone receptor [0041] Expression of the progesterone receptor (PR) has been described in breast, endometrial, prostate, ovarian, and several other cancers. Anti progestins have been shown to have an inhibitory effect on the growth of different type of cancer cells, and antiprogestin treatment has been studied in breast, endometrial, and prostate cancers and uterine sarcomas.
  • the effects of progesterone are mediated by two distinct nuclear receptor proteins, PRA and PRB, two transcriptional isoforms of the single PR gene. In luminal epithelial cells of the normal breast and in normal endometrium, both PR isoforms are expressed and are required to mediate the physiological effects of progestin ligands. The two PR isoforms have both been detected in malignant tissues, such as breast, endometrial, ovarian and prostate cancers.
  • the ratio of anti-progestin to excipient is about 0.01% w/w to about 1% w/w. In some embodiments, the ratio of anti-progestin to excipient is about 0.01% w/w to about 0.1% w/w. In some embodiments, the ratio of anti-progestin to excipient is about 0.05% w/w to about 25% w/w. In some embodiments, the ratio of anti-progestin to excipient is about 0.05% w/w to about 20% w/w. In some embodiments, the ratio of anti-progestin to excipient is about 0.05% w/w to about 15% w/w.
  • the hydroxypropyl methylcellulose is present at about 2% w/w of the composition. In some embodiments, the hydroxypropyl methylcellulose is present at about 5% w/w of the composition. In some embodiments, the hydroxypropyl methylcellulose is present at about 10% w/w of the composition. In some embodiments, the hydroxypropyl methylcellulose is present at about 15% w/w of the composition. In some embodiments, the hydroxypropyl methylcellulose is present at about 20% w/w of the composition. In some embodiments, the hydroxypropyl methylcellulose is present at about 25% w/w of the composition. In some embodiments, the hydroxypropyl methylcellulose is present at about 26% w/w of the composition.
  • the polymorphic or crystalline forms of onapristone as provided for herein also encompass derivatives.
  • the term "derivative” includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like. Methods of preparing these derivatives are known to a person skilled in the art. For example, ether derivatives are prepared by the coupling of the corresponding alcohols. Amide and ester derivatives are prepared from the corresponding carboxylic acid by a reaction with amines and alcohols, respectively.
  • the stable crystalline form of onapristone exhibits an x- ray powder diffraction pattern (XRPD) having characteristic peaks expressed in degrees 2- theta at approximately 21.22, 12.82, 14.34, 16.14, 18.58, 18.18, 16.78, 11.66, 24.02, and 9.74 with a peak tolerance of +/- 0.2 degrees 2-theta.
  • XRPD x- ray powder diffraction pattern
  • the dosage form is a suspension. In some embodiments, the dosage form is a wafer. In some embodiments, the anti-progestin is onapristone and the dosage form is selected from the group consisting of pill, tablet, capsule, syrup, buccal, sublingual, bead, film, gel, granule, gum, paste, suspension, and wafer.
  • the maximum plasma concentration (Cmax) of the anti- progestin (e.g., onapristone) following the administration of about lOmg of an extended- release pharmaceutical composition to a subject twice per day is at least 240 ng/ml over 8-12 hours.
  • use of the extended-release pharmaceutical composition leads to a steady-state plasma concentration of the anti-progestin.
  • the steady state plasma concentration is achieved between 4 and 16 days following administration. In some embodiments, the steady state plasma concentration is achieved at about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 days following administration. In some embodiments, the steady state plasma concentration is achieved at at least 4 days following administration.
  • the extended-release pharmaceutical composition is administered to a subject twice per day, and the steady state plasma concentration is achieved at about 8 days following administration.
  • the SERM is any SERM known in the art. Examples of other SERMS are described in U.S. Patent No. 7,612,114, U.S. U.S. Patent No. 7,960,412, U.S. Patent No. 8,399,520, U.S. Patent Publication No. US 2009-0325930, and U.S. Patent Publication No.
  • the SERM or SERD can be administered to a patient in an amount of about 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg,
  • elacestrant may be mediating some level of agonist activity, while a higher dose results in more extensive SERM activity and an effective blockade in estrogen signaling, thereby exacerbating vasomotor symptoms.
  • a high dose of elacestrant may be about 15 mg/kg to about lOOOmg/kg, about 15 mg/kg to about 250 mg/kg, about 15 mg/kg to about 200 mg/kg, about 15 mg/kgto about 150 mg/kg, about 15 mg/kg to about 100 mg/kg, about 15 mg/kg to about 75 mg/kg, about 20 mg/kg to about 500 mg/kg, about 20 mg/kg to about 250 mg/kg, about 20 mg/kg to about 200 mg/kg, about 20 mg/kg to about 150 mg/kg, about 20 mg/kg to about 100 mg/kg, about 20 mg/kg to about 75 mg/kg, about 25 mg/kg to about 500 mg/kg, about 25 mg/kg to about250 mg/kg, about 25 mg/kg to about 200 mg/kg, about 25 mg/kg to about 150 mg/kg, about 25 mg/kg to about 100 mg/kg, or about 25 mg/kg to about 75 mg/kg.
  • a high dose of elacestrant may be more than about 15 mg/kg, 20 mg/kg, about 25 mg/kg, about 30mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 105 mg/kg, about 110 mg/kg, about 115 mg/kg, about 120 mg/kg, about 125 mg/kg, about 130 mg/kg, about 135 mg/kg, about 140 mg/kg, about 145 mg/kg, about 150 mg/kg, about 155 mg/kg, about 160 mg/kg, about 165 mg/kg, about 170 mg/kg, about 175 mg/kg, about 180 mg/kg, about 185 mg/kg, about 190 mg/kg, about 195 mg/kg, about 200
  • elacestrant can be administered to a patient in an amount of about 2mg to about lOOOmg, about 10 mg to about 800 mg, about 100 mg to about 600 mg, about 200 mg to about 500 mg, or any amount in-between any of the recited ranges.
  • the SERM or SERD of the present disclosure can be administered via any appropriate route.
  • the SERM or SERD is administered by oral administration.
  • the SERM or SERD is administered by intravenous administration.
  • the SERM or SERD is administered by intradermal injection.
  • the SERM or SERD is administered by intramuscular injection.
  • the SERM or SERD is administered by subcutaneous injection.
  • the dosage form of the SERM or SERD can be any dosage form suitable for the selected route of administration.
  • the dosage form is a pill.
  • the dosage form is a tablet.
  • the dosage form is a capsule.
  • the dosage form is a syrup.
  • the dosage form is buccal.
  • the dosage form is sublingual.
  • the dosage form is a bead.
  • the dosage form is a film.
  • the dosage form is a gel.
  • the dosage form is a granule.
  • the dosage form is a gum.
  • the dosage form is a paste.
  • Treatments having durations of days, weeks, months, or years are encompassed by the embodiments provided for herein. Treatment may be discontinued and then restarted. Maintenance doses may or may not be administered after an initial treatment.
  • the SERM or SERD is administered at least once per day. In some embodiments, the SERM or SERD is administered once per day. In some embodiments, the SERM or SERD is administered twice per day. In some embodiments, the SERM or SERD is elacestrant and is administered at least once per day. In some embodiments, the SERM or SERD is elacestrant and is administered once per day. In some embodiments, the SERM or SERD is elacestrant and is administered twice per day.
  • the estrogen receptor-positive is metastatic.
  • the methods described above may be used to treat an estrogen receptor positive cancer of the brain.
  • the cancer may include subtypes of brain tumors that may express ER, such as Breast Cancer Brain Metastases (BCBM), Astrocytoma, Chondrosarcoma, Craniopharyngioma, Glioblastoma, Glioma, Hemangioma, Medulloblastoma, Meningioma, Neurofibroma, Neuronal and Mixed Neuronal-Glial Tumors, Oligoastrocytoma, Pituitary Tumor, PNET - (primitive neuroectodermal tumor), Schwannomak, or Leptomeningeal metastases.
  • BCBM Breast Cancer Brain Metastases
  • Astrocytoma Chondrosarcoma
  • Craniopharyngioma Craniopharyngioma
  • Glioblastoma Glioma
  • Hemangioma Medullob
  • Astrocytoma is a type of cancer of the brain that originate in astrocytes, which are a particular kind of glial cells, start-shaped brains cells in the cerebrum. Low ERb expression hasbeen shown to be associated with the progression of astrocytoma.
  • Chondrosarcoma is a type of tumor that affects the bones and joints. Chondrosarcomagrow from the types of cells that make cartilage in the skull. In the head, these tumors grow inside the bones at the base of the back part of the skull and may be very close to the nerves andblood vessels around the brainstem. ER is present and active in chondrosarcoma tumors.
  • Primitive neuroestodermal tumor is a neural crest tumor.
  • the majority of the cells in the PNET are derived from neuroectoderm, but have not developed and differentiated in the waya normal neuron would, and so the cells appear "primitive.
  • ERa may be present and may increase metastatic potential via extracellular signal -regulated Kinase (ERK) activation.
  • Schwannoma (also known as an "neurilemmoma,” “neurinoma,” “neurolemmoma,” and “Schwann cell tumor”) is a benign nerve sheath tumor composed of Schwann cells, whichnormally produce the insulating myelin sheath covering peripheral nerves. Schwannoma may express ERa.
  • the methods described above may further include a combination treatment of the fixed dosage form with other drugs and/or other conventional cancer therapies, such as hormone therapy.
  • Endocrine therapy also known as hormonal therapy, hormone therapy, and hormone treatment, is a treatment that adds, blocks, or removes hormones.
  • hormones may begiven to adjust low hormone levels.
  • Synthetic hormones or other drugs may be given to block the body's natural hormones to slow or stop the growth of certain cancers (such as prostate and breast cancer).
  • Endocrine therapy may also include surgery to remove the gland that makes a certain hormones.
  • compositions may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., liposomes and suppositories.
  • the form depends on the intended mode of administration and therapeutic application.
  • Typical compositions are in the form of injectable or infusible solutions.
  • the mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the therapeutic molecule is administered by intravenous infusion or injection.
  • the therapeutic molecule is administered by intramuscular or subcutaneous injection.
  • the therapeutic molecule is administered locally, e.g., by injection, or topical application, to a target site.
  • the pharmaceutical compositions can be lyophilized and
  • compositions typically should be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high therapeutic molecule concentration.
  • Sterile injectable solutions can be prepared by incorporating the active compound (i.e., therapeutic molecule) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the methods of preparation can be vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • a method of treating a subject having a cancer comprises administering to the subject a pharmaceutical composition as provided for herein.
  • the subject is a human subject.
  • the cancer is prostate cancer, endometrial cancer, breast cancer, ovarian cancer, brain cancer, endometrial cancer, uterine leiomyoma, lung cancer, bile duct cancer, lung cancer, bone cancer, esophagus cancer, kidney cancer, pancreatic cancer, intestine cancer, stomach cancer, urinary tract cancer, skin cancer, liver cancer, thyroid cancer, uterine endometrioid, or any other progesterone receptor-positive gynecologic cancer.
  • the tumor is also tested to determine if it is ER + .
  • the tumor is positive for ER and PR, such as set forth herein.
  • the anti-progestin or pharmaceutically acceptable salt or solvate thereof is administered in a synergistic therapeutically effective amount.
  • a synergistic therapeutically effective amount is an amount less than what would be utilized as a monotherapy.
  • a synergistic therapeutically effective amount is an amount that allows the second component to be used at an amount less than what would be utilized as a monotherapy.
  • a synergistic therapeutically effective amount is an amount that results in a greater degree of treatment or percentage of beneficial effect than what would result when utilized as a monotherapy.
  • the anti-progestin is present in the composition in an amount from about 2mg to about 50mg.
  • the selective estrogen receptor modulator and or degrader or pharmaceutically acceptable salt or solvate thereof is administered in a synergistic therapeutically effective amount.
  • a synergistic therapeutically effective amount is an amount less than what would be utilized as a monotherapy.
  • a synergistic therapeutically effective amount is an amount that allows the second component to be used at an amount less than what would be utilized as a monotherapy.
  • a synergistic therapeutically effective amount is an amount that results in a greater degree of treatment or percentage of beneficial effect than what would result when utilized as a monotherapy.
  • the amount of SERM or SERD is any amount in between the amounts provided for herein. In some embodiments, the SERM or SERD is elacestrant.
  • a method of treating a subject having cancer comprising administering to the subject a combination of an anti-progestin, or a pharmaceutically acceptable salt or solvate thereof; and a selective estrogen receptor modulator and/or degrader, or a pharmaceutically acceptable salt thereof or solvate thereof.
  • the anti-progestin is onapristone having the formula of
  • the purity of the anti-progestin is at least about 90% w/w, at least about 91% w/w, at least about 92% w/w, at least about 93% w/w, at least about 94% w/w, at least about 95% w/w, at least about 96% w/w, at least about 97% w/w, at least about 98% w/w, or at least about 99% w/w.
  • the extended-release pharmaceutical composition comprises about 5% (wt/wt) the anti-progestin (e.g., onapristone), about 20.5% (wt/wt) lactose monohydrate, about 20.5% (wt/wt) microcrystalline cellulose, about 20% (wt/wt) pregelatinized starch, about 33% (wt/wt) hydroxypropyl methylcellulose, about 0.5% silicon dioxide, and about 0.5% magnesium stearate.
  • the anti-progestin e.g., onapristone
  • cancer is endometrial cancer, breast cancer, ovarian cancer, brain cancer, endometrial cancer, uterine leiomyoma, lung cancer, bile duct cancer, lung cancer, bone cancer, esophagus cancer, kidney cancer, pancreatic cancer, intestine cancer, stomach cancer, urinary tract cancer, skin cancer, prostate cancer, liver cancer, thyroid cancer, uterine endometrioid, or any other progesterone receptor-positive gynecologic cancer.
  • a method of treating a subject having a cancer comprising administering to the subject the pharmaceutical composition of any one of embodiments 55-58.
  • any one of embodiments 59-60 wherein the cancer is prostate cancer, endometrial cancer, breast cancer, ovarian cancer, brain cancer, endometrial cancer, uterine leiomyoma, lung cancer, bile duct cancer, lung cancer, bone cancer, esophagus cancer, kidney cancer, pancreatic cancer, intestine cancer, stomach cancer, urinary tract cancer, skin cancer, liver cancer, thyroid cancer, uterine endometrioid, or any other progesterone receptor-positive gynecologic cancer.
  • Example 1 Synergistic relationship of onapristone and elacestrant in MCF-7 Xenograft model
  • the synergistic relationship between onapristone and elacestrant for the treatment of breast cancer is assessed using a MCF-7 xenograft model in female athymic nude mcie as described in the art. Briefly, three days prior to tumor cell implantation, estrogen pellets (0.36 mg E2, 60-day release; Alternative Research of America, Sarasota, FL) are implanted subcutaneously between the scapulae of all test animals using a sterilized trochar.
  • mice Fourteen days after tumor cell implantation (designated as day 1 of the study) mice will be randomized into groups of vehicle, onapristone alone, elacestrant alone, or onapristone and elacestrant, where the combined treatment regimen will be assessed at varying doses. Tumor volumes will be evaluated twice per week.
  • Subjects are treated with varying concentrations of onapristone and elacestrant. Progress of tumor growth is measured by traditional assessments known in the art. The combination of onapristone and elacestrant is found to be effective in treating breast tumors in a subject synergistically as compared to each compound alone.
  • Example 5 Synergistic relationship between onapristone and elacestrant in MCF-7 cells.
  • Adherent cells were washed with PBS and dissociated enzymatically in 0.25% trypsin-EDTA (Invitrogen). The cells were sieved through a 40-pm sieve (BD Falcon). 1000 cells per well were plated in 24-well ultra-low attachment plates (Coming) and grown in cell culture medium plus the treatment indicated in Table 2 (elacestrant, 10 nM; onapristone, 100 nM; elacestrant, 10 nM plus onapristone, 100 nM). Tumorspheres were allowed to grow for approximately 10 days. The tumorsphere were analyzed by total number and scored by manual counting using a unifonnly scaled grid. Data are presented as the average ⁇ SD of six independent measurements.
  • Table 2 Primary tumorsphere assay in ER + /PR + MCF-7 cells treated with elacestrant (10 nM), onapristone (100 nM), or both. Values are normalized to vehicle control (100%). [0139] A cell line that is considered to have little or very low progesterone receptor expression was also tested as a negative control and found not to have a difference between the drugs alone and in combination (data not shown).

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Abstract

Les présents modes de réalisation concernent, en partie, des méthodes de traitement de sujets souffrant d'un cancer positif au récepteur des oestrogènes au récepteur de la progestérone par administration d'une combinaison d'un modulateur sélectif de récepteur d'oestrogène (SERM) et/ou d'un agent de dégradation sélectif de récepteur des oestrogènes (SERD) et d'une anti-progestine au sujet. Les présents modes de réalisation concernent également, en partie, des méthodes de traitement de sujets souffrant d'un cancer qui est résistant à un modulateur du récepteur des oestrogènes par administration de la combinaison au sujet.
PCT/US2023/063858 2022-03-08 2023-03-07 Compositions comprenant des anti-progestines et des modulateurs sélectifs des récepteurs des oestrogènes et leurs procédés d'utilisation WO2023172909A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140271819A1 (en) * 2013-03-12 2014-09-18 Stefan Proniuk Onapristone polymorphic forms and methods of use
WO2015149045A1 (fr) * 2014-03-28 2015-10-01 Duke University Méthode de traitement du cancer faisant intervenir des modulateurs sélectifs des récepteurs des œstrogènes
US20160279146A1 (en) * 2013-11-11 2016-09-29 Limoxifen B.V. Methods and pharmaceutical formulations for treatment of selective estrogen-receptor modulator-induced adverse drug reactions
US20200376004A1 (en) * 2015-12-15 2020-12-03 Context Biopharma Inc. Amorphous onapristone compositions and methods of making the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140271819A1 (en) * 2013-03-12 2014-09-18 Stefan Proniuk Onapristone polymorphic forms and methods of use
US20160279146A1 (en) * 2013-11-11 2016-09-29 Limoxifen B.V. Methods and pharmaceutical formulations for treatment of selective estrogen-receptor modulator-induced adverse drug reactions
WO2015149045A1 (fr) * 2014-03-28 2015-10-01 Duke University Méthode de traitement du cancer faisant intervenir des modulateurs sélectifs des récepteurs des œstrogènes
US20200376004A1 (en) * 2015-12-15 2020-12-03 Context Biopharma Inc. Amorphous onapristone compositions and methods of making the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NISHINO ET AL.: "Potentiation of the antitumor effect of tamoxifen by combination with the antiprogestin onapristone", THE JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, vol. 116, 14 June 2009 (2009-06-14), pages 187 - 190, XP026349663 *

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