WO2022182982A1 - Methods for treating c-kit kinase mediated diseases and disorders using a selective c-kit kinase inhibitor - Google Patents

Methods for treating c-kit kinase mediated diseases and disorders using a selective c-kit kinase inhibitor Download PDF

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WO2022182982A1
WO2022182982A1 PCT/US2022/017893 US2022017893W WO2022182982A1 WO 2022182982 A1 WO2022182982 A1 WO 2022182982A1 US 2022017893 W US2022017893 W US 2022017893W WO 2022182982 A1 WO2022182982 A1 WO 2022182982A1
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treatment cycle
days
patient
therapeutic agent
day
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French (fr)
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Steven P. SWEENEY
Stephen YOO
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Third Harmonic Bio, Inc.
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Publication of WO2022182982A1 publication Critical patent/WO2022182982A1/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
    • A61K31/435—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
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present disclosure provides a method of treating a c-kit kinase mediated disease or disorder, comprising orally administering to a patient in need thereof a dose of Compound 1 in an amount of from about 10 mg to about 1,000 mg in order to treat the c-kit kinase mediated disease or disorder.
  • Compound 1 or “study drug” refers to N-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, a compound having the following chemical structure:
  • salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate (mesylate), 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • dosage amounts of a therapeutic agent are disclosed in terms of mass, the disclosed amount refers to the mass of the pure freebase form of the therapeutic agent.
  • compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
  • the invention provides methods for treating patients suffering from a c-kit kinase mediated disease or disorder by administering to the patient Compound 1, or a pharmaceutically acceptable salt thereof.
  • the invention provides methods for treating patients suffering from a c-kit kinase mediated disease or disorder by administering to the patient Compound 1, or a pharmaceutically acceptable salt thereof, in certain dosages.
  • the invention also provides methods of determining patient populations that may derive particular benefit from the therapeutic methods of the invention.
  • One aspect of the invention provides a method of treating a c-kit kinase mediated disease or disorder.
  • the method comprises orally administering to a patient in need thereof a dose of Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of from about 10 mg to about 1,000 mg.
  • the dose of Compound 1, or a pharmaceutically acceptable salt thereof is from about 10 mg to about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 200 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 200 mg to about 400 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 200 mg to about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 300 mg to about 500 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 400 mg to about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 800 mg to about 1,000 mg.
  • the dose of Compound 1, or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, or about 1,000 mg.
  • the dose of Compound 1, or a pharmaceutically acceptable salt thereof is about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 800 mg, or about 1,000 mg.
  • the dose of Compound 1, or a pharmaceutically acceptable salt thereof is about 200 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 400 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 500 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1,000 mg.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient no more frequently than twice per day. In some embodiments,
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 7 days. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 14 days. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 21 days. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 1 month. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 3 months. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day, for an indefinite period of time.
  • the dose of Compound 1, or a pharmaceutically acceptable salt thereof is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 82,000 ng h/mL. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 72,500 ng h/mL.
  • Another aspect of the invention provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a first therapeutic agent according to a first treatment cycle lasting at least 10 days, in order to treat the c-kit kinase mediated disease or disorder, wherein the first therapeutic agent is Compound 1, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle.
  • the method comprises administering to the patient in need thereof the first therapeutic agent according to a first treatment cycle lasting 14 days, wherein a therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the first treatment cycle.
  • the non-treatment cycle lasts 7 days. In some embodiments, the non-treatment cycle lasts 10 days. In some embodiments, the non-treatment cycle lasts 14 days. In some embodiments, the non-treatment cycle lasts 21 days. In some embodiments, the non treatment cycle lasts 28 days.
  • Another aspect of the invention provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a first therapeutic agent, wherein the first therapeutic agent is Compound 1, or a pharmaceutically acceptable salt thereof.
  • the first treatment cycle lasts at least 3 days. In some embodiments, the first treatment cycle lasts at least 7 days. In some embodiments, the first treatment cycle lasts at least 10 days. In some embodiments, the first treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 21 days. In some embodiments, the first treatment cycle lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, or at least 21 days.
  • the first treatment cycle lasts 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the first treatment cycle lasts 3 days. In some embodiments, the first treatment cycle lasts 7 days. In some embodiments, the first treatment cycle lasts 10 days. In some embodiments, the first treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 21 days.
  • the non-treatment cycle lasts at least 2 days. In some embodiments, the non-treatment cycle lasts at least 5 days. In some embodiments, the non-treatment cycle lasts at least 7 days. In some embodiments, the non-treatment cycle lasts at least 10 days. In some embodiments, the non-treatment cycle lasts at least 14 days. In some embodiments, the non treatment cycle lasts at least 21 days. In some embodiments, the non-treatment cycle lasts at least 28 days.
  • the non-treatment cycle lasts 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the non-treatment cycle lasts 2 days. In some embodiments, the non-treatment cycle lasts 5 days. In some embodiments, the non treatment cycle lasts 7 days. In some embodiments, the non-treatment cycle lasts 10 days. In some embodiments, the non-treatment cycle lasts 14 days. In some embodiments, the non-treatment cycle lasts 21 days. In some embodiments, the non-treatment cycle lasts 28 days.
  • the method further comprises a second treatment cycle that takes place after the non-treatment cycle.
  • the first therapeutic agent is administered to the patient according to a second treatment cycle during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
  • the therapeutically effective amount of the first therapeutic agent is administered to the patient no more frequently than twice per day on each day of the second treatment cycle.
  • the therapeutically effective amount of the first therapeutic agent is administered to the patient twice per day on each day of the second treatment cycle.
  • the therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the second treatment cycle.
  • the second treatment cycle lasts at least 3 days. In some embodiments, the second treatment cycle lasts at least 7 days. In some embodiments, the second treatment cycle lasts at least 10 days. In some embodiments, the second treatment cycle lasts at least 14 days. In some embodiments, the second treatment cycle lasts at least 21 days. In some embodiments, the second treatment cycle lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, or at least 21 days.
  • Another aspect of the invention provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a first therapeutic agent, wherein the first therapeutic agent is a c-kit kinase inhibitor.
  • the invention provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a first therapeutic agent according to a first treatment cycle lasting at least 10 days, in order to treat the c-kit kinase mediated disease or disorder, wherein the first therapeutic agent is c-kit kinase inhibitor, and a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle.
  • the c-kit kinase inhibitor is a small organic compound, or a pharmaceutically acceptable salt thereof.
  • the c-kit kinase inhibitor is avapritinib, or a pharmaceutically acceptable salt thereof.
  • Regorafenib and pharmaceutically acceptable salts thereof are described in International Publication No. WO 2005/009961, in Example 1.
  • Polymorphic forms of regorafenib are described in International Publication No. WO 2008/058644.
  • the c-kit kinase inhibitor is dasatinib, or a pharmaceutically acceptable salt thereof.
  • Dasatinib N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l- piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate, alternatively known as BMS-354B25, SPRYCEL® and Dasanix, is a compound with the following structure:
  • Dasatinib and pharmaceutically acceptable salts thereof are described in U.S. Patent No. 6,596,746. Methods of treatment using dasatinib and salts thereof are described in U.S. Patent Nos. 7,125,875 and 7,153,856. Processes of making dasatinib and polymorphs and salt forms of dasatinib are described in U.S. Patent Nos. 7,491,725 and 8,680,103.
  • Pexidartinib is disclosed in U.S. Pat. No. 7,893,075, U.S. Publication No. 2014-0037617 and U.S. Publication No. 2013-0274259. Crystalline freebase and salt forms of pexidartinib are disclosed in International Publication No. WO 2016/179415.
  • the c-kit kinase inhibitor is pexidartinib hydrochloride.
  • Cabozantinib is disclosed in International Publication No. W02005/030140, as Compound 12, Example 48.
  • the c-kit kinase inhibitor is cabozantinib s- malate.
  • Cabozantinib and salts thereof are also described in U.S. Patents Nos. 8,877,776; 7,579,473; 8,497,284; 9,724,342; 9,717,720; 10,039,757; and 10,034,873.
  • the c-kit kinase inhibitor is M4205, or a pharmaceutically acceptable salt thereof.
  • the c-kit kinase inhibitor is ripretinib, or a pharmaceutically acceptable salt thereof.
  • Ripretinib, l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro- l,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea also known as DCC-2618, is a compound with the following structure:
  • Tandutinib and related compounds are described in U.S. Patent No. 6,982,266.
  • the c-kit kinase inhibitor is tandutinib hydrochloride.
  • the c-kit kinase inhibitor is DCC-3014, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is AC710, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is tyrphostin AG1296, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is SU14813, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is AZD2932, or a pharmaceutically acceptable salt thereof.
  • the c-kit kinase inhibitor is an antibody. In some embodiments, the c-kit kinase inhibitor is an antibody selected from CDX-0159, CDX-0158, NN-2101, NN- 2901, FSI-174 and JSP-191. In some embodiments, the c-kit kinase inhibitor is CDX-0159. In some embodiments, the c-kit kinase inhibitor is CDX-0158. In some embodiments, the c-kit kinase inhibitor is NN-2101. In some embodiments, the c-kit kinase inhibitor is NN-2901. In some embodiments, the c-kit kinase inhibitor is FSI-174. In some embodiments, the c-kit kinase inhibitor is J SP- 191.
  • the method further comprises a non-treatment cycle that takes place after the first treatment cycle, wherein during the non-treatment cycle the patient does not receive the first therapeutic agent.
  • the non-treatment cycle lasts at least 2 days. In some embodiments, the non-treatment cycle lasts at least 5 days. In some embodiments, the non-treatment cycle lasts at least 7 days. In some embodiments, the non-treatment cycle lasts at least 10 days. In some embodiments, the non-treatment cycle lasts at least 14 days. In some embodiments, the non treatment cycle lasts at least 21 days. In some embodiments, the non-treatment cycle lasts at least 28 days.
  • the non-treatment cycle lasts 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the non-treatment cycle lasts 2 days. In some embodiments, the non-treatment cycle lasts 5 days. In some embodiments, the non treatment cycle lasts 7 days. In some embodiments, the non-treatment cycle lasts 10 days. In some embodiments, the non-treatment cycle lasts 14 days. In some embodiments, the non-treatment cycle lasts 21 days. In some embodiments, the non-treatment cycle lasts 28 days.
  • the method further comprises a second treatment cycle that takes place after the non-treatment cycle.
  • the first therapeutic agent is administered to the patient according to a second treatment cycle during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
  • the second treatment cycle lasts at least 3 days. In some embodiments, the second treatment cycle lasts at least 7 days. In some embodiments, the second treatment cycle lasts at least 10 days. In some embodiments, the second treatment cycle lasts at least 14 days. In some embodiments, the second treatment cycle lasts at least 21 days. In some embodiments, the second treatment cycle lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, or at least 21 days.
  • the second treatment cycle lasts 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the second treatment cycle lasts 3 days. In some embodiments, the second treatment cycle lasts 7 days. In some embodiments, the second treatment cycle lasts 10 days. In some embodiments, the second treatment cycle lasts 14 days. In some embodiments, the second treatment cycle lasts 21 days.
  • Additional exemplary features that may characterize the Second, Third, and Fourth Therapeutic Methods described herein are provided below and include, for example, the dosage amounts and the use of biomarkers to determine the duration of the first treatment cycle, non treatment cycle and second treatment cycle.
  • the duration of the first treatment cycle is determined based on the value of one or more pharmacodynamic parameters in a sample collected from the patient.
  • the one or more pharmacodynamic parameters are concentration levels of one or more biomarkers indicative of effective treatment of a c-kit kinase mediated disease or disorder.
  • the one or more biomarkers indicative of effective treatment of a c-kit kinase mediated disease or disorder is a biomarker used to determine c-kit engagement, for instance, measurement of stem cell factor concentration in a sample collected from the patient.
  • the duration of the first treatment cycle is determined based on mast cell density in a skin biopsy collected from the patient.
  • the first treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below a threshold determined to indicate effective treatment of the c-kit kinase mediated disease or disorder.
  • the first treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 75% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle.
  • the first treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 50% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle. In some embodiments, the first treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 25% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle.
  • the first therapeutic agent if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 3 days, and mast cell density measured from a skin biopsy collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 3 additional days.
  • the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 25% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 50% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 75% from pretreatment levels.
  • the duration of the first treatment cycle is determined based on the concentration of serum tryptase in a blood sample collected from the patient. In some embodiments, the first treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below a threshold determined to indicate effective treatment of the c-kit kinase mediated disease or disorder. In some embodiments, the first treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 75% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle.
  • the first treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 50% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle. In some embodiments, the first treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 25% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle.
  • the first therapeutic agent if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 3 days, and serum tryptase concentration measured from a blood sample collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 3 additional days.
  • the first therapeutic agent if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 10 days, and serum tryptase concentration measured from a blood sample collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 5 additional days.
  • the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 50% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 75% from pretreatment levels.
  • the duration of the non-treatment cycle is determined based on the value of one or more pharmacodynamics parameters in a sample collected from the patient. In some embodiments, the one or more pharmacodynamics parameters are concentration levels of one or more biomarkers indicative of mast cell recovery from the treatment during the first treatment cycle.
  • the non-treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient has returned to at least 50% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle. In some embodiments, the non-treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient has returned to at least 25% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle.
  • the duration of the non-treatment cycle is determined based on the serum tryptase concentration measured from a blood sample collected from the patient.
  • the non-treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is above a threshold determined to indicate recovery of mast cells that had been depleted through the administration of the first therapeutic agent during the first treatment cycle.
  • the non-treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient has returned to at least 75% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle.
  • the non-treatment cycle if the non-treatment cycle has lasted for a duration of at least 2 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to a level determined to indicate recovery of mast cells from depletion due to treatment with the first therapeutic agent during the first treatment cycle, then the non-treatment cycle is extended for at least 2 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to a level determined to indicate recovery of mast cells from depletion due to treatment with the first therapeutic agent during the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days.
  • the non-treatment cycle if the non-treatment cycle has lasted for a duration of at least 7 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to at least 75% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days.
  • the non-treatment cycle if the non-treatment cycle has lasted for a duration of at least 7 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to at least 50% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to at least 25% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days.
  • the duration of the second treatment cycle is determined based on the value of one or more pharmacodynamics parameters in a sample collected from the patient.
  • the one or more pharmacodynamics parameters are concentration levels of one or more biomarkers indicative of effective treatment of a c-kit kinase mediated disease or disorder.
  • the duration of the second treatment cycle is determined based on mast cell density in a skin biopsy collected from the patient.
  • the second treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below a threshold determined to indicate effective treatment of the c-kit kinase mediated disease or disorder.
  • the second treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 75% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the second treatment cycle.
  • the second treatment cycle is continued for at least 7 additional days.
  • the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 25% from pretreatment levels.
  • the first therapeutic agent is orally administered to the patient in an amount from about 10 mg to about 1,000 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 10 mg to about 200 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 200 mg to about 400 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 300 mg to about 500 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 400 mg to about 800 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 800 mg to about 1,000 mg on each day of the first treatment cycle.
  • the first therapeutic agent is orally administered to the patient in a dose of about 10 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 30 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 100 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 200 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 300 mg on each day of the first treatment cycle.
  • the dose of the first therapeutic agent during the second treatment cycle is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 82,000 ng h/mL. In some embodiments, the dose of the first therapeutic agent during the second treatment cycle is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 72,500 ng h/mL.
  • the first treatment cycle lasts at least 14 days, and the non treatment cycle lasts at least 7 days. In some embodiments, the first treatment cycle lasts at least 14 days, and the non-treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 14 days, and the non-treatment cycle lasts at least 21 days. In some embodiments, the first treatment cycle lasts at least 14 days, and the non-treatment cycle lasts at least 28 days.
  • the first treatment cycle lasts 14 days, and the non-treatment cycle lasts 7 days. In some embodiments, the first treatment cycle lasts 14 days, and the non treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 14 days, and the non-treatment cycle lasts 21 days. In some embodiments, the first treatment cycle lasts 14 days, and the non-treatment cycle lasts 28 days.
  • the first treatment cycle lasts at least 14 days, the non-treatment cycle lasts at least 7 days and the second treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 14 days, the non-treatment cycle lasts at least 14 days and the second treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 14 days, the non -treatment cycle lasts at least 21 days and the second treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 14 days, the non-treatment cycle lasts at least 28 days and the second treatment cycle lasts at least 14 days.
  • Additional exemplary features that may characterize the First, Second, Third, and Fourth Therapeutic Methods described herein are provided below and include, for example, the identity of the patient, Compound 1 formulations and exemplary c-kit kinase mediated diseases and disorders. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features. 1.
  • Pharmaceutical Compositions include, for example, the identity of the patient, Compound 1 formulations and exemplary c-kit kinase mediated diseases and disorders. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features. 1.
  • the patient is in a fasted state when the c-kit kinase inhibitor is administered. In some embodiments, the patient is in a fed state when the c-kit kinase inhibitor is administered. In some embodiments, the c-kit kinase inhibitor is administered to the patient orally once per day wherein the administration takes place at the same time each day. In some embodiments, the c-kit kinase inhibitor is administered to the patient orally once per day, in the morning. In some embodiments, the c-kit kinase inhibitor is administered to the patient orally once per day within 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes of the patient waking.
  • Chronic urticaria is a disease where mast cells are known to play a critical role in disease pathology (Church, et al., Immunological Reviews, 2018, 282(1), 232-247.).
  • Drugs that inhibit activators (e.g. Xolair) and mediators (e.g. anti-histamines) of mast cells are commonly used and are effective in urticaria patients (Johal, et al., Asthma and Immunology, 2019, 1-29.).
  • activators e.g. Xolair
  • mediators e.g. anti-histamines
  • Serum CTX Collagen cross linked C-telopeptide
  • KIT liver-resident macrophages
  • the subject population for the study will include healthy adult subjects who satisfy all entry criteria.
  • Subjects must, in the opinion of the Investigator, be able to participate in all scheduled evaluations, likely to complete all required tests, and likely to be compliant.
  • Part 2 Subjects participating in Part 2 must be willing and able to consume the entire high-fat, high-calorie breakfast meal in the designated timeframe.
  • Subject is on active immunosuppressive drug defined as at least one dose within 28 days prior to Day 1. Received or used an investigational product (including placebo) or device within the following time period prior to the first dosing day in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Vaccinated within 14 days prior to the first dose or intention to receive vaccination during the study. COVID-19 vaccination is allowed after the follow-up (Part 1 and Part 2) or first follow-up (Part 3). History of clinically significant sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation. The subject currently smokes or uses nicotine-containing products.
  • Recent (within 7 days) allergic reaction e.g. bee stings, food, or other allergen.
  • Subject has a fever defined as a temperature > 37.8 °C or any reports of fever resulting from bacterial or viral infection within 7 days prior to Day 1.
  • Part 3 only: Subject has forearm tattoos that interfere with the ability to collect a biopsy from a tattoo-free area.
  • concomitant medication is needed during the study, this medication must be recorded, stating its generic name, time of administration, dose, route, frequency and duration, as well as the reason for administration.
  • the use of a concomitant medication during the study should be discussed with the Investigator and Medical Monitor before administration, except in the case of necessary treatment of adverse events or where appropriate medical care necessitates that therapy should begin before the Investigator can consult with the Medical Monitor.
  • Paracetamol (up to 3g/day for 2 days) may be used for minor ailments during the course of the study, at the discretion of the Investigator, without prior consultation with the Sponsor’s Medical Monitor.
  • the use of lidocaine is permitted for skin biopsies.
  • Fitzpatrick scale also Fitzpatrick skin typing test; or Fitzpatrick phototyping scale
  • Hematology, chemistry, coagulation, and urinalysis samples will be collected for Parts 1 and 2 during the screening period, and on day -1, day 1 pre-dose, day 8, day 24, day 48, day 72 and at EOS. Hematology, chemistry, coagulation, and urinalysis samples will be collected for Part 3 during the screening period, and on days -1, 1, 2, 3, 6, 9, 12, 14, 15, 17, 22 and 70.
  • Stem Cell Factor sampling will be conducted on day 1 pre-dose, and day 72 in Parts 1 and 2, and on days 1, 7, 14, 22, 29, 42, 56, and 70 in Part 3.
  • CTX sampling will be conducted on day 1 pre-dose and on day 14 at 4 hours post-dose in Part 3.
  • Serum tryptase sampling will be conducted pre dose on days 1 and 14 and on days 2, 3, 6, 9, 12, 15 and 17 in Part 3.
  • 4b hydroxycholesterol sampling will be conducted pre dose on days 1 and 14 and on days 2, 3, 6, 9, 12, and 15 in Part 3.
  • PK blood sampling will be conducted pre-first dose, and at time points 0.5h, lh, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h and 72h, and optionally also at time points lOh and 16h in Parts 1 and 2.
  • PK and metabolic blood sampling will be conducted on day 1 pre-dose and at time points: 0.5h, lh, 1.5h, 2h, 3h, 4h, 6h, 8h, lOh, 12h, and 16h and then once per day on days 2-17 in Part 3.
  • PK urine collection will be conducted pre-dose on day 1, and on day 1 and day 14 at 0-6 hours, 6-12 hours, and 12-24 hours post-dose.
  • Skin biopsies will be collected in Part 3 on day 1 and day 14, both pre-dose.
  • the skin biopsies scheduled during Follow-up (Day 29 and Day 42) may be moved to one of the other Follow-up study days.
  • Samples for metabolic profiling will be pooled and analyzed using LC/HRMS in order to identify unique human metabolites and determine if those metabolites are present at >10% total drug-related exposure (TDRE). This analysis will be performed using an aliquot of stored PK samples. No extra blood sampling is necessary.
  • Vital sign assessments will be performed according to the standard procedures and will include measurements of supine blood pressure, pulse rate, pulse oximetry and temporal temperature. Vital sign measurements will be collected after the subject has been resting for 5 minutes.
  • Physical examination will be performed according to standard procedures and consists of inspection, percussion, palpation, and auscultation. Additionally, hair (roots) and skin will be checked for any noticeable color changes. At some time points, symptom-driven physical examinations will be performed.
  • Clinically relevant findings that are observed after the screening assessment must be recorded.
  • Clinically relevant findings found after study drug initiation and meeting the definition of an AE must be recorded.
  • ECGs will be evaluated and classified as normal or abnormal. In case of “abnormal”, the abnormality has to be described.
  • HR, PR, QRS, and QT will be provided on the print-out of the ECG apparatus.
  • Bazett (QT/RR 1/2 )/Fridericia (QT/RR 1/3 ) QTc is automatically calculated by the ECG apparatus and provided on the print-out.
  • three recordings will be made with an interval of approximately 1 minute between recordings. Evaluation of average recordings will be performed according to QPS SOP. Any repeat measurement will also be done in triplicate. All other recordings will be single (one recording of at least 3 complexes).
  • Clinically significant laboratory abnormalities must be reported by the investigator as an AE or SAE as appropriate.
  • the blood samples will be taken under fasted conditions, if possible. Subjects will not be allowed to eat or drink (except water) for a period of 4 h prior to blood sampling. As a rule, the blood samples will be taken from the subject by puncture of a vein in the cubital or the antebrachial region. The samples will be sent to the local certified laboratory in accordance with specifications.
  • a serum pregnancy test will be performed at Screening. On Day -1 of every study period, the pregnancy test will be done with serum or urine. A urine pregnancy test will be performed at Follow-Up (or at early termination). The results must be available prior to dosing. Serology
  • virus serology will be assessed (HIV, hepatitis B and hepatitis C). Cardiodynamic Assessments
  • the subjects will remain in a resting semi-lying position for 1 hour prior to (first) dosing up to 4 hour after study drug administration except for study drug administration and blood sampling (sitting position) or measurement of vital signs and ECG (supine position). Furthermore, subjects will be supinely resting for at least 10 minutes before and 5 minutes after each following time point.
  • ECG extractions coincide with safety ECGs, vital signs assessment and blood draws, procedures will be carried out in said order. If subjects need to stand up during this timeframe (e.g., if they need to go to the restroom), study staff must ensure that the subj ects remain in the supine position 15 min prior to scheduled testing at the planned time points.
  • the 12-lead Holter and ECG equipment will be supplied and supported by ERT. All ECG data will be collected using a Global Instrumentation (Manlius, NY, USA) M12R ECG continuous 12 lead digital recorder. The continuous 12-lead digital ECG data will be stored onto SD memory cards. ECGs to be used in the analyses will be selected by pre-determined time points as defined in the Table of Assessments and will be read centrally by ERT.
  • the primary analysis lead is lead II. If lead II is not analyzable, then primary lead of analysis will be changed to another lead for the entire subject data set.
  • Mean hourly heart rate analysis will be performed and include a summary of change from baseline and placebo corrected change from baseline (if applicable) for each subject. Central tendency analysis will be used to describe any changes over time. Heart rate nadir and time to heart rate nadir will be summarized by subject using descriptive statistics and will include categorical outlier analysis.
  • Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter recordings using the ‘TQT Plus method’, a computer-assisted and statistical process utilized by ERT.
  • the method enables extraction of ECGs with the lowest HR variability and noise within the protocol-specified extraction time window (e.g., the HR and QT changes from beat-to-beat in the range of ⁇ 10%).
  • 10 ECG replicates will be extracted from a 5-minute “ECG window” (typically, the last 5 minutes of the 15-minute period when the subject is maintained in a supine or semi-recumbent quiet position).
  • Expert-precision QT analysis may be performed on all analyzable (non-artifact) beats in the 10 ECG replicates.
  • Statistical quality control procedures are used to review and assess all beats and identify “high” and “low” confidence beats using several criteria, including:
  • Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all replicates that are deemed “high confidence” is performed using COMPAS software. All low confidence beats are reviewed manually and adjudicated using pass-fail criteria. The final QC assessment is performed by a cardiologist. The beats found acceptable by manual review are included in the analysis. The median QT, QTc, and RR value from each extracted replicate is calculated, and then the mean of all available medians from a nominal timepoint is used as the subject’s reportable value at that timepoint.
  • Morphological analyses will be performed with a focus on detecting changes in T-wave morphology and appearance of abnormal U waves.
  • the analyses will evaluate change-from- baseline (i.e., treatment-emergent changes).
  • T-wave morphology and U-wave presence will be summarized in frequency tables with counts and percentages for both number of subjects and number of time points.
  • the number and percentage of subjects in each treatment group having changes from baseline that represent the appearance of the morphological abnormality will be summarized.
  • the total number of time points having a particular change event will be summarized in terms of number and percentage based on the number of observed time points across all subjects within a treatment group.
  • treatment-emergent changes will be assessed, i.e., changes not present at baseline.
  • the category will be deemed as present if observed in any replicate at the time point.
  • the category will be deemed as present if observed in any replicate from all time points that constitute baseline.
  • Cardiodynamic ECG evaluation will be described in a separate statistical analysis plan (SAP).
  • Part 1 Part 2 and Part 3: Safety and tolerability parameters include physical examination, adverse events, clinical laboratory values, vital signs and ECGs (3 -lead telemetry and 12-lead ECGs).
  • Part 1 and Part 2 PK parameters for Compound 1 include: Cmax, tmax, ti / 2, AUCo- t , AUCo- i handedf, CL/F and V z /F.
  • Part 1 and Part 3 For the cardiodynamic evaluation on ECGs extracted from Holters in Part 1 and Part 3, the following endpoints will be used:
  • PK parameters for Compound 1 include: Cmax, tmax, ti / 2, AUCo-t, AUCo-tau, AUCo- inf, CL/F (Day 1 only), Vz/F (Day 1 only), Cmin, Cmin,ss, CLss/F, Vss/F, Cssavg, and AR.
  • Part 1 and Part 3 PD parameters include: Serum tryptase levels (Part 3 only), Stem Cell Factor (SCF) (Part 1 and Part 3), CTX (Part 3 only), mast cell counts in skin (Part 3 only), 4P-hydroxycholesterol (Part 3 only).
  • SCF Stem Cell Factor
  • CTX Part 3 only
  • mast cell counts in skin Part 3 only
  • 4P-hydroxycholesterol Part 3 only
  • Part 3 Compound 1 metabolic profile in plasma.
  • the plasma PK parameters for Compound 1 will be derived by non-compartmental analysis of the plasma concentration-time profiles. The following pharmacokinetic parameters will be reported:
  • AUC Area under the plasma concentration-time curve
  • the total amount of dose excreted in urine from 0 (pre-dose) to end of collection (Ae);
  • the total amount of dose excreted in urine from 0 (pre-dose) to 24 hours (Aeo-24);
  • the study will be monitored by a Safety Review Committee (SRC). Safety, tolerability and available PK and/or PD data up to and including 72 hours after the last administered dose of at least 6 evaluable subjects will be assessed by the SRC prior to ascending from one dose-level cohort to the next-higher dose-level cohort and prior to transitioning to Part 2 and Part 3.
  • SRC Safety Review Committee
  • the SRC will make one of the following determinations: (1) To continue with the study as planned. (2) To continue with the study as planned and evaluate additional or alternate time points for safety evaluations. (3) To continue with the study by repeating a dose level, selecting an alternative dose level between the current dose level and the next planned dose level, or selecting an alternative dose level between the current dose level and any previous lower dose level. [00288] The SRC, Principal Investigator or sponsor may terminate dose escalation at any time if continuing to a higher dose level would jeopardize the safety of the subjects. SRC reports will be submitted to the Ethics Committee for approval of dose escalation.
  • SAE serious adverse event
  • Two (2) or more subjects who receive Compound 1 exhibit tachycardia, defined as resting supine heart rate >130 beats per minute, persisting for at least 10 minutes.
  • the SRC may stop dose escalation at any time if the SRC determines that dose escalation would pose undue risk to subjects. If dose escalation is not stopped, the SRC may recommend ascending to the planned next-higher dose level cohort, ascending to a dose level lower than the planned next-higher dose level cohort, or a repeat dosing at the current dose level.
  • Adverse events include:
  • Adverse events should be assessed by the investigators as to whether or not there is a reasonable possibility of causal relationship to the study drug and reported as either related or unrelated.
  • a clinical event including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals.
  • the response to withdrawal of the drug should be clinically plausible.
  • the event must be definitive pharmacologically or phenomenologically, using a satisfactory re-challenge procedure if necessary.
  • - Probable A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information is not required to fulfill this definition.
  • a clinical event including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.
  • a Serious Adverse Event is defined by the International Conference on Harmonization (ICH) guidelines as any AE fulfilling at least one of the following criteria:
  • Life-threatening refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death if it were more severe.
  • SAEs Important medical events that may not immediately result in death, be life-threatening, or require hospitalization may be considered as SAEs when, based upon appropriate medical judgment, they may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions above.
  • All-treated set This analysis set includes all randomized subjects who received study drug (at least one dose).
  • Safety set This analysis set includes subjects from the all-treated set who had at least one safety assessment post-baseline. The safety set will be employed in the analysis of tolerability and safety variables.
  • Per-protocol set This analysis set comprises all subjects included in the All-treated set who did not violate the protocol in a way that might affect the evaluation of the effect of the study drug(s) on the primary endpoint, i.e., without major protocol violations or deviations.
  • the Per- protocol set will be employed in the analysis of PK variables.
  • the per-protocol analysis set will be used for all PK analyses. Individual subject listings will be provided for Compound 1. Mean and individual plasma concentration-time profiles for Compound 1 will be presented graphically for each group. PK variables will be summarized using arithmetic mean, standard deviation, geometric mean, median, minimum, maximum, and CV%. Attainment of steady-state conditions will be determined by visual inspection of the trough plasma concentrations.
  • Cardiodynamic Mean hourly heart rate will be analyzed for Part 1 (SAD) and Part 3 (MAD) as described in F. Study Assessments: Mean Hourly Heartrate.
  • the effect of Compound 1 on the placebo-corrected AQTcF, AHR (heart rate), APR, and AQRS (AAQTcF, AAHR, AAPR, and AAQRS) will also be evaluated at each post-dosing time point ('by-time point' analysis).
  • an analysis of categorical outliers will be performed for changes in HR, PR, QRS, and QTcF, and descriptive analysis of mean hourly HR will be performed.
  • Optional cardiodynamic evaluation and precision QT may be performed for Part 1 (SAD) and Part 3 (MAD), based on observed PK and other project considerations.
  • the analysis will be based on concentration-QTc (C-QTc) modeling of the relationship between the plasma concentrations of Compound 1 and its potential metabolites and change-from-baseline QTcF (AQTcF) with the intent to exclude an effect of placebo-corrected AQTcF (AAQTcF) > 10 msec at clinically relevant plasma concentrations.
  • C-QTc concentration-QTc
  • Serum tryptase levels SCF, CTX, 4P-hydroxy cholesterol and mast cell counts will be listed.
  • PD markers will be evaluated graphically and descriptive statistics of absolute values and change from baseline at each time point will be tabulated by treatment.
  • dose and PK parameters e.g., AUCs and C max
  • PD evaluations e.g., serum tryptase and mast cell counts
  • Additional types of relationships may be explored using nonlinear mixed-effect PK/PD modeling approaches if warranted.
  • dose and PK parameters e.g., AUCs and C max
  • safety evaluations e.g., ECGs

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Abstract

The present invention provides methods of treating c-kit kinase mediated diseases and disorders comprising orally administering to a patient in need thereof between 10 mg to 1000 mg of N-(5-(5-((1R, 2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2- methylphenyl)imidazo[1l,2-a]pyridine-3-carboxamide. Also provided is a method of treating a c-kit kinase mediated disease or disorder wherein the N-(5-(5-((1R, 2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3- carboxamide is administered, at least daily, in a first treatment cycle lasting at least 10 days.

Description

METHODS FOR TREATING C-KIT KINASE MEDIATED DISEASES AND DISORDERS USING A SELECTIVE C-KIT KINASE INHIBITOR
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No. 63/154,072, filed February 26, 2021, and U.S. Provisional Application No. 63/203,676, filed July 28, 2021, the entirety of each of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present disclosure relates to methods of treating c-kit kinase mediated diseases and disorders using a selective c-kit kinase inhibitor.
BACKGROUND
[0003] Mast-cell associated diseases afflict a substantial number of patients. For example, the incidence of asthma has been increasing the United States, where more than 25 million people in the United States have been reported to be suffering from asthma. The compound N-(5-(5- ((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, described in WO 2013/033070 Al, is a selective inhibitor of c-kit kinase, useful for the depletion of mast cells and thus is useful for treating mast-cell associated diseases including asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes and type II diabetes. Generally, the terms “c-kit kinase” and “KIT” both refer to the receptor tyrosine kinase protein encoded by proto-oncogene c-KIT, alternatively known as tyrosine-protein kinase KIT, CD117 or mast/stem cell growth factor receptor.
[0004] There remains a need in the art for methods for improved methods for administering N- (5-(5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2- a]pyridine-3 -carboxamide to a patient in need thereof and methods for treating c-kit associated diseases using the same. SUMMARY OF THE INVENTION
[0005] The present disclosure provides methods of treating c-kit kinase mediated diseases comprising administering to a patient in need thereof N-(5-(5-((lR,2S)-2-fluorocyclopropyl)- 1, 2, 4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3 -carboxamide. In general, the methods and dosing protocols disclosed herein are useful for treating mast-cell associated diseases as described herein.
PET ATT /ED DESCRIPTION OF THE INVENTION
[0006] The present disclosure provides methods for administering a selective c-kit kinase inhibitor to a patient suffering from a c-kit kinase mediated disease or disorder, wherein the selective c-kit kinase inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
Compound 1
[0007] In some embodiments, the present disclosure provides a method of treating a c-kit kinase mediated disease or disorder, comprising orally administering to a patient in need thereof a dose of Compound 1 in an amount of from about 10 mg to about 1,000 mg in order to treat the c-kit kinase mediated disease or disorder.
[0008] In some embodiments, the present disclosure provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a first therapeutic agent according to a first treatment cycle lasting at least 10 days, wherein the first therapeutic agent is Compound 1, and a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle. In some embodiments, the dosing protocol further comprises a non-treatment cycle following the first treatment cycle, wherein during the non-treatment cycle the patient does not receive the first therapeutic agent for a duration of at least 5 days. In some embodiments, the dosing protocol further comprises a second treatment cycle lasting at least 10 days, during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
Definitions
[0009] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.
[0010] As used herein, the term “Compound 1” or “study drug” refers to N-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, a compound having the following chemical structure:
Figure imgf000004_0001
[0011] Compound 1 is active in a variety of assays and therapeutic models, acting as a selective inhibitor of c-kit kinase. Compound 1 can be prepared according to example FI 10 of WO 2013/033070 Al, which is incorporated by reference herein, as summarized in the Scheme 1 provided below:
Figure imgf000004_0002
Figure imgf000004_0004
Figure imgf000004_0003
Scheme 1. Preparation of Compound 1
[0012] The terms “a,” “an” and “the” as used herein mean “one or more” and include the plural unless the context is inappropriate.
[0013] The term “about” means within 10% of the stated value. In certain embodiments, the value may be within 8%, 6%, 4%, 2%, or 1% of the stated value.
[0014] As used herein, the term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
[0015] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results. Unless specified otherwise, an effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
[0016] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use in vivo or ex vivo.
[0017] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Martin in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]
[0018] As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a patient, is capable of providing a compound of this invention. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
[0019] Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW3, wherein W is C1-4 alkyl, and the like.
[0020] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate (mesylate), 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, NEE+, and NW4 + (wherein W is a C1-4 alkyl group), and the like.
[0021] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
[0022] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. [0023] Throughout the description, where dosage amounts of a therapeutic agent are disclosed in terms of mass, the disclosed amount refers to the mass of the pure freebase form of the therapeutic agent.
[0024] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
I. Therapeutic Methods
[0025] The invention provides methods for treating patients suffering from a c-kit kinase mediated disease or disorder by administering to the patient Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention provides methods for treating patients suffering from a c-kit kinase mediated disease or disorder by administering to the patient Compound 1, or a pharmaceutically acceptable salt thereof, in certain dosages. The invention also provides methods of determining patient populations that may derive particular benefit from the therapeutic methods of the invention.
A. First Method
[0026] One aspect of the invention provides a method of treating a c-kit kinase mediated disease or disorder. The method comprises orally administering to a patient in need thereof a dose of Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of from about 10 mg to about 1,000 mg.
[0027] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 200 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 200 mg to about 400 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 200 mg to about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 300 mg to about 500 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 400 mg to about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 800 mg to about 1,000 mg.
[0028] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, or about 1,000 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 800 mg, or about 1,000 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 400 mg, or about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 10 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 200 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 400 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 500 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 800 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1,000 mg.
[0029] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient no more frequently than twice per day. In some embodiments,
Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient no more frequently than once per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient once per day (QD). In some embodiments,
Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient twice per day (BID). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient once every other day (QOD). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient two or more times per day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient once per day or twice per day.
[0030] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 7 days. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 14 days. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 21 days. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 1 month. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day for at least 3 months. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof is administered to the patient every day, for an indefinite period of time.
[0031] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 82,000 ng h/mL. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 72,500 ng h/mL.
B. Second Method
[0032] Another aspect of the invention provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a first therapeutic agent according to a first treatment cycle lasting at least 10 days, in order to treat the c-kit kinase mediated disease or disorder, wherein the first therapeutic agent is Compound 1, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle..
[0033] In some embodiments, the first treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 21 days. [0034] In some embodiments, the first treatment cycle lasts 10 days. In some embodiments, the first treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 21 days.
[0035] In some embodiments, the method comprises administering to the patient in need thereof the first therapeutic agent according to a first treatment cycle lasting 14 days, wherein a therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the first treatment cycle.
[0036] In some embodiments, the method further comprises a non-treatment cycle that takes place after the first treatment cycle, wherein during the non-treatment cycle the patient does not receive the first therapeutic agent for a duration of at least 7 days.
[0037] In some embodiments, the non-treatment cycle lasts at least 10 days. In some embodiments, the non-treatment cycle lasts at least 14 days. In some embodiments, the non treatment cycle lasts at least 21 days. In some embodiments, the non-treatment cycle lasts at least 28 days.
[0038] In some embodiments, the non-treatment cycle lasts 7 days. In some embodiments, the non-treatment cycle lasts 10 days. In some embodiments, the non-treatment cycle lasts 14 days. In some embodiments, the non-treatment cycle lasts 21 days. In some embodiments, the non treatment cycle lasts 28 days.
[0039] In some embodiments, the method further comprises a second treatment cycle that takes place after the non-treatment cycle. In some embodiments, after the non-treatment cycle, the first therapeutic agent is administered to the patient according to a second treatment cycle lasting at least 10 days during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
[0040] In some embodiments, the second treatment cycle lasts at least 14 days. In some embodiments, the second treatment cycle lasts at least 21 days.
[0041] In some embodiments, the second treatment cycle lasts 10 days. In some embodiments, the second treatment cycle lasts 14 days. In some embodiments, the second treatment cycle lasts 21 days. [0042] C. Third Method
[0043] Another aspect of the invention provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a first therapeutic agent, wherein the first therapeutic agent is Compound 1, or a pharmaceutically acceptable salt thereof.
[0044] In some embodiments, the method comprises administering to the patient in need thereof the first therapeutic agent according to a first treatment cycle, wherein a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle.
[0045] In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient no more frequently than twice per day on each day of the first treatment cycle. In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient twice per day on each day of the first treatment cycle. In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the first treatment cycle.
[0046] In some embodiments, the first treatment cycle lasts at least 3 days. In some embodiments, the first treatment cycle lasts at least 7 days. In some embodiments, the first treatment cycle lasts at least 10 days. In some embodiments, the first treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 21 days. In some embodiments, the first treatment cycle lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, or at least 21 days.
[0047] In some embodiments, the first treatment cycle lasts 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the first treatment cycle lasts 3 days. In some embodiments, the first treatment cycle lasts 7 days. In some embodiments, the first treatment cycle lasts 10 days. In some embodiments, the first treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 21 days. [0048] In some embodiments, the method comprises administering to the patient in need thereof the first therapeutic agent according to a first treatment cycle lasting 14 days, wherein a therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the first treatment cycle.
[0049] In some embodiments, the method further comprises a non-treatment cycle that takes place after the first treatment cycle, wherein during the non-treatment cycle the patient does not receive the first therapeutic agent.
[0050] In some embodiments, the non-treatment cycle lasts at least 2 days. In some embodiments, the non-treatment cycle lasts at least 5 days. In some embodiments, the non-treatment cycle lasts at least 7 days. In some embodiments, the non-treatment cycle lasts at least 10 days. In some embodiments, the non-treatment cycle lasts at least 14 days. In some embodiments, the non treatment cycle lasts at least 21 days. In some embodiments, the non-treatment cycle lasts at least 28 days. In some embodiments, the non-treatment cycle lasts at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, or at least 28 days.
[0051] In some embodiments, the non-treatment cycle lasts 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the non-treatment cycle lasts 2 days. In some embodiments, the non-treatment cycle lasts 5 days. In some embodiments, the non treatment cycle lasts 7 days. In some embodiments, the non-treatment cycle lasts 10 days. In some embodiments, the non-treatment cycle lasts 14 days. In some embodiments, the non-treatment cycle lasts 21 days. In some embodiments, the non-treatment cycle lasts 28 days.
[0052] In some embodiments, the method further comprises a second treatment cycle that takes place after the non-treatment cycle. In some embodiments, after the non-treatment cycle, the first therapeutic agent is administered to the patient according to a second treatment cycle during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle. [0053] In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient no more frequently than twice per day on each day of the second treatment cycle. In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient twice per day on each day of the second treatment cycle. In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the second treatment cycle.
[0054] In some embodiments, the second treatment cycle lasts at least 3 days. In some embodiments, the second treatment cycle lasts at least 7 days. In some embodiments, the second treatment cycle lasts at least 10 days. In some embodiments, the second treatment cycle lasts at least 14 days. In some embodiments, the second treatment cycle lasts at least 21 days. In some embodiments, the second treatment cycle lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, or at least 21 days.
[0055] In some embodiments, the second treatment cycle lasts 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the second treatment cycle lasts 3 days. In some embodiments, the second treatment cycle lasts 7 days. In some embodiments, the second treatment cycle lasts 10 days. In some embodiments, the second treatment cycle lasts 14 days. In some embodiments, the second treatment cycle lasts 21 days.
D. Fourth Method
[0056] Another aspect of the invention provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a first therapeutic agent, wherein the first therapeutic agent is a c-kit kinase inhibitor. In a more specific embodiment, the invention provides a method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a first therapeutic agent according to a first treatment cycle lasting at least 10 days, in order to treat the c-kit kinase mediated disease or disorder, wherein the first therapeutic agent is c-kit kinase inhibitor, and a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle. In certain embodiments, the c-kit kinase inhibitor is a small organic compound, or a pharmaceutically acceptable salt thereof. In certain embodiments, the first therapeutic agent is (a) BLU-263, avapritinib, masitinib, HT-KIT, CGT-9846, AZD 3229, axitinib, foretinib, regorafenib, sorafenib, dasatinib, imatinib, pazopanib, pexidartinib, lenvatinib, cabozantinib, M4205, dovitinib, chiauranib, ripretinib, sitravatinib, flumatinib, amuvatinib, linifanib, telatinib, motesanib, tandutinib, toceranib, AST 487, KΪ20227, SU14813, ISCK03, OSI-930, PLX647, DCC- 3014, AC710, tyrphostin AG1296, SU14813, AZD2932, c-Kit-IN-1, c-Kit-IN-2, CHMFL-ABL- KIT-155, KG5, PD180970, JTSTJ-38158471 , or HG-7-85-01; or a pharmaceutically acceptable salt thereof; or (b) CDX-0159, CDX-0158, NN-2101, NN-2901, FSI-174 or JSP-191.
1. Small molecule c-kit kinase inhibitors
[0057] In some embodiments, the c-kit kinase inhibitor is a small organic compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is avapritinib, BLU-263, masitinib, HT-KIT, CGT-9846, AZD 3229, axitinib, foretinib, regorafenib, sorafenib, dasatinib, imatinib, pazopanib, pexidartinib, lenvatinib, cabozantinib, M4205, dovitinib, chiauranib, ripretinib, sitravatinib, flumatinib, amuvatinib, linifanib, telatinib, motesanib, tandutinib, toceranib, AST 487, KΪ20227, SU14813, ISCK03, OSI-930, PLX647, DCC-3014, AC710, tyrphostin AG1296, SU14813, AZD2932, c-Kit-IN-1, c-Kit-IN-2, CHMFL- ABL-KIT - 155, KG5, PD180970, JNJ-38158471, or HG-7-85-01, or a pharmaceutically acceptable salt of any of the aforementioned.
[0058] Exemplary small molecule c-kit kinase inhibitors are disclosed below. The entire disclosure of each of the patent documents and scientific articles referred to below is incorporated by reference.
[0059] In some embodiments, the c-kit kinase inhibitor is avapritinib, or a pharmaceutically acceptable salt thereof. Avapritinib, (S)-l-(4-fluorophenyl)-l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)ethan- 1 -amine, alternatively known as AYVAKIT™ and Ayvakyt is a compound with the following structure:
Figure imgf000015_0001
[0060] Avapritinib is disclosed in U.S. Patent Nos. 9,200,002; 9,944,651; and 9,994,575. The synthesis of avapritinib is disclosed in International Publication No. WO 2015/057873. Crystalline forms of avapritinib are disclosed in International Publication No. WO 2020/210669.
[0061] In some embodiments, the c-kit kinase inhibitor is masitinib, or a pharmaceutically acceptable salt thereof. Masitinib, N-(4-methyl-3-((4-(pyridin-3-yl)thiazol-2-yl)amino)phenyl)-4- ((4-methylpiperazin- l-yl)m ethyl )benzamide, alternatively known as AB1010, MASIVET®, and Kinavet, is a compound with the following structure:
Figure imgf000015_0002
[0062] Masitinib is disclosed in U.S. Patent Nos. 7,423,055, and the synthesis of masitinib is disclosed in International Publication No. WO 2008/098949. In some embodiments, the c-kit kinase inhibitor is the mesylate salt of masitinib.
[0063] In some embodiments, the c-kit kinase inhibitor is CGT-9486, or a pharmaceutically acceptable salt thereof. CGT-9486 is alternatively known as PLX-9486.
[0064] In some embodiments, the c-kit kinase inhibitor is a compound disclosed in one of International Publication Nos. WO 2014/194127, WO 2016/16464, WO 2017/019804, WO 2017/053243, WO 2017/100201, WO 2017/161045, WO 2018/226846, WO 2014/145051 and WO 2019/075243. In some embodiments, the c-kit kinas inhibitor is (S)-4-(6-(3,5- dimethylisoxazol-4-yl)-l-(l-(pyridin-2-yl)ethyl)-lH-pyrrolo[3,2-b]pyridin-3-yl)benzoic acid:
Figure imgf000016_0001
[0065] (S)-4-(6-(3,5-dimethylisoxazol-4-yl)-l-(l-(pyridin-2-yl)ethyl)-lH-pyrrolo[3,2- b]pyridin-3-yl)benzoic acid is disclosed in International Publication Nos. WO 2014/145051 and WO 2019/075243.
[0066] In some embodiments, the c-kit kinase inhibitor is AZD 3229, or a pharmaceutically acceptable salt thereof. AZD 3229, N-[4-[[5-fluoro-7-(2-methoxyethoxy)-4- quinazolinyl]amino]phenyl]-4-(l-methylethyl)-lH-l,2,3-triazole-l-acetamide, is a compound with the following structure:
Figure imgf000016_0002
[0067] AZD 3229 is disclosed in Banks, et al., Science Translational Medicine, 29 Apr 2020: Vol. 12, Issue 541, eaaz2481.
[0068] In some embodiments, the c-kit kinase inhibitor is axitinib, or a pharmaceutically acceptable salt thereof. Axitinib, N-Methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-lH-indazol-6- yl]sulfanyl]benzamide, alternatively known as AG 013736 and INLYTA®, is a compound with the following structure:
Figure imgf000017_0001
[0069] Axitinib, as well as pharmaceutically acceptable salts thereof, is described in U.S. Pat. No. 6,534,524. Methods of making axitinib are described in U.S. Pat. Nos. 6,884,890 and 7,232,910, in U.S. Publication Nos. 2006/0091067 and 2007/0203196 and in International Publication No. WO 2006/048745. Dosage forms of axitinib are described in U.S. Publication No. 2004/0224988. Polymorphic forms and pharmaceutical compositions of axitinib are also described in U.S. Pat. No. 8,791,140 and U.S. Publication Nos. 2006/0094763, 2008/0274192, and 2014/0248347. Uses of axitinib, including use as a single agent or in combination treatment, are described in U.S. Pat. No. 7,141,581 and in U.S. Publication No. 2014/0288125.
[0070] In some embodiments, the c-kit kinase inhibitor is foretinib, or a pharmaceutically acceptable salt thereof. Foretinib, Afl-[3-Fluoro-4-( { 6-methoxy-7-[3-(morpholin-4- yl)propoxy]quinolin-4-yl } oxy)phenyl]-A'1-(4-fluorophenyl)cyclopropane- 1 , 1 -di carboxamide, alternatively known as GSK1363089 and XL880, is a compound with the following structure:
Figure imgf000017_0002
[0071] Foretinib and pharmaceutically acceptable salts thereof, are described in International Publication No. WO 2005/030140. Methods of treatment using foretinib are described in International Publication No. WO 2012/071321.
[0072] In some embodiments, the c-kit kinase inhibitor is regorafenib, or a pharmaceutically acceptable salt thereof. Regorafenib, 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)-3- fluorophenoxy)-N-methylpicolinamide, alternatively known as BAY 73-4506 and STIVARGA®, is a compound with the following structure:
Figure imgf000018_0001
[0073] Regorafenib and pharmaceutically acceptable salts thereof, are described in International Publication No. WO 2005/009961, in Example 1. Polymorphic forms of regorafenib are described in International Publication No. WO 2008/058644.
[0074] In some embodiments, the c-kit kinase inhibitor is sorafenib, or a pharmaceutically acceptable salt thereof. Sorafenib, 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)- amino]phenoxy}-N-methylpyridine-2-carboxamide, alternatively known as BAY 43-9006 and NEXAVAR®, is a compound with the following structure:
Figure imgf000018_0002
[0075] Sorafenib and pharmaceutically acceptable salts thereof, are described in International Publication Nos. WO 2000/042012, in Example Cla, and in WO 2003/068228. Crystalline salt forms of sorafenib are described in International Publication No. WO 2006/034797. In some embodiments, the c-kit kinas inhibitor is sorafenib tosylate.
[0076] In some embodiments, the c-kit kinase inhibitor is dasatinib, or a pharmaceutically acceptable salt thereof. Dasatinib, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l- piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate, alternatively known as BMS-354B25, SPRYCEL® and Dasanix, is a compound with the following structure:
Figure imgf000018_0003
[0077] Dasatinib and pharmaceutically acceptable salts thereof, are described in U.S. Patent No. 6,596,746. Methods of treatment using dasatinib and salts thereof are described in U.S. Patent Nos. 7,125,875 and 7,153,856. Processes of making dasatinib and polymorphs and salt forms of dasatinib are described in U.S. Patent Nos. 7,491,725 and 8,680,103.
[0078] In some embodiments, the c-kit kinase inhibitor is imatinib, or a pharmaceutically acceptable salt thereof. Imatinib, 4-[(4-methylpiperazin-l-yl)methyl]-/V-[4-methyl-3-[(4-pyridin- 3-ylpyrimidin-2-yl)amino]phenyl]benzamide, alternatively known as STI571, GLEEVEC® and GLIVEC®, is a compound with the following structure:
Figure imgf000019_0001
[0079] Imatinib and pharmaceutically acceptable salts thereof, are described in European Patent No. EP0564409B1. Processes of making imatinib and polymorphs and salt forms of imatinib are described in International Publication No. WO 1999/003854.
[0080] In some embodiments, the c-kit kinase inhibitor is pazopanib, or a pharmaceutically acceptable salt thereof. Pazopanib, 5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2- yl]amino]-2-methylbenzenesulfonamide is a compound with the following structure:
Figure imgf000019_0002
[0081] The hydrochloride salt of pazopanib is alternatively known as GW786034 HC1 and VORIENT®. Pazopanib and pharmaceutically acceptable salts thereof, are described in U.S. Patent Nos. 7,105,530 and 7,262,203. The HC1 salt form and pharmaceutical compositions of pazopanib are described in U.S. Patent No. 8,114,885. Processes of making imatinib and polymorphs and salt forms of imatinib are described in International Publication No. WO 1999/003854. In some embodiments, the c-kit kinase inhibitor is a hydrochloride salt of pazopanib. [0082] aln some embodiments, the c-kit kinase inhibitor is pexidartinib, or a pharmaceutically acceptable salt thereof. Pexidartinib, 5-((5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6- (trifluorom ethyl)pyri din-3 -yl)methyl)pyridin-2-amine, alternatively known as PLX-3397, and TURALIO®, is a compound with the following structure:
Figure imgf000020_0001
[0083] Pexidartinib is disclosed in U.S. Pat. No. 7,893,075, U.S. Publication No. 2014-0037617 and U.S. Publication No. 2013-0274259. Crystalline freebase and salt forms of pexidartinib are disclosed in International Publication No. WO 2016/179415. In some embodiments, the c-kit kinase inhibitor is pexidartinib hydrochloride.
[0084] In some embodiments, the c-kit kinase inhibitor is lenvatinib, or a pharmaceutically acceptable salt thereof. Lenvatinib, 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7- methoxyquinoline-6-carboxamide, alternatively known as E7080 and LENVIMA®, is a compound with the following structure:
Figure imgf000020_0002
[0085] Lenvatinib and methods of making and using lenvatinib are disclosed in U.S. Publication Nos. US2004/0053908, US2007/0004773, US2007/0037849, US2007/0078159, US2007/0117842 and US2017/0233344. In some embodiments, the c-kit kinase inhibitor is Lenvatinib mesylate.
[0086] In some embodiments, the c-kit kinase inhibitor is cabozantinib, or a pharmaceutically acceptable salt thereof. Cabozantinib, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4- fluorophenyl)cy cl opropane- 1,1 -dicarboxamide, alternatively known as XL 184, BMS-907351, and CABOMETYX®, is a compound with the following structure:
Figure imgf000021_0001
[0087] Cabozantinib is disclosed in International Publication No. W02005/030140, as Compound 12, Example 48. In some embodiments, the c-kit kinase inhibitor is cabozantinib s- malate. Cabozantinib and salts thereof are also described in U.S. Patents Nos. 8,877,776; 7,579,473; 8,497,284; 9,724,342; 9,717,720; 10,039,757; and 10,034,873.
[0088] In some embodiments, the c-kit kinase inhibitor is M4205, or a pharmaceutically acceptable salt thereof. M4205, N-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-6-(7-(3-(pyrrolidin-l- yl)propoxy)imidazo[l,2-a]pyri din-3 -yl)pyrimidin-4-amine, is a compound with the following structure:
Figure imgf000021_0002
[0089] In some embodiments, the c-kit kinase inhibitor is dovitinib, or a pharmaceutically acceptable salt thereof. Dovitinib, 4-amino-5-fluoro-3-(6-(4-methylpiperazin-l-yl)-lH- benzo[d]imidazol-2-yl)quinolin-2(lH)-one, alternatively known as TKI258, and CHIR-258, is a compound with the following structure:
Figure imgf000021_0003
[0090] Dovitinib is disclosed in U.S. Patent No. 6,774,237 and International Publication No. WO 2006/127926. In some embodiments, the c-kit kinase inhibitor is dovitinib lactate hydrate. [0091] In some embodiments, the c-kit kinase inhibitor is chiauranib, or a pharmaceutically acceptable salt thereof. Chiauranib, N-(2-aminophenyl)-6-((7-methoxyquinolin-4-yl)oxy)-l- naphthamide, alternatively known as CS2164, is a compound with the following structure:
Figure imgf000022_0001
[0092] Chiauranib is disclosed in U.S. Patent No. 8,211,901 as compound 31.
[0093] In some embodiments, the c-kit kinase inhibitor is ripretinib, or a pharmaceutically acceptable salt thereof. Ripretinib, l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro- l,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, also known as DCC-2618, is a compound with the following structure:
Figure imgf000022_0002
[0094] Ripretinib is disclosed in U.S. Patent Nos. 8,940,756; 8,461,179; and 8,188,113.
[0095] In some embodiments, the c-kit kinase inhibitor is sitravatinib, or a pharmaceutically acceptable salt thereof. Sitravatinib, N-(3-fluoro-4-((2-(5-(((2- methoxy ethyl)amino)methyl)pyri din-2 -yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4- fluorophenyl)cy cl opropane- 1,1 -dicarboxamide, also known as MGCD516, or MG-516, is a compound with the following structure:
Figure imgf000023_0001
[0096] Sitravatinib is disclosed in U.S. Patent No. 8,404,846 as Example 15. In some embodiments, the c-kit kinase inhibitor is sitravatinib malate.
[0097] In some embodiments, the c-kit kinase inhibitor is flumatinib, or a pharmaceutically acceptable salt thereof. Flumatinib, 4-[(4-methylpiperazin-l-yl)methyl]-N-[6-methyl-5-[(4- pyridin-3-ylpyrimidin-2-yl)amino]pyridin-3-yl]-3-(trifluoromethyl)benzamide, also known as HHGV678, is a compound with the following structure:
Figure imgf000023_0002
[0098] Flumatinib is disclosed in U.S. Patent No. 8,183,242 as Example 11. In some embodiments, the c-kit kinase inhibitor is flumatinib mesylate.
[0099] In some embodiments, the c-kit kinase inhibitor is amuvatinib, or a pharmaceutically acceptable salt thereof. Amuvatinib, N-(benzo[d][l,3]dioxol-5-ylmethyl)-4-(benzofuro[3,2- d]pyrimidin-4-yl)piperazine-l-carbothioamide, also known as MP470, and HPK 56, is a compound with the following structure:
Figure imgf000024_0001
[00100] Amuvatinib is disclosed in U.S. Patent No. 8,552,018 as compound (III-1-3). In some embodiments, the c-kit kinase inhibitor is amuvatinib hydrochloride.
[00101] In some embodiments, the c-kit kinase inhibitor is linifanib, or a pharmaceutically acceptable salt thereof. Linifanib, l-[4-(3-amino-lH-indazol-4-yl)phenyl]-3-(2-fluoro-5- methylphenyl)urea, also known as ABT-869, and AL-39324, is a compound with the following structure:
Figure imgf000024_0002
[00102] Linifanib is disclosed in Drugs R D. 2010 Jul; 10(2): 111-122.
[00103] In some embodiments, the c-kit kinase inhibitor is telatinib, or a pharmaceutically acceptable salt thereof. Telatinib, 4-(((4-((4-chlorophenyl)amino)furo[2,3-d]pyridazin-7- yl)oxy)methyl)-N-methylpicolinamide, also known as Bay 57-9352, is a compound with the following structure:
Figure imgf000024_0003
[00104] Telatinib and related compounds are disclosed in U.S. Patent No. 6,689,883.
[00105] In some embodiments, the c-kit kinase inhibitor is motesanib, or a pharmaceutically acceptable salt thereof. Motesanib, 4N-(3,3-Dimethyl-2,3-dihydro-lH-indol-6-yl)-2-{[(pyridin-4- yl)methyl]amino}pyridine-3-carboxamide, also known as AMG 706, is a compound with the following structure:
Figure imgf000025_0001
[00106] Motesanib and related compounds are described in U.S. Patent No. 8,642,624. In some embodiments, the c-kit kinase inhibitor is motesanib diphosphate.
[00107] In some embodiments, the c-kit kinase inhibitor is tandutinib, or a pharmaceutically acceptable salt thereof. Tandutinib, 4-[6-methoxy-7-(3-piperidin-l-ylpropoxy)quinazolin-4-yl]- /V-(4-propan-2-yloxyphenyl)piperazine-l -carboxamide, also known as MLN518, CT53518, and NSC726292, is a compound with the following structure:
Figure imgf000025_0002
[00108] Tandutinib and related compounds are described in U.S. Patent No. 6,982,266. In some embodiments, the c-kit kinase inhibitor is tandutinib hydrochloride.
[00109] In some embodiments, the c-kit kinase inhibitor is toceranib, or a pharmaceutically acceptable salt thereof. Toceranib, (Z)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4- dimethyl-N-(2-(pyrrolidin-l-yl)ethyl)-lH-pyrrole-3-carboxamide, also known as PALLADIA® SU11654, and PHA 291639E, is a compound with the following structure:
Figure imgf000026_0001
[00110] Toceranib and related compounds are described in U.S. Patent No. 6,573,293 as Example 129. In some embodiments, the c-kit kinase inhibitor is toceranib phosphate.
[00111] In some embodiments, the c-kit kinase inhibitor is HT-KIT, or a pharmaceutically acceptable salt thereof.
[00112] In some embodiments, the c-kit kinase inhibitor is BLU-263, or a pharmaceutically acceptable salt thereof.
[00113] In some embodiments, the c-kit kinase inhibitor is a c-kit kinase inhibitor disclosed in U.S. Patent No. 10,000,496.
[00114] In some embodiments, the c-kit kinase inhibitor is AST 487, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is KΪ20227, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is SU14813, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is ISCK03, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is OSI-930, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is PLX647, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is DCC-3014, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is AC710, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is tyrphostin AG1296, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is SU14813, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is AZD2932, or a pharmaceutically acceptable salt thereof. In some embodiments, the c- kit kinase inhibitor is c-Kit-IN-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is c-Kit-IN-2, or a pharmaceutically acceptable salt thereof.
In some embodiments, the c-kit kinase inhibitor is CHMFL-ABL-KIT-155, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is KG5, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is PD 180970, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is JNJ-38158471, or a pharmaceutically acceptable salt thereof. In some embodiments, the c-kit kinase inhibitor is or HG-7-85-01, or a pharmaceutically acceptable salt thereof.
2. Antibody c-kit kinase inhibitors
[00115] In some embodiments, the c-kit kinase inhibitor is an antibody. In some embodiments, the c-kit kinase inhibitor is an antibody selected from CDX-0159, CDX-0158, NN-2101, NN- 2901, FSI-174 and JSP-191. In some embodiments, the c-kit kinase inhibitor is CDX-0159. In some embodiments, the c-kit kinase inhibitor is CDX-0158. In some embodiments, the c-kit kinase inhibitor is NN-2101. In some embodiments, the c-kit kinase inhibitor is NN-2901. In some embodiments, the c-kit kinase inhibitor is FSI-174. In some embodiments, the c-kit kinase inhibitor is J SP- 191.
[00116] In some embodiments, the c-kit kinase inhibitor is an antibody disclosed in one of International Publication Nos. WO 2020/076105, WO 2021/107566, WO 2020/112687, WO 2020/242895, WO 2012/103165, WO 2014/018625, WO 2015/179737, or WO 2007/127317 or U.S. Patent No. 10,239,943, each of which is incorporated by reference in its entirety.
3. Treatment Cycles
[00117] In some embodiments, the method comprises administering to the patient in need thereof the first therapeutic agent according to a first treatment cycle, wherein a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle.
[00118] In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient no more frequently than twice per day on each day of the first treatment cycle. In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient twice per day on each day of the first treatment cycle. In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the first treatment cycle. [00119] In some embodiments, the first treatment cycle lasts at least 3 days. In some embodiments, the first treatment cycle lasts at least 7 days. In some embodiments, the first treatment cycle lasts at least 10 days. In some embodiments, the first treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 21 days. In some embodiments, the first treatment cycle lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, or at least 21 days.
[00120] In some embodiments, the first treatment cycle lasts 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the first treatment cycle lasts 3 days. In some embodiments, the first treatment cycle lasts 7 days. In some embodiments, the first treatment cycle lasts 10 days. In some embodiments, the first treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 21 days.
[00121] In some embodiments, the method comprises administering to the patient in need thereof the first therapeutic agent according to a first treatment cycle lasting 14 days, wherein a therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the first treatment cycle.
[00122] In some embodiments, the method further comprises a non-treatment cycle that takes place after the first treatment cycle, wherein during the non-treatment cycle the patient does not receive the first therapeutic agent.
[00123] In some embodiments, the non-treatment cycle lasts at least 2 days. In some embodiments, the non-treatment cycle lasts at least 5 days. In some embodiments, the non-treatment cycle lasts at least 7 days. In some embodiments, the non-treatment cycle lasts at least 10 days. In some embodiments, the non-treatment cycle lasts at least 14 days. In some embodiments, the non treatment cycle lasts at least 21 days. In some embodiments, the non-treatment cycle lasts at least 28 days. In some embodiments, the non-treatment cycle lasts at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, or at least 28 days.
[00124] In some embodiments, the non-treatment cycle lasts 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the non-treatment cycle lasts 2 days. In some embodiments, the non-treatment cycle lasts 5 days. In some embodiments, the non treatment cycle lasts 7 days. In some embodiments, the non-treatment cycle lasts 10 days. In some embodiments, the non-treatment cycle lasts 14 days. In some embodiments, the non-treatment cycle lasts 21 days. In some embodiments, the non-treatment cycle lasts 28 days.
[00125] In some embodiments, the method further comprises a second treatment cycle that takes place after the non-treatment cycle. In some embodiments, after the non-treatment cycle, the first therapeutic agent is administered to the patient according to a second treatment cycle during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
[00126] In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient no more frequently than twice per day on each day of the second treatment cycle. In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient twice per day on each day of the second treatment cycle. In some embodiments, the therapeutically effective amount of the first therapeutic agent is administered to the patient once per day on each day of the second treatment cycle.
[00127] In some embodiments, the second treatment cycle lasts at least 3 days. In some embodiments, the second treatment cycle lasts at least 7 days. In some embodiments, the second treatment cycle lasts at least 10 days. In some embodiments, the second treatment cycle lasts at least 14 days. In some embodiments, the second treatment cycle lasts at least 21 days. In some embodiments, the second treatment cycle lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, or at least 21 days.
[00128] In some embodiments, the second treatment cycle lasts 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In some embodiments, the second treatment cycle lasts 3 days. In some embodiments, the second treatment cycle lasts 7 days. In some embodiments, the second treatment cycle lasts 10 days. In some embodiments, the second treatment cycle lasts 14 days. In some embodiments, the second treatment cycle lasts 21 days.
E. Additional Exemplary Features of the Second, Third, and Fourth Therapeutic Methods
[00129] Additional exemplary features that may characterize the Second, Third, and Fourth Therapeutic Methods described herein are provided below and include, for example, the dosage amounts and the use of biomarkers to determine the duration of the first treatment cycle, non treatment cycle and second treatment cycle.
1. Use of Biomarkers to Determine Treatment Regimen
[00130] In some embodiments, the duration of the first treatment cycle is determined based on the value of one or more pharmacodynamic parameters in a sample collected from the patient. In some embodiments, the one or more pharmacodynamic parameters are concentration levels of one or more biomarkers indicative of effective treatment of a c-kit kinase mediated disease or disorder. In some embodiments, the one or more biomarkers indicative of effective treatment of a c-kit kinase mediated disease or disorder is a biomarker used to determine c-kit engagement, for instance, measurement of stem cell factor concentration in a sample collected from the patient.
[00131] In some embodiments, the duration of the first treatment cycle is determined based on mast cell density in a skin biopsy collected from the patient. In some embodiments, the first treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below a threshold determined to indicate effective treatment of the c-kit kinase mediated disease or disorder. In some embodiments, the first treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 75% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle. In some embodiments, the first treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 50% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle. In some embodiments, the first treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 25% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle.
[00132] In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 3 days, and mast cell density measured from a skin biopsy collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 3 additional days. In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 10 days, and mast cell density measured from a skin biopsy collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 5 additional days. In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 14 days, and mast cell density measured from a skin biopsy collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 7 additional days. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 25% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 50% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 75% from pretreatment levels.
[00133] In some embodiments, the duration of the first treatment cycle is determined based on the concentration of serum tryptase in a blood sample collected from the patient. In some embodiments, the first treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below a threshold determined to indicate effective treatment of the c-kit kinase mediated disease or disorder. In some embodiments, the first treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 75% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle. In some embodiments, the first treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 50% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle. In some embodiments, the first treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 25% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle.
[00134] In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 3 days, and serum tryptase concentration measured from a blood sample collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 3 additional days. In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 10 days, and serum tryptase concentration measured from a blood sample collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 5 additional days. In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the first treatment cycle for a duration of at least 14 days, and serum tryptase concentration measured from a blood sample collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the first treatment cycle is continued for at least 7 additional days. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 25% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 50% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 75% from pretreatment levels. [00135] In some embodiments, the duration of the non-treatment cycle is determined based on the value of one or more pharmacodynamics parameters in a sample collected from the patient. In some embodiments, the one or more pharmacodynamics parameters are concentration levels of one or more biomarkers indicative of mast cell recovery from the treatment during the first treatment cycle.
[00136] In some embodiments, the duration of the non-treatment cycle is determined based on mast cell density in a skin biopsy collected from the patient. In some embodiments, the non treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is above a threshold determined to indicate recovery of mast cells that had been depleted through the administration of the first therapeutic agent during the first treatment cycle. In some embodiments, the non-treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient has returned to at least 75% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle. In some embodiments, the non-treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient has returned to at least 50% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle. In some embodiments, the non-treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient has returned to at least 25% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle.
[00137] In some embodiments, if the non-treatment cycle has lasted for a duration of at least 2 days, and mast cell density measured from a skin biopsy collected from the patient has not returned to a level determined to indicate recovery of mast cells from depletion due to treatment with the first therapeutic agent during the first treatment cycle, then the non-treatment cycle is extended for at least 2 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and mast cell density measured from a skin biopsy collected from the patient has not returned to a level determined to indicate recovery of mast cells from depletion due to treatment with the first therapeutic agent during the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and mast cell density measured from a skin biopsy collected from the patient has not returned to at least 75% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle, then the non- treatment cycle is extended for at least 7 additional days. In some embodiments, if the non treatment cycle has lasted for a duration of at least 7 days, and mast cell density measured from a skin biopsy collected from the patient has not returned to at least 50% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and mast cell density measured from a skin biopsy collected from the patient has not returned to at least 25% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days.
[00138] In some embodiments, the duration of the non-treatment cycle is determined based on the serum tryptase concentration measured from a blood sample collected from the patient. In some embodiments, the non-treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is above a threshold determined to indicate recovery of mast cells that had been depleted through the administration of the first therapeutic agent during the first treatment cycle. In some embodiments, the non-treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient has returned to at least 75% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle. In some embodiments, the non-treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient has returned to at least 50% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle. In some embodiments, the non-treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient has returned to at least 25% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle.
[00139] In some embodiments, if the non-treatment cycle has lasted for a duration of at least 2 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to a level determined to indicate recovery of mast cells from depletion due to treatment with the first therapeutic agent during the first treatment cycle, then the non-treatment cycle is extended for at least 2 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to a level determined to indicate recovery of mast cells from depletion due to treatment with the first therapeutic agent during the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to at least 75% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to at least 50% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days. In some embodiments, if the non-treatment cycle has lasted for a duration of at least 7 days, and serum tryptase concentration measured from a blood sample collected from the patient has not returned to at least 25% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the first treatment cycle, then the non-treatment cycle is extended for at least 7 additional days.
[00140] In some embodiments, the duration of the second treatment cycle is determined based on the value of one or more pharmacodynamics parameters in a sample collected from the patient. In some embodiments, the one or more pharmacodynamics parameters are concentration levels of one or more biomarkers indicative of effective treatment of a c-kit kinase mediated disease or disorder.
[00141] In some embodiments, the duration of the second treatment cycle is determined based on mast cell density in a skin biopsy collected from the patient. In some embodiments, the second treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below a threshold determined to indicate effective treatment of the c-kit kinase mediated disease or disorder. In some embodiments, the second treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 75% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the second treatment cycle. In some embodiments, the second treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 50% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the second treatment cycle. In some embodiments, the second treatment cycle ends once the mast cell density measured from a skin biopsy collected from the patient is below 25% of the mast cell density measured from a skin biopsy collected from the patient before the onset of the second treatment cycle.
[00142] In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the second treatment cycle for a duration of at least 3 days, and mast cell density measured from a skin biopsy collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the second treatment cycle is continued for at least 3 additional days. In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the second treatment cycle for a duration of at least 10 days, and mast cell density measured from a skin biopsy collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the second treatment cycle is continued for at least 5 additional days. In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the second treatment cycle for a duration of at least 14 days, and mast cell density measured from a skin biopsy collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the second treatment cycle is continued for at least 7 additional days. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 25% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 50% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in mast cell density of at least 75% from pretreatment levels.
[00143] In some embodiments, the duration of the second treatment cycle is determined based on the concentration of serum tryptase in a blood sample collected from the patient. In some embodiments, the second treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below a threshold determined to indicate effective treatment of the c-kit kinase mediated disease or disorder. In some embodiments, the second treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 75% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the second treatment cycle. In some embodiments, the second treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 50% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the second treatment cycle. In some embodiments, the second treatment cycle ends once the serum tryptase concentration measured from a blood sample collected from the patient is below 25% of the serum tryptase concentration measured from a blood sample collected from the patient before the onset of the second treatment cycle.
[00144] In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the second treatment cycle for a duration of at least 3 days, and serum tryptase concentration measured from a blood sample collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the second treatment cycle is continued for at least 3 additional days. In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the second treatment cycle for a duration of at least 10 days, and serum tryptase concentration measured from a blood sample collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the second treatment cycle is continued for at least 5 additional days. In some embodiments, if the first therapeutic agent has been administered to the patient on each day of the second treatment cycle for a duration of at least 14 days, and serum tryptase concentration measured from a blood sample collected from the patient has not decreased from pretreatment levels by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, then the second treatment cycle is continued for at least 7 additional days. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 25% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 50% from pretreatment levels. In some embodiments, the amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder is a decrease in serum tryptase concentration of at least 75% from pretreatment levels. 2. Dosages amounts for the First Treatment Cycle and Second Treatment Cycle
[00145] In some embodiments, the first therapeutic agent is orally administered to the patient on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient on each day of the second treatment cycle.
[00146] In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 10 mg to about 1,000 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 10 mg to about 200 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 200 mg to about 400 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 300 mg to about 500 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 400 mg to about 800 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 800 mg to about 1,000 mg on each day of the first treatment cycle.
[00147] In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 800 mg, or about 1,000 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 800 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 400 mg, or about 800 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 10 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 30 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 100 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 200 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 300 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 400 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 500 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 800 mg on each day of the first treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 1,000 mg on each day of the first treatment cycle.
[00148] In some embodiments, the dose of the first therapeutic agent during the first treatment cycle is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 82,000 ng h/mL. In some embodiments, the dose of the first therapeutic agent during the first treatment cycle is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 72,500 ng h/mL.
[00149] In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 10 mg to about 1,000 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 10 mg to about 200 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 200 mg to about 400 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 300 mg to about 500 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 400 mg to about 800 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in an amount from about 800 mg to about 1,000 mg on each day of the second treatment cycle.
[00150] In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 800 mg, or about 1,000 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 10 mg, about 30 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 800 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 0 mg, about 30 mg, about 100 mg, about 200 mg, about 400 mg, or about 800 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 10 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 30 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 100 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 200 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 300 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 400 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 500 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 800 mg on each day of the second treatment cycle. In some embodiments, the first therapeutic agent is orally administered to the patient in a dose of about 1,000 mg on each day of the second treatment cycle.
[00151] In some embodiments, the dose of the first therapeutic agent during the second treatment cycle is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 82,000 ng h/mL. In some embodiments, the dose of the first therapeutic agent during the second treatment cycle is such that the patient’s Compound 1 blood plasma AUCo-24hr does not exceed about 72,500 ng h/mL.
3. Exemplary Treatment Cycles
[00152] In some embodiments, the first treatment cycle lasts at least 14 days, and the non treatment cycle lasts at least 7 days. In some embodiments, the first treatment cycle lasts at least 14 days, and the non-treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 14 days, and the non-treatment cycle lasts at least 21 days. In some embodiments, the first treatment cycle lasts at least 14 days, and the non-treatment cycle lasts at least 28 days.
[00153] In some embodiments, the first treatment cycle lasts 14 days, and the non-treatment cycle lasts 7 days. In some embodiments, the first treatment cycle lasts 14 days, and the non treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 14 days, and the non-treatment cycle lasts 21 days. In some embodiments, the first treatment cycle lasts 14 days, and the non-treatment cycle lasts 28 days.
[00154] In some embodiments, the first treatment cycle lasts at least 14 days, the non-treatment cycle lasts at least 7 days and the second treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 14 days, the non-treatment cycle lasts at least 14 days and the second treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 14 days, the non -treatment cycle lasts at least 21 days and the second treatment cycle lasts at least 14 days. In some embodiments, the first treatment cycle lasts at least 14 days, the non-treatment cycle lasts at least 28 days and the second treatment cycle lasts at least 14 days.
[00155] In some embodiments, the first treatment cycle lasts 14 days, the non-treatment cycle lasts 7 days and the second treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 14 days, the non-treatment cycle lasts 14 days and the second treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 14 days, the non-treatment cycle lasts 21 days and the second treatment cycle lasts 14 days. In some embodiments, the first treatment cycle lasts 14 days, the non-treatment cycle lasts 28 days and the second treatment cycle lasts 14 days.
F. Additional Exemplary Features of the First, Second, Third, and Fourth Therapeutic Methods
[00156] Additional exemplary features that may characterize the First, Second, Third, and Fourth Therapeutic Methods described herein are provided below and include, for example, the identity of the patient, Compound 1 formulations and exemplary c-kit kinase mediated diseases and disorders. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features. 1. Pharmaceutical Compositions
[00157] In some embodiments, the Compound 1, or a pharmaceutically acceptable salt thereof, being administered to the patient in need thereof is formulated as part of a pharmaceutical composition. In some embodiments, the c-kit kinase inhibitor being administered to the patient in need thereof is formulated as part of a pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration to the patient.
[00158] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. 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.
2. Patient Populations That May Derive Particular Benefits from the Therapeutic Methods
[00159] The methods may be further characterized according to patient populations that may derive particular benefits from the therapeutic methods. For example, in certain embodiments, the patient is a human. In certain embodiments, the patient is an adult human. In certain embodiments, the patient is a geriatric human. In certain embodiments, the patient is a pediatric human.
3. C-Kit Kinase Mediated Diseases and Disorders
[00160] The method may be further characterized according to the c-kit kinase mediated disease or disorder that is to be treated in the patient. In some embodiments, the c-kit kinase mediated disease or disorder is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrosis disease, or a dermatological disease. In some embodiments, the c-kit kinase mediated disease or disorder is a mast-cell associated disease. In some embodiments, the c-kit kinase mediated disease or disorder is an inflammatory disorder. In some embodiments, the c-kit kinase mediated disease or disorder is an autoimmune disorder. [00161] In some embodiments, the disease or disorder is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes or type II diabetes. In some embodiments, the c-kit mediated disease or disorder is urticaria.
[00162] In some embodiments, the disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD), or ulcerative colitis. In some embodiments, the disease or disorder is mast cell gastrointestinal disease. In some embodiments, the disease or disorder is prurigo nodularis. In some embodiments, the disease or disorder is allergic conjunctivitis. In some embodiments, the disease or disorder is eosinophilic esophagitis. In some embodiments, the disease or disorder is mast cell activation syndrome. In some embodiments, the disease or disorder is eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD). In some embodiments, the disease or disorder is ulcerative colitis.
4. Food Effect and Treatment Timing
[00163] The method may be further characterized according to the fed or fasted state of the patient at the time of dosing.
[00164] In some embodiments, the patient is in a fasted state when Compound 1 is administered. In some embodiments, a patient is considered to be in a fasted state if they have not eaten food or drank a liquid, other than water, for at least 10 hours. In some embodiments, a patient is considered to be in a fasted state if they have not eaten food or drank a liquid, other than water, for at least 8 hours. In some embodiments, the patient remains in a fasted state for up to 4 hours following the administration of Compound 1.
[00165] In some embodiments, the patient is in a fed state when Compound 1 is administered. A patient is considered to be in a fed state if they have ingested a high fat, high calorie meal within the prior 30 minutes. [00166] The method may be further characterized according to the timing of the dosing of Compound 1. In some embodiments, Compound 1 is administered to the patient orally once per day wherein the administration takes place at the same time each day. In some embodiments, Compound 1 is administered to the patient orally once per day, in the morning. In some embodiments, Compound 1 is administered to the patient orally once per day within 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes of the patient waking. In some embodiments, Compound 1 is administered to the patient orally once per day, in the evening. In some embodiments, Compound 1 is administered to the patient orally once per day within 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes of the patient falling asleep.
[00167] In some embodiments, the patient is in a fasted state when the c-kit kinase inhibitor is administered. In some embodiments, the patient is in a fed state when the c-kit kinase inhibitor is administered. In some embodiments, the c-kit kinase inhibitor is administered to the patient orally once per day wherein the administration takes place at the same time each day. In some embodiments, the c-kit kinase inhibitor is administered to the patient orally once per day, in the morning. In some embodiments, the c-kit kinase inhibitor is administered to the patient orally once per day within 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes of the patient waking. In some embodiments, the c-kit kinase inhibitor is administered to the patient orally once per day, in the evening. In some embodiments, the c-kit kinase inhibitor is administered to the patient orally once per day within 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes of the patient falling asleep.
5. Combination Therapy Dosing Considerations
[00168] In some embodiments, the therapeutic methods of the invention further comprise administration of a second therapeutic agent for the treatment of a c-kit kinase mediated disease or disorder. In embodiments where more than one therapeutic agent is administered, the amount of each therapeutic agent and the relative timing of administration of each therapeutic agent may be selected in order to achieve a desired combined therapeutic effect. For example, when administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously, and the like. [00169] In certain embodiments, the therapeutic agents may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
6. Use of Biomarkers to Modify Dosage Amounts
[00170] In some embodiments, the dosage amount of Compound 1, or a pharmaceutically acceptable salt thereof that is administered to the patient can be determined based on the value of one or more pharmacodynamic parameters in a sample collected from the patient. In some embodiments, the one or more pharmacodynamic parameters are concentration levels of one or more biomarkers indicative of effective treatment of a c-kit kinase mediated disease or disorder.
[00171] In some embodiments, the dosage amount of Compound 1, or a pharmaceutically acceptable salt thereof that is administered to the patient is increased or decreased based on the mast cell density measured from a skin biopsy collected from the patient.
[00172] In some embodiments, if after an initial period of treatment with Compound 1, or a pharmaceutically acceptable salt thereof, at a first dosage level, the mast cell density measured from a skin biopsy collected from the patient has not decreased by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, as compared to the mast cell density measured from a skin biopsy collected from the patient before the onset of treatment, then Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient at a second dosage level that is higher than the first dosage level.
[00173] In some embodiments, if after an initial period of treatment with Compound 1, or a pharmaceutically acceptable salt thereof, at a first dosage level, the mast cell density measured from a skin biopsy collected from the patient has decreased by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, as compared to the mast cell density measured from a skin biopsy collected from the patient before the onset of treatment, then Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient at a second dosage level that is lower than the first dosage level. In some embodiments, the lower second dosage level is administered on a trial basis and the mast cell density of the patient is monitored to ensure that the second dosage level is sufficient to maintain effective treatment of the c-kit kinase mediated disease or disorder. If the lower second dosage level is determined to not be effective in treating the c-kit kinase mediated disease or disorder based on the mast cell density measured from a skin biopsy collected from the patient, then the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, should be reverted back to the first dosage level.
[00174] In some embodiments, the initial period of treatment is at least 3 days, at least 5 days, at least 7 days, or at least 14 days. In some embodiments, the decreased mast cell density that indicates effective treatment of the c-kit kinase mediated disease or disorder is at least a 25% decrease, at least a 50% decrease, or at least a 75% decrease.
[00175] In some embodiments, the dosage amount of Compound 1, or a pharmaceutically acceptable salt thereof that is administered to the patient is increased or decreased based on the serum tryptase concentration measured from a blood sample collected from the patient.
[00176] In some embodiments, if after an initial period of treatment with Compound 1, or a pharmaceutically acceptable salt thereof, at a first dosage level, the serum tryptase concentration measured from a blood sample collected from the patient has not decreased by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, as compared to the serum tryptase concentration measured from a blood sample collected from the patient before the onset of treatment, then Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient at a second dosage level that is higher than the first dosage level.
[00177] In some embodiments, if after an initial period of treatment with Compound 1, or a pharmaceutically acceptable salt thereof, at a first dosage level, the serum tryptase concentration measured from a blood sample collected from the patient has decreased by an amount determined to indicate effective treatment of the c-kit kinase mediated disease or disorder, as compared to the serum tryptase concentration measured from a blood sample collected from the patient before the onset of treatment, then Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient at a second dosage level that is lower than the first dosage level. In some embodiments, the lower second dosage level is administered on a trial basis and the serum tryptase concentration of the patient is monitored to ensure that the second dosage level is sufficient to maintain effective treatment of the c-kit kinase mediated disease or disorder. If the lower second dosage level is determined to not be effective in treating the c-kit kinase mediated disease or disorder based on the serum tryptase concentration measured from a blood sample collected from the patient, then the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, should be reverted back to the first dosage level.
[00178] In some embodiments, the initial period of treatment is at least 3 days, at least 5 days, at least 7 days, or at least 14 days. In some embodiments, the decreased mast cell density that indicates effective treatment of the c-kit kinase mediated disease or disorder is at least a 25% decrease, at least a 50% decrease, or at least a 75% decrease.
[00179] In any of the methods described above wherein the dosage of Compound 1 is modified based on a measured biomarker, the present invention also contemplates analogous methods, wherein an alternative c-kit kinase inhibitor disclosed in the Fourth Method is used in place of Compound 1.
II. Compositions for Medical Use
[00180] Compound 1, pharmaceutically acceptable salts thereof and pharmaceutically acceptable compositions thereof may be used to treat a c-kit kinase mediated disease or disorder described herein. The use may be according to a method described herein. For example, one aspect of the invention provides N-(5-(5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2- methylphenyl)imidazo[l,2-a]pyridine-3 -carboxamide, or a pharmaceutically acceptable salt thereof, for use in treating a c-kit kinase mediated disease or disorder, wherein said compound is orally administered at a dose in an amount of from about 10 mg to about 1,000 mg. Embodiments described herein in connection with the methods for treatment may be applied in connection with Compound 1 for use in treating a c-kit kinase mediated diseases or disorders described herein. Embodiments described herein in connection with the methods for treatment may be applied in connection with any c-kit kinase inhibitor disclosed herein, such as those described in the Fourth Method, for use in treating a c-kit kinase mediated diseases or disorders described herein.
III. Preparation of a Medicament
[00181] Compound 1, pharmaceutically acceptable salts thereof and pharmaceutically acceptable compositions thereof may be used in the preparation of a medicament to treat a c-kit kinase mediated disease or disorder described herein. The use of the prepared medicament may be according to a method described herein. For example, one aspect of the invention provides use of the compound N-(5-(5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2- methylphenyl)imidazo[l,2-a]pyridine-3 -carboxamide, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for oral administration to treat a c-kit kinase mediated disease or disorder, wherein the medicament is for oral administered to provide the compound in an amount of from about 10 mg to about 1,000. Embodiments described herein in connection with the methods for treatment may be applied in connection with Compound 1 for use in the preparation of a medicament for treating a c-kit kinase mediated diseases or disorders described herein. Embodiments described herein in connection with the methods for treatment may be applied in connection with any c-kit kinase inhibitor disclosed herein, such as those described in the Fourth Method, for use in the preparation of a medicament for treating a c-kit kinase mediated diseases or disorders described herein.
IV. Medical Kits
[00182] Another aspect of the invention provides a medical kit comprising, for example, (i) a composition or dosage form comprising Compound 1 described herein, and (ii) instructions for treating a c-kit kinase mediated disease or disorder according to methods described herein. For example, in some embodiments, a medical kit of the invention comprises individual dosage forms of Compound 1, formulated for oral administration, in a dosage amount described herein. In some embodiments, the medical kit further comprises a set of instructions detailing the dosing regimen by which Compound 1 should be administered, for example, according to the First Method and/or Second Method.
[00183] In some embodiments, the invention provides a medical kit, as described above, wherein a different c-kit kinase inhibitor disclosed herein, such as those described in the Fourth Method, is included instead of Compound 1.
[00184] All features of each of the aspects of the disclosure apply to all other aspects mutatis mutandis. Each of the references referred to herein, including but not limited to patents, patent applications and journal articles, is incorporated by reference herein as though fully set forth in its entirety.
[00185] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner. EXAMPLES
[00186] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the invention.
EXAMPLE 1 - Oral Administration of Compound 1 to Human Subjects
[00187] Compound 1 is to be orally administered to healthy human subjects according to a clinical study, and the safety, tolerability, and pharmacokinetic properties will be evaluated. The study includes a single ascending dose (SAD), food effect, and multiple ascending dose (MAD) evaluation of safety, tolerability, and pharmacokinetics in healthy volunteers with planned doses of Compound 1 from 10 mg to 1,000 mg.
A. Study Design
[00188] The study is a randomized, placebo-controlled, Phase 1 study in three parts: single ascending doses (Part 1, double-blind), food effect (Part 2, open-label), and multiple ascending doses (Part 3, double-blind). Safety, tolerability and available PK and/or PD data will be assessed by the Safety Review Committee (SRC) between each cohort in Part 1 and Part 3 and prior to initiation of Part 2 and Part 3.
Part 1 (SAD)
[00189] Eligibility will be assessed during a screening period of up to 28 days. For the treatment period, subjects will check into the clinic one day prior to dosing (Day -1). Under supervision of an experienced physician, the study drug [Compound 1 or placebo] will be administered in the morning of Day 1 in a fasted state (after an overnight fast of at least 10 hours). Subjects will fast for 4 hours following dosing. Subjects will be released from the clinic on Day 4 after all required study procedures are completed and if medically justified. Subjects will return to the clinic between Day 8 and Day 11 of the treatment period for a follow-up visit.
[00190] Six (6) single ascending doses are planned to be tested in 6 cohorts of 8 healthy subjects
(6 active, 2 placebo) (Cohort 1:1 to Cohort 1:6). The starting dose will be 10 mg of Compound 1.
After each cohort completes dosing, a dose escalation meeting will take place. Escalation to the next higher dose level may occur only after evaluation of the safety and available PK and/or PD results up to and including 72 hours post-dose of at least 6 evaluable subjects. Dose(s) lower or higher than those proposed below may be studied based on safety, and available PK and/or PD results.
[00191] Sentinel dosing will be employed in all cohorts. Thus, within each cohort initially 1 subject will receive Compound 1 and 1 subject will receive placebo. Provided no clinically significant safety issues are noted in the 24 hours after dosing of the initial 2 subjects of a cohort as judged by the investigator, the remaining 6 subjects of the cohort can be dosed.
[00192] The proposed dose regimen for Part 1 is provided below:
Cohort 1:1: 10 mg Compound 1 (n=6) or placebo (n=2)
Cohort 1:2: 30 mg Compound 1 (n=6) or placebo (n=2)
Cohort 1:3: 100 mg Compound 1 (n=6) or placebo (n=2)
Cohort 1:4: 200 mg Compound 1 (n=6) or placebo (n=2)
Cohort 1:5: 400 mg Compound 1 (n=6) or placebo (n=2)
Cohort 1:6: 800 mg Compound 1 (n=6) or placebo (n=2)
[00193] The actual dose for Cohort 1 :2 to Cohort 1 :6 will be based on the safety and PK and/or PD results of all preceding cohorts, but the maximum predicted daily exposure will not exceed an AUC of 82,000 ng*h/mL.
Part 2 (Food Effect)
[00194] Eligibility will be assessed during a screening period of up to 28 days. In the first treatment period subjects will be randomized to receive a single dose of Compound 1 in either a fasted or a fed state. In the second treatment period, subjects will receive a single dose of Compound 1 under the alternate status.
[00195] For the first treatment period, subjects will check into the clinic one day prior to dosing
(Day -1). Under supervision of an experienced physician, Compound 1 will be administered in the morning of Day 1 in a fasted state (after an overnight fast of at least 10 hours) or a fed state (after ingestion of a standardized, high-fat, high calorie breakfast within 30 minutes prior to drug administration). Subjects will fast for 4 hours following dosing. Subjects will be released from the clinic on Day 4 of the first treatment period after all required study procedures are completed and if medically justified. Subjects will return to the clinic for a second treatment period after a washout of at least 7 days between the treatments. In the second treatment period, subjects will again be released from the clinic on Day 4 after all required study procedures are completed and if medically justified. Subjects will return to the clinic between Day 8 and Day 11 of the second treatment period for a follow-up visit.
[00196] One (1) single dose of Compound 1 is planned to be tested in fasted and fed state in 1 cohort of 12 healthy subjects (Cohort 2:1). This part will consist of 2 fixed-sequence, crossover treatment periods. The treatments will be separated by a washout period of at least 7 days. The dose level will be selected based on the emerging results of Part 1 and will be at least one level below the highest dose previously found to be well tolerated. Part 2 can start when at least 4 cohorts in Part 1 have been completed.
Part 3 (MA D)
[00197] Eligibility will be assessed during a screening period of up to 28 days. For the treatment period, subjects will check into the clinic one day prior to first dosing (Day -1). Under supervision of an experienced physician, study drug [Compound 1 or placebo] will be administered in the morning of Day 1 to Day 14, after an overnight fast of at least 10 hours. Subjects will remain fasted for 4 hours following the morning dose administration on Day 1 and Day 14. Dosing may be adapted to Q12H dosing of Compound 1 or placebo. Subjects will be released from the clinic on Day 17 after all required study procedures are completed and if medically justified. Subjects will return to the clinic for follow-up visits on Day 22, Day 29, Day 42, Day 56, and Day 70/“end of study” (EOS). A follow-up phone call will be made on Day 77.
[00198] Four (4) multiple ascending doses of Compound 1 administered over 14 days are planned to be tested in 4 cohorts of 8 healthy subjects (6 active, 2 placebo) (Cohort 3:1 to Cohort 3:4). One (1) additional dose level (Cohort 3:5), consisting of 8 subjects (6 active, 2 placebo), may be added.
[00199] The opening dose of Part 3 (Cohort 3:1) must be at least 1 dose level below the maximum daily dose considered well tolerated in Part 1. Escalation to the next higher dose level may occur only after evaluation of the safety and available PK and/or PD results up to and including 72 hours post-dose on Day 14 of at least 6 evaluable subjects. The selected doses will not exceed a mean maximum predicted daily exposure of 82,000 ng*h/mL. If additional dose cohorts are needed, the dose increments will increase the predicted exposures by no more than 2- fold.
[00200] The dosing regimen (once daily dosing [QD]), may be adapted to once every 12 hours [Q12H] based on review of at least 3 cohorts of Part 1.
B. Investigational Product (IP)
[00201] Compound 1 and matching Placebo will be encapsulated by an unblinded pharmacist. In order to minimize the risks of unblinding, the pharmacist/designee is not involved in any other aspect of the study. All study drugs will be dispensed by the investigator or a person under his/her supervision.
[00202] Active Compound 1 500 mg/g powder for oral dosing preparation (Drug Product Intermediate) and Placebo powder for oral dosing preparation will be provided in LDPE bags in HDPE bottles. Under the supervision of the pharmacist, the study drug will be manufactured into capsules and packed per subject for each dosing occasion, according to the randomization list.
[00203] First dosing will take place in the morning between 8:00 and 11 :00. The study drug and matching placebo will be taken orally with 240 mL of water (when 240 mL is not enough, 50 mL of additional water will be given).
[00204] In Part 1 and Part 3, on fasting PK profile days subjects will not be allowed to eat or drink (except water) from at least 10 hours pre-dose up to 4 hours post-dose. On these days, water is not allowed from 2 hours pre-dose up to 2 hours post-dose, except for the water used for study drug administration. On all other days, subjects will not be allowed to eat or drink (except water) from at least 1 hour pre-dose up to 1 hour post-dose.
[00205] In Part 2, dosing will be after an overnight fast of at least 10 hours (fasted status) or after an overnight fast of at least 10 hours and within 5 minutes of consumption of a high-fat breakfast (fed status) that must be eaten within 30 minutes. Subjects will not be allowed to eat or drink (except water) until 4 hours post-dose. The intake of water is not allowed from 1 hour pre-dose up to 1 hour post-dose, except for the water used for study drug administration.
[00206] In case of Q12H dosing, subjects will not be allowed to eat or drink (except water) from at least 2 hours before the evening dose up to 2 hours after the evening dose. [00207] The time of administration of Compound 1 or placebo will be recorded.
C. Dose Selection
[00208] An allometric scaling approach was utilized and then compared to the Maximum Safe Recommended Dose (FDA Guidance for Industry, 2005). In addition, an estimate of the anticipated therapeutic dose range (ATD) was considered in the context of the dosing recommendation.
[00209] A starting dose of 10 mg is expected to be greater than 50 fold below the free Compound 1 exposures achieved at the “no observed adverse effect level” (NOAEL) in a 28 day GLP repeat dose female rat toxicology study. The proposed single ascending dose escalation scheme is 30, 100, 200, 400 and 800 mg, but is subject to adjustment. For single and multiple doses, the NOAEL in the 28-day GLP female rat (AUCo-24 = 82,000 ng h/mL) will not be exceeded. This exposure is comparable to the NOAEL in a 14-day non-GLP male dog study, in which no testicular effects were observed (72,500 ng h/mL).
D. Biomarkers
[00210] Chronic urticaria is a disease where mast cells are known to play a critical role in disease pathology (Church, et al., Immunological Reviews, 2018, 282(1), 232-247.). Drugs that inhibit activators (e.g. Xolair) and mediators (e.g. anti-histamines) of mast cells are commonly used and are effective in urticaria patients (Johal, et al., Asthma and Immunology, 2019, 1-29.). Without intending to be limited to any particular theory, it is hypothesized that a reduction in mast cell numbers in the skin correlates with disease activity improvement in patients with chronic urticaria.
[00211] Part 3 of the study includes the taking of biopsies in the volar forearm in order to measure the relationship between Compound 1 exposure and mast cell reduction. The following biomarkers are also measured, due to their relationship to mast cell function.
Serum tryptase
[00212] Serum tryptase is a protein component of mast cells, which are a type of immune cell, typically produced during an allergic response and is considered a specific marker of mast cell burden and activation (Schwartz, et al., Immunol Allergy Clin North Am, 2006, 26:451-63.).
Stem Cell Factor [00213] Stem cell factor (also known as SCF, KIT-ligand, KL, or steel factor) is a cytokine that binds to the KIT receptor (CD117). SCF plays a key role in mast cell development, gametogenesis, and melanogenesis and is the principal growth and differentiation factor for human mast cells.
4/l-hydroxycholesterol and 4({-hydroxycholesterol/cholesterol ratio
[00214] 4P-hydroxy cholesterol is an endogenous CYP3A marker which is being used to evaluate the potential induction of cytochrome P450 (CYP) 3 A due to Compound 1.
CTX
[00215] Serum CTX (Collagen cross linked C-telopeptide) is a reference bone resorption marker and a downstream biomarker for CSF-1R inhibition. Compound 1 is 48-fold less selective for CSF- 1R than KIT and therefore significant inhibition is not expected at therapeutically relevant exposures. However, since CSF-1R inhibition is known to reduce the number of liver-resident macrophages (Kupffer cells), which are involved in the normal elimination of plasma enzymes, the analysis of serum CTX levels may provide a mechanistic explanation of abnormal laboratory findings should they be observed.
E. Study Eligibility Criteria / Patient Selection
[00216] The subject population for the study will include healthy adult subjects who satisfy all entry criteria.
Inclusion Criteria
[00217] The following criteria must be met by all subjects considered for study participation:
1. Subj ects must understand the nature of the study and must provide signed and dated written informed consent in accordance with local regulations before the conduct of any study- related procedures.
2. Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, laboratory tests and ECG recording. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if, in the opinion of the Investigator, the finding is (a) unlikely to introduce additional risk to the subject, (b) will not interfere with study procedures or confound study results, and (c) is not otherwise exclusionary (see Exclusion Criteria). 3. In Part 1 and 2, men and women aged 18-65 years (inclusive) at the time of Screening will be enrolled, and in Part 3 vasectomized men and women aged 18-65 years (inclusive) at the time of Screening will be enrolled.
4. Women of child-bearing potential must agree not to attempt to become pregnant and to use a highly effective form of hormonal (excluding oral contraceptives) or non-hormonal birth control, or abstinence during the study and for 90 days after the (last) study drug administration. Postmenopausal women must have had >12 months of spontaneous amenorrhea (with documented follicle-stimulating hormone (FSH) >30 mlU/mL). Surgically sterile women are defined as those who have had a hysterectomy, bilateral ovariectomy, or bilateral tubal ligation. Women who are surgically sterile must provide documentation of the procedure by an operative report or by ultrasound. All women must have a negative pregnancy test result on Day -1 before (first) administration of study medication.
5. Male subjects in Part 1 and Part 2 who are biologically capable of having children must remain sexually abstinent, or avoid impregnating his partner during the study (including washout periods) and for at least 90 days after the (last) dose of study medication, and must use a combination of two methods of contraception during the study. Male subjects in Part 3 must have had a vasectomy at least 4 months prior to the Screening Visit and must have completed post-surgical follow up to confirm success of the vasectomy.
6. Body weight of at least 50.0 kg for men and 45.0 kg for women and Body Mass Index within the range of 17.5-32.0 kg/m2 (inclusive) at Screening.
7. Subjects must, in the opinion of the Investigator, be able to participate in all scheduled evaluations, likely to complete all required tests, and likely to be compliant.
8. Subjects participating in Part 2 must be willing and able to consume the entire high-fat, high-calorie breakfast meal in the designated timeframe.
9. Part 3 only: Subjects must be willing and able to undergo multiple skin biopsies.
Exclusion Criteria
[00218] Subjects will be excluded if they meet any of the following criteria: A positive urine drug screen/alcohol breath test at Screening or Day -1 of the (first) treatment period. A positive Hepatitis B surface antigen or positive Hepatitis C antibody result at Screening. A positive test for human immunodeficiency virus (HIV) antibody at Screening. Alanine aminotransferase, aspartate aminotransferase, or total bilirubin levels greater than the upper limit of normal (ULN) at Screening or Day -1 of the (first) treatment period. One test result up to 1.25 x the ULN is allowed. One retest at Screening and on Day -1 of the (first) treatment period is allowed. Subjects with Gilbert’s Syndrome are permitted to have total bilirubin values outside the 1.25 x the ULN, as judged by the Investigator, as long as the AST and ALT are WNL. Serum creatinine greater than the ULN at Screening or Day -1 of the (first) treatment period. One retest is allowed. Part 3 only: Serum tryptase levels below 2 pg/l or above the ULN at Screening. Subj ect is symptomatic or being actively treated for an acute disease or progressive chronic disease. A history or presence of cancer or of a clinically significant hepatic, biliary, renal, gastrointestinal, cardiovascular, endocrine, pulmonary, ophthalmologic, immunologic, hematologic, dermatologic, or neurologic abnormality. Evidence or history of anemia, thrombocytopenia, or leukopenia. Hemoglobin, Platelet count, or White blood cell count below the lower limit of normal (LLN) at screening. Hemoglobin, Platelet count, or White blood cell count below the lower limit of normal (LLN) on Day -1 of the (first) treatment period if clinically significant. One retest is allowed at each visit. Pre-existing urticaria or atopic dermatitis. History of melanoma (subjects who are at least 6 months from successful treatment of basal cell carcinoma or squamous cell carcinoma are allowed). A history of chronic urinary tract infections. Subject reports diagnosis of, or suspected, PKU (phenylketonuria) disorder. Use of any prescription or non-prescription drugs (excluding paracetamol), antacids, vitamins, herbal, and dietary supplements (including St John’s Wort) within 14 days (or 28 days if the drug is a potential hepatic enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. Subject is on active immunosuppressive drug defined as at least one dose within 28 days prior to Day 1. Received or used an investigational product (including placebo) or device within the following time period prior to the first dosing day in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Vaccinated within 14 days prior to the first dose or intention to receive vaccination during the study. COVID-19 vaccination is allowed after the follow-up (Part 1 and Part 2) or first follow-up (Part 3). History of clinically significant sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation. The subject currently smokes or uses nicotine-containing products. Former smokers will be eligible, provided they have not smoked for at least 3 months prior to the first dose of study drug. Positive cotinine test results at Screening or Day -1 of the (first) treatment period are reason for exclusion. One (1) cotinine re-test may be performed on Day -1 of the (first) treatment period for otherwise eligible subjects who were recently exposed to passive smoke inhalation. History of regular alcohol consumption within 3 months of the study defined as an average weekly intake of >21 alcoholic drinks/week for men or >14 alcoholic drinks/week for women. Regularly consumed (e.g., more days than not) excessive quantities of xanthine-containing products (e.g., more than five cups of coffee or the equivalent per day) within 30 days prior to (first) dose administration. Donated blood or plasma within 3 months prior to (first) dose administration, or, where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 3 month period. A positive pregnancy test (at Screening or on Day -1 of the (first) treatment period) or lactation. A history or presence of any disease, condition, or surgery likely to affect drug absorption, distribution, metabolism, or excretion. A clinically significant abnormality on physical examination, ECG, or laboratory evaluations at Screening or between Screening and (first) dose administration. An average (of three) corrected QT interval measurements corrected according to the Fridericia rule (QTcF > 450 msec for males and > 470 msec for females) during controlled rest at screening or family history of long QT syndrome, heart failure or hypokalemia. Any clinically significant abnormalities in rhythm, conduction, or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, in the judgement of the Investigator or Medical Monitor, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy. PR (PQ) interval shortening < 120 msec (PR < 120 msec but > 110 msec is acceptable if there is no evidence of ventricular pre-excitation). PR (PQ) interval prolongation (> 220 msec), intermittent second- or third-degree AV block (Wenckebach block while asleep or in deep rest is not exclusionary). Persistent or intermittent complete bundle branch block (BBB), incomplete left bundle branch block (iLBBB), incomplete right bundle branch block (iRBBB) (if judged clinically significant by the investigator) or intraventricular conduction delay (IVCD) with QRS > 120 msec. 32. A clinically significant vital signs abnormality, as judged by the principal investigator, at screening or Day -1 of the (first) treatment period. This includes, but is not limited to, the following, in the supine position: (a) systolic blood pressure < 90 or >150 mmHg, (b) diastolic blood pressure <40 or > 95 mmHg, or (c) heart rate < 45 or >100 beats per minute.
33. Significant (> 10%) weight loss or gain within 30 days prior to screening or between Screening and (first) dose administration.
34. A history of clinically significant symptomatic orthostatic hypotension (i.e., postural syncope), as judged by the Investigator.
35. The subject is, in the opinion of the Investigator or Medical Monitor, unlikely to comply with the protocol or is unsuitable for any reason.
36. Unsatisfactory venous access.
37. History of allergic disease (severe allergies, food allergies, etc.) that require prescription medication.
38. Recent (within 7 days) allergic reaction (e.g. bee stings, food, or other allergen).
39. History of asthma requiring the use of inhaled or systemic prescription medication within the past 5 years.
40. Subject sensitivity or allergy to Lidocaine.
41. Subject has a fever defined as a temperature > 37.8 °C or any reports of fever resulting from bacterial or viral infection within 7 days prior to Day 1.
42. Part 3 only: History of excessive bleeding or any other contraindication for skin biopsy.
43. Part 3 only: Subject has forearm tattoos that interfere with the ability to collect a biopsy from a tattoo-free area.
Concomitant Medication
[00219] From 2 weeks or 5 half-lives (whichever is longer) prior to the first dose of study drug until the EOS, prescribed or over-the-counter medication (including antacids, vitamins, herbal remedies, and dietary supplements (including St. John’s Wort)) is not allowed, except for medication that is required for the treatment of adverse events. If the drug is a potential hepatic enzyme inducer the time period is extended from 28 days prior to the first dose of study drug until EOS. Occasional use of paracetamol is allowed.
[00220] From 2 weeks prior to the first dose until the EOS, subjects are not allowed to get a vaccination. COVID-19 vaccination is not allowed from 2 weeks prior to the first dose until the follow-up (Part 1 and Part 2) or first follow-up (Part 3).
[00221] If concomitant medication is needed during the study, this medication must be recorded, stating its generic name, time of administration, dose, route, frequency and duration, as well as the reason for administration. The use of a concomitant medication during the study should be discussed with the Investigator and Medical Monitor before administration, except in the case of necessary treatment of adverse events or where appropriate medical care necessitates that therapy should begin before the Investigator can consult with the Medical Monitor.
[00222] Paracetamol (up to 3g/day for 2 days) may be used for minor ailments during the course of the study, at the discretion of the Investigator, without prior consultation with the Sponsor’s Medical Monitor. The use of lidocaine is permitted for skin biopsies.
Physical Activities
[00223] From Screening until the EOS examination, the subjects should refrain from excessive physical exercise and strenuous sports activities (endurance sports).
Dietary Aspects, Alcohol and Smoking
[00224] Consumption of food or beverages containing xanthine derivatives or xanthine-related compounds or energy drink is not permitted from 48 hours prior to dosing until the last PK blood sample of the treatment period has been collected.
[00225] Consumption of food or beverages containing grapefruit, Seville oranges, starfruit, pomegranate, pineapple, or pomelo is not permitted from 48 hours prior to dosing until the last PK blood sample of the treatment period has been collected.
[00226] Drinking of alcoholic beverages is not permitted from 48 hours prior to arrival at the clinic until the last PK sample of that study period has been collected. Smoking is not permitted during the study.
F. Study Assessments Informed Consent
[00227] After adequate explanation of the aims, methods, objectives of the study and potential hazards of the study drug and after adequately answering any questions subjects may have, a written informed consent from each individual participating in this study will be obtained.
Medical History and Baseline Demographics
[00228] All relevant medical history (including family history) will be documented. Baseline demographics including sex, month and year of birth and ethnicity will be recorded. The Fitzpatrick scale (also Fitzpatrick skin typing test; or Fitzpatrick phototyping scale) will be used to classify skin color.
Prior and Concomitant Medications
[00229] All prior and concomitant medications taken from 28 days prior to (first) dosing until EOS or started during the course of the study will be recorded on the Concomitant Medications page. Concomitant Medications initiated, stopped, up-titrated or down-titrated for an AE will be recorded on the Concomitant Medications page.
Timing for Sampling
[00230] Hematology, chemistry, coagulation, and urinalysis samples will be collected for Parts 1 and 2 during the screening period, and on day -1, day 1 pre-dose, day 8, day 24, day 48, day 72 and at EOS. Hematology, chemistry, coagulation, and urinalysis samples will be collected for Part 3 during the screening period, and on days -1, 1, 2, 3, 6, 9, 12, 14, 15, 17, 22 and 70.
[00231] Stem Cell Factor sampling will be conducted on day 1 pre-dose, and day 72 in Parts 1 and 2, and on days 1, 7, 14, 22, 29, 42, 56, and 70 in Part 3.
[00232] CTX sampling will be conducted on day 1 pre-dose and on day 14 at 4 hours post-dose in Part 3. Serum tryptase sampling will be conducted pre dose on days 1 and 14 and on days 2, 3, 6, 9, 12, 15 and 17 in Part 3. 4b hydroxycholesterol sampling will be conducted pre dose on days 1 and 14 and on days 2, 3, 6, 9, 12, and 15 in Part 3. [00233] PK blood sampling will be conducted pre-first dose, and at time points 0.5h, lh, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h and 72h, and optionally also at time points lOh and 16h in Parts 1 and 2. PK and metabolic blood sampling will be conducted on day 1 pre-dose and at time points: 0.5h, lh, 1.5h, 2h, 3h, 4h, 6h, 8h, lOh, 12h, and 16h and then once per day on days 2-17 in Part 3. PK urine collection will be conducted pre-dose on day 1, and on day 1 and day 14 at 0-6 hours, 6-12 hours, and 12-24 hours post-dose.
[00234] Skin biopsies will be collected in Part 3 on day 1 and day 14, both pre-dose. The skin biopsies scheduled during Follow-up (Day 29 and Day 42) may be moved to one of the other Follow-up study days.
Procedures for Blood Sampling
[00235] About 2 mL of blood for the PK samples will be collected via vena puncture or via an intravenous (i.v.) catheter placed in a vein in the arm following the local standard procedures.
Bioanalysis
[00236] The concentrations of Compound 1 in plasma (all cohorts) and urine (Part 3, one cohort only) will be determined using a validated LC-MS/MS assay. Concentrations will be calculated by interpolation from a calibration curve. Quality control samples will be analyzed throughout the study. Their measured concentrations will be used to determine overall precision and accuracy of the analyses.
Compound 1 Metabolic Profiling (Part 3 Only)
[00237] Samples for metabolic profiling will be pooled and analyzed using LC/HRMS in order to identify unique human metabolites and determine if those metabolites are present at >10% total drug-related exposure (TDRE). This analysis will be performed using an aliquot of stored PK samples. No extra blood sampling is necessary.
Vital Signs
[00238] Vital sign assessments will be performed according to the standard procedures and will include measurements of supine blood pressure, pulse rate, pulse oximetry and temporal temperature. Vital sign measurements will be collected after the subject has been resting for 5 minutes.
Weight and Height
[00239] The subject’s body weight will be measured using a validated balance. Body weight will be recorded with 1 decimal. The subject's height is measured without wearing shoes. The BMI will be calculated from the weight and height recorded at screening. BMI (kg/m2) = weight (kg)/height2 (m2).
Physical Examination
[00240] Physical examination will be performed according to standard procedures and consists of inspection, percussion, palpation, and auscultation. Additionally, hair (roots) and skin will be checked for any noticeable color changes. At some time points, symptom-driven physical examinations will be performed.
[00241] Clinically relevant findings that are observed after the screening assessment must be recorded. Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new AE or worsening of previously existing condition) must be recorded.
12-lead ECG
[00242] Subjects will be in a supine position for 5 minutes prior to the measurements. ECGs will be evaluated and classified as normal or abnormal. In case of “abnormal”, the abnormality has to be described. HR, PR, QRS, and QT will be provided on the print-out of the ECG apparatus. Bazett (QT/RR1/2)/Fridericia (QT/RR1/3) QTc is automatically calculated by the ECG apparatus and provided on the print-out. For the screening ECG and the Day 1 pre-dose ECG, three recordings will be made with an interval of approximately 1 minute between recordings. Evaluation of average recordings will be performed according to QPS SOP. Any repeat measurement will also be done in triplicate. All other recordings will be single (one recording of at least 3 complexes).
3-lead ECG (Telemetry) [00243] Telemetry monitoring will be set on alarm and used for evaluation of any cardiac event. Results will be analyzed by the investigator and significant findings will be reported. Clinically significant abnormal findings (as judged by the investigator) will be recorded as AE.
Laboratory Assessments
[00244] Clinically significant laboratory abnormalities must be reported by the investigator as an AE or SAE as appropriate. The blood samples will be taken under fasted conditions, if possible. Subjects will not be allowed to eat or drink (except water) for a period of 4 h prior to blood sampling. As a rule, the blood samples will be taken from the subject by puncture of a vein in the cubital or the antebrachial region. The samples will be sent to the local certified laboratory in accordance with specifications.
Table 1A: Summary of Clinical Laboratory Tests
Figure imgf000065_0001
3 Only if urine dipstick is positive and marked as at least ‘++’ for erythrocytes or albumin. b Performed at Screening. On Day -1, the pregnancy test will be done with serum or urine. Other pregnancy tests will be done with urine. c Required of females only during screening. d Samples will be collected and stored for potential analysis.
Drug and Cotinine Screen
[00245] For a urine drug screening, the following compounds will be assessed: amphetamine, barbiturates, benzodiazepines, cocaine, marijuana (THC), methadone, methamphetamine, morphine, phencyclidine, and tricyclic antidepressants. To check if a subject has been smoking, cotinine will be assessed in urine.
Pregnancy Test
[00246] A serum pregnancy test will be performed at Screening. On Day -1 of every study period, the pregnancy test will be done with serum or urine. A urine pregnancy test will be performed at Follow-Up (or at early termination). The results must be available prior to dosing. Serology
[00247] At Screening, virus serology will be assessed (HIV, hepatitis B and hepatitis C). Cardiodynamic Assessments
[00248] For the Holter ECG evaluation, the subjects will remain in a resting semi-lying position for 1 hour prior to (first) dosing up to 4 hour after study drug administration except for study drug administration and blood sampling (sitting position) or measurement of vital signs and ECG (supine position). Furthermore, subjects will be supinely resting for at least 10 minutes before and 5 minutes after each following time point. When ECG extractions coincide with safety ECGs, vital signs assessment and blood draws, procedures will be carried out in said order. If subjects need to stand up during this timeframe (e.g., if they need to go to the restroom), study staff must ensure that the subj ects remain in the supine position 15 min prior to scheduled testing at the planned time points.
[00249] The 12-lead Holter and ECG equipment will be supplied and supported by ERT. All ECG data will be collected using a Global Instrumentation (Manlius, NY, USA) M12R ECG continuous 12 lead digital recorder. The continuous 12-lead digital ECG data will be stored onto SD memory cards. ECGs to be used in the analyses will be selected by pre-determined time points as defined in the Table of Assessments and will be read centrally by ERT.
[00250] The following principals will be followed in ERT’s core laboratory:
• ECG readers are blinded to the subject, visit and treatment allocation
• A limited number of readers will be employed for the study
• Baseline and on-treatment ECGs for a particular subject will be over-read on the same lead and will be analyzed by the same reader.
• The primary analysis lead is lead II. If lead II is not analyzable, then primary lead of analysis will be changed to another lead for the entire subject data set.
[00251] The following is a brief description of ECG analysis methods utilized by ERT’s core laboratory. Mean Hourly Heart Rate
[00252] Mean hourly heart rate analysis will be performed and include a summary of change from baseline and placebo corrected change from baseline (if applicable) for each subject. Central tendency analysis will be used to describe any changes over time. Heart rate nadir and time to heart rate nadir will be summarized by subject using descriptive statistics and will include categorical outlier analysis.
TQT Plus ECG Extraction Technique
[00253] Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter recordings using the ‘TQT Plus method’, a computer-assisted and statistical process utilized by ERT. The method enables extraction of ECGs with the lowest HR variability and noise within the protocol-specified extraction time window (e.g., the HR and QT changes from beat-to-beat in the range of <10%). At each protocol-specified timepoint, 10 ECG replicates will be extracted from a 5-minute “ECG window” (typically, the last 5 minutes of the 15-minute period when the subject is maintained in a supine or semi-recumbent quiet position).
Expert-Precision QT Analysis
[00254] Expert-precision QT analysis may be performed on all analyzable (non-artifact) beats in the 10 ECG replicates. Statistical quality control procedures are used to review and assess all beats and identify “high” and “low” confidence beats using several criteria, including:
• QT or QTc values exceeding or below certain thresholds (biologically unlikely).
• RR values exceeding or below certain thresholds (biologically unlikely).
• Rapid changes in QT, QTc or RR from beat to beat.
[00255] Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all replicates that are deemed “high confidence” is performed using COMPAS software. All low confidence beats are reviewed manually and adjudicated using pass-fail criteria. The final QC assessment is performed by a cardiologist. The beats found acceptable by manual review are included in the analysis. The median QT, QTc, and RR value from each extracted replicate is calculated, and then the mean of all available medians from a nominal timepoint is used as the subject’s reportable value at that timepoint.
[00256] Morphological analyses will be performed with a focus on detecting changes in T-wave morphology and appearance of abnormal U waves. The analyses will evaluate change-from- baseline (i.e., treatment-emergent changes).
[00257] The analysis results for T-wave morphology and U-wave presence will be summarized in frequency tables with counts and percentages for both number of subjects and number of time points. The number and percentage of subjects in each treatment group having changes from baseline that represent the appearance of the morphological abnormality will be summarized. The total number of time points having a particular change event will be summarized in terms of number and percentage based on the number of observed time points across all subjects within a treatment group.
[00258] For T-wave morphology and U-wave presence, treatment-emergent changes will be assessed, i.e., changes not present at baseline. For each category of T-wave morphology and of U-waves, the category will be deemed as present if observed in any replicate at the time point. For baseline, the category will be deemed as present if observed in any replicate from all time points that constitute baseline.
[00259] Cardiodynamic ECG evaluation will be described in a separate statistical analysis plan (SAP).
Skin Biopsy
[00260] Skin samples (3 mm) will be taken from the volar forearm.
Serum Tryptase
[00261] About 5 mL blood will be collected via vena puncture or via an i.v. catheter placed in a vein in the arm following the local standard procedures. Information on equipment and further details on the procedures on the sampling are documented in a separate lab manual. Stem Cell Factor
[00262] About 3 mL blood will be collected via vena puncture or via an i.v. catheter placed in a vein in the arm following the local standard procedures. Information on equipment and further details on the procedures on the sampling are documented in a separate instruction manual.
4 fl-hy dr oxy cholesterol
[00263] About 4 mL blood will be collected via vena puncture or via an i.v. catheter placed in a vein in the arm following the local standard procedures. Information on equipment and further details on the procedures on the sampling are documented in a separate lab manual.
CTX
[00264] About 1 mL blood will be collected via vena puncture or via an i.v. catheter placed in a vein in the arm following the local standard procedures. Information on equipment and further details on the procedures on the sampling are documented in a separate lab manual. Samples will be stored frozen until determination is made regarding sample analysis. If not analyzed, the samples will be destroyed at the end of the study.
Order of Assessments
[00265] In case several study procedures are scheduled at the same time point, the following sequence should be followed pre-dose: ECG, vital signs, asking for adverse events, PK blood sampling, blood sampling for clinical laboratory tests and PD assessments, and skin biopsy. Post dose, the following sequence should be followed: PK blood sampling, blood sampling for clinical laboratory tests, ECG, vital signs, asking for adverse events. Enough time should be reserved for all assessments to be performed so that the administration of study drug and the PK blood sampling is done at the scheduled time point.
Allowed Time Windows for PK, PD and Safety Assessments [00266] Allowed time windows are provided in Table IB. Table IB: Allowed Time Windows
Figure imgf000070_0001
G. Endpoints
Primary Endpoints
[00267] Part 1, Part 2 and Part 3: Safety and tolerability parameters include physical examination, adverse events, clinical laboratory values, vital signs and ECGs (3 -lead telemetry and 12-lead ECGs).
Secondary Endpoints
[00268] Part 1 and Part 2: PK parameters for Compound 1 include: Cmax, tmax, ti/2, AUCo-t, AUCo- i„f, CL/F and Vz/F.
[00269] Part 1 and Part 3 : For the cardiodynamic evaluation on ECGs extracted from Holters in Part 1 and Part 3, the following endpoints will be used:
Change-from -baseline heart rate (HR), QTcF, PR and QRS (DHR, DQTcF, DPR, DQRS);
- Placebo-corrected DHR, DQTcF, DPR, DQRS (DDHR, DDQTcF, DDPR, DDQRS); Categorical outliers for QTcF, HR, PR, and QRS;
- Frequency of treatment-emergent changes of T-wave morphology and U-wave presence. [00270] Part 3 : PK parameters for Compound 1 include: Cmax, tmax, ti/2, AUCo-t, AUCo-tau, AUCo- inf, CL/F (Day 1 only), Vz/F (Day 1 only), Cmin, Cmin,ss, CLss/F, Vss/F, Cssavg, and AR.
Exploratory Endpoints
[00271] Part 1 and Part 3 : PD parameters include: Serum tryptase levels (Part 3 only), Stem Cell Factor (SCF) (Part 1 and Part 3), CTX (Part 3 only), mast cell counts in skin (Part 3 only), 4P-hydroxycholesterol (Part 3 only).
[00272] Part 3 : Compound 1 metabolic profile in plasma.
H. Study Parameters
Pharmacokinetic Parameters
[00273] The plasma PK parameters for Compound 1 will be derived by non-compartmental analysis of the plasma concentration-time profiles. The following pharmacokinetic parameters will be reported:
[00274] Single Dose Regimen - Part 1, Part 2 and Part 3 on Day 1 :
- Maximum observed plasma concentration (Cmax);
Time tO Cmax (tmax);
Terminal elimination half-life (ti/2);
Area under the plasma concentration-time curve (AUC) from time of dosing (zero) to time t of the last measured concentration above the limit of quantification (AUCo-t);
Area under the plasma concentration-time curve from time zero to infinity (AUCo-inf); Area under the plasma concentration-time curve (AUC) from time of dosing (zero) to the ending of the dosing interval tau (AUCo-tau) of Part 3;
Apparent total body clearance (CL/F);
Apparent volume of distribution (Vz/F).
[00275] Multiple Dose Regimen - Part 3 on Day 14:
- Maximum observed plasma concentration (Cmax);
Time tO Cmax (tmax);
- Minimum observed plasma concentration (Cmin);
- Minimum observed plasma concentration at steady state (Cmin M;
Terminal elimination half-life (ti/2) (if reliably estimable); Area under the plasma concentration-time curve (AUC) from time of dosing (zero) to time t of the last measured concentration above the limit of quantification (AUCo-t);
Area under the plasma concentration-time curve from time zero to infinity (AUCo-inf); Area under the plasma concentration-time curve (AUC) from time of dosing (zero) to the ending of the dosing interval tau (AUCo-tau);
Apparent total body clearance at steady state (CLSS/F);
Apparent volume of distribution at steady state (Vss/F);
Average plasma concentration at steady state (CSSavg= AUCo tau);
Accumulation ratio (AR) for Cmax and AUCo-tau.
Additional parameters may be calculated as data allows and as appropriate.
The following are defined as urine PK parameters for Compound 1 :
[00276] Multiple Dose Regimen - Part 3 (one cohort only):
The total amount of dose excreted in urine from 0 (pre-dose) to end of collection (Ae); The total amount of dose excreted in urine from 0 (pre-dose) to 24 hours (Aeo-24);
The percentage (%) cumulative dose excreted in urine from 0 (pre-dose) to 48 hours (Feo-48);
The clearance (CLr).
[00277] Attainment of steady-state conditions will be determined by visual inspection of the trough plasma concentrations.
Calculation of Pharmacokinetic Parameters and Assumptions
[00278] The measured individual plasma concentrations of Compound 1 will be used to directly obtain Cmax and tmax. AUCo-t will be calculated according to the linear up/log down trapezoidal method using the measured concentration-time values above the lower limit of quantification (LLOQ). AUCo-inf will be calculated by combining AUCo-t and AUCextra. AUCextm represents an extrapolated value obtained by Ct/lz, where Ct is the last plasma concentration measured above the LLOQ and lz represents the terminal elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. The half-life of Compound 1 will be calculated as follows: t½ = In 2 / lz. The PK parameters will be based on actual blood sampling times [h] (relative to the corresponding administration time) rounded to two digits and negative pre-dose times will be set to zero. Cardiodynamic Parameters
[00279] For the cardiodynamic evaluation on ECGs extracted from Holters in Part 1 and Part 3, the following endpoints will be used:
Change-from -baseline heart rate (HR), QTcF, PR and QRS (DHR, DQTcF, DPR, DQRS);
- Placebo-corrected DHR, DQTcF, DPR, DQRS (DDHR, DDQTcF, DDPR, DDQRS); Categorical outliers for QTcF, HR, PR, and QRS;
- Frequency of treatment-emergent changes of T-wave morphology and U-wave presence.
[00280] Alternatively, the following end points will be used:
Continuous mean hourly Heart Rate (HR) data will be analyzed for Part 1 (SAD) and Part 3 (MAD) using the following parameters:
• Observed HR as well as change-from-baseline heart rate (AHR);
• Placebo-corrected change in HR (AAHR).
The following parameters will be captured for use in optional cardiodynamic analyses including precision QT analysis:
• Observed values as well as change-from-baseline QTcF, PR and QRS (AQTcF, APR, AQRS);
• Placebo-corrected AQTcF, APR, AQRS (AAQTcF, AAPR, AAQRS);
• T-wave morphology and U-wave presence.
Pharmacodynamic/Exploratory Parameters
[00281] The following are defined as PD parameters:
Serum tryptase levels (Part 3 only);
SCF (Part 1 and Part 3 only);
- Mast cell counts in skin (Part 3 only);
- CTX (Part 3 only)
4P-hydroxycholesterol levels (Part 3 only);
Compound 1 metabolic profile in plasma (Part 3 only).
Safety and Tolerability Parameters [00282] Baseline is defined as the last value measured prior to (the first) Compound 1 intake (vital signs, ECG, laboratory parameters), unless otherwise specified.
[00283] The following parameters have been defined as parameters regarding safety and tolerability:
Change from baseline to each scheduled time point up to EOS for vital signs.
Change from baseline to each scheduled time point up to EOS for ECG parameters. Change from baseline to each scheduled time point up to EOS for clinical laboratory tests. Treatment-emergent adverse events up to EOS.
Treatment-emergent adverse events leading to premature discontinuation of study drug. Treatment-emergent SAEs up to EOS.
I. Study Drug Dose Escalation, Discontinuation and Study Withdrawal
[00284] The study will be monitored by a Safety Review Committee (SRC). Safety, tolerability and available PK and/or PD data up to and including 72 hours after the last administered dose of at least 6 evaluable subjects will be assessed by the SRC prior to ascending from one dose-level cohort to the next-higher dose-level cohort and prior to transitioning to Part 2 and Part 3.
Determination of Dose Escalation/Subsequent Dosing
[00285] The decision to escalate to the next dose level will not take place until the SRC has reviewed the blinded safety and tolerability data, including but not limited to vital signs, ECG results, clinical laboratory tests, and adverse events through 72 hours after the last dose for all subjects dosed.
[00286] Additionally, an interim PK analysis of available plasma Compound 1 data and/or PD data may be reviewed as part of the dose escalation assessment. Any available blood PK and/or PD data may be reviewed as part of the dose escalation assessment.
[00287] After the review of each dose level, the SRC will make one of the following determinations: (1) To continue with the study as planned. (2) To continue with the study as planned and evaluate additional or alternate time points for safety evaluations. (3) To continue with the study by repeating a dose level, selecting an alternative dose level between the current dose level and the next planned dose level, or selecting an alternative dose level between the current dose level and any previous lower dose level. [00288] The SRC, Principal Investigator or sponsor may terminate dose escalation at any time if continuing to a higher dose level would jeopardize the safety of the subjects. SRC reports will be submitted to the Ethics Committee for approval of dose escalation.
Dose Escalation Stopping Criteria
[00289] Dose escalation will stop if any of the following criteria are met:
One (1) or more subjects who receive Compound 1 experience a serious adverse event (SAE) which is considered to be at least possibly related to the study medication.
One (1) or more participants who receive Compound 1 experience any clinically significant adverse events related to the study medication that the Sponsor and Investigator consider a safety concern.
One (1) or more subjects who reach a Compound 1 plasma AUCo-24 of > 82,000 ng h/mL. Two (2) or more subjects who receive Compound 1 have QTc prolongation, defined as an average absolute (regardless of baseline value) QTcF >500 msec or an increase of QTcF >60 msec above baseline, confirmed by repeating after 5 minutes, and determined post dose.
Two (2) or more subjects who receive Compound 1 exhibit hypotension, defined as resting supine diastolic blood pressure <30 mmHg, an symptomatic fall in systolic blood pressure to below 70 mmHg, persisting for at least 10 minutes on repeated assessment.
Two (2) or more subjects who receive Compound 1 exhibit hypertension, defined as an increase in resting systolic blood pressure to above 180 mmHg, persisting for at least 10 minutes, or an increase in resting diastolic blood pressure to above 105 mmHg, persisting for at least 10 minutes.
Two (2) or more subjects who receive Compound 1 exhibit tachycardia, defined as resting supine heart rate >130 beats per minute, persisting for at least 10 minutes.
Two (2) or more subjects who receive Compound 1 exhibit symptomatic bradycardia, defined as heart rate <40 beats per minute, or asymptomatic bradycardia, defined as resting supine heart rate <30 beats per minute while awake, persisting for at least 10 minutes.
One (1) or more subjects who receive Compound 1 fulfills Hy’s law, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x upper limit of normal (ULN) and total bilirubin >2 x ULN, in the absence of a significant increase in alkaline phosphatase (ALP) and in the absence of an alternative diagnosis that explains the increase in total bilirubin (confirmed by repeating within 24 hours).
Two (2) or more subjects who receive Compound 1 exhibit ALT, AST, total bilirubin, or ALP >3 x ULN accompanied by significant increase in other liver function test (confirmed by repeating within 24 hours).
Two (2) or more subjects who receive Compound 1 exhibit hematologic toxicity, defined as one or more of the following (confirmed by repeating within 24 hours):
• Leukocyte count <2.5 x 109/L
• Neutrophil count <1.0 x 109/L
• Platelet count <75 x 109/L
• Hemoglobin<6.52 mmol/L (male) or <5.9 mmol/L (female)
[00290] In addition, the SRC may stop dose escalation at any time if the SRC determines that dose escalation would pose undue risk to subjects. If dose escalation is not stopped, the SRC may recommend ascending to the planned next-higher dose level cohort, ascending to a dose level lower than the planned next-higher dose level cohort, or a repeat dosing at the current dose level.
Re-initiation of Dose Escalation
[00291] If dose escalation is terminated due to the criteria noted above, reduced and/or repeat dose levels (as allowed per protocol) may be administered to provide additional data regarding the frequency and/or severity of adverse events. If the SRC agrees that these additional data suggest that the observations that initially resulted in a termination of dose escalation were not attributable to study drug, then dose escalation may be allowed to continue.
Cessation of Dosing for an Individual Subject
[00292] If a subject has a clinically significant event in the opinion of the PI and in consultation with THB, dose administration for this subject will cease beginning with the next scheduled dose regardless of assignment to active Compound 1 or placebo. All assessments scheduled for the follow-up visit should be performed upon early withdrawal (within 7 - 10 days after the final dose received). If dosing is stopped for a subject, the subject will be considered to be withdrawn from the study (i.e., not completed). The PI may request that the subject remain confined for a period of time appropriate to evaluate safety for that subject. Confinement is not to exceed that planned for the study. The subject will undergo the follow-up visit assessments 7 - 10 days after the last dose.
Cessation of Dosing Within a Dose Level
[00293] The PI or THB alone may stop further dosing for all subjects within a dose level/cohort at any time if they deem that continuing to dose would jeopardize the safety of the subjects. In the event that dosing is stopped, the PI may request that the subjects remain confined for a period of time appropriate to evaluate safety provided that confinement is not to exceed that planned for the study.
Study Drug Interruption or Discontinuation
[00294] The investigator must temporarily interrupt or permanently discontinue the study drug if continued administration of the study drug is believed to be contrary to the best interests of the subject. The interruption or premature discontinuation of study drug might be triggered by an AE, a diagnostic or therapeutic procedure, an abnormal assessment (e.g., ECG or laboratory abnormalities), for administrative reasons (in particular withdrawal of the subject’s consent), when a subject is lost to follow-up, or in case of severe violation of study restrictions or clinic rules, as judged by the Investigator. If the reason for discontinuation from study drug is an abnormal result on a laboratory test, vital sign, ECG recording, or physical examination, this information will be recorded as an AE. The subject will remain under the supervision of the investigator until satisfactory health has returned. The reason for study drug interruption or premature discontinuation must be documented and the sponsor must be informed.
[00295] If the Sponsor terminates or suspends the study, the Investigator or his/her designee should promptly inform the IEC (and/or regulatory authorities where required) of a temporary halt including the reason for such an action.
Study Discontinuation
[00296] Subjects may withdraw from the study at any time without prejudice to their future medical care by the physician or at the institution. The withdrawal of a subject from the study should be discussed where possible with the Medical Monitor before the subject stops taking the investigational product. If investigational product is discontinued, the final evaluations are to be performed as completely as possible. Drop-outs might be replaced but only upon mutual agreement between the investigator and the Sponsor, unless withdrawal is due to a drug-related AE. The replacing subject will receive the same treatment as was assigned to the subject whom he/she replaces.
Subject’s Follow-up after Study Discontinuation
[00297] The subjects will be advised that participation in these investigations is voluntary. Furthermore, the subjects may request that from the time point of withdrawal no more data will be recorded and that all biological samples collected in the course of the study will be destroyed.
[00298] In the case of premature discontinuation after study drug intake, the assessments scheduled for the EOS examination will be performed as soon as possible after study drug intake, as per investigator judgement, unless the subject withdrew informed consent.
J. Adverse Events
[00299] Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment is considered an adverse event (AE). An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A treatment-emergent AE is any AE temporally associated with the use of a study drug, whether or not considered related to the study drug.
[00300] Adverse events include:
- Exacerbation of a pre-existing disease.
Increase in frequency or intensity of a pre-existing episodic disease or medical condition.
- Disease or medical condition detected or diagnosed after study drug administration even though it may have been present prior to the start of the study.
Continuous persistent disease or symptoms present at baseline that worsen following the start of the study.
- Lack of efficacy in the acute treatment of a life-threatening disease.
- Events considered by the investigator to be related to study-mandated procedures. Abnormal assessments, e.g., ECG, vital signs or physical examination findings, must be reported as adverse events if they represent a clinically significant finding that was not present at baseline or worsened during the course of the study.
- Laboratory test abnormalities must be reported as adverse events if they represent a clinically significant finding, symptomatic or not, which was not present at baseline or worsened during the course of the study or led to dose reduction, interruption or permanent discontinuation of study drug.
[00301] Adverse events do not include:
- Medical or surgical procedure, e.g., surgery, endoscopy, tooth extraction, transfusion. However, the event leading to the procedure is an AE.
- Pre-existing disease or medical condition that does not worsen.
Situations in which an adverse change has not occurred, e.g., hospitalizations for cosmetic elective surgery or for social and/or convenience reasons.
Overdose of either study drug or concomitant medication without any signs or symptoms.
[00302] The intensity of clinical adverse events is graded on a three-point scale: mild, moderate, severe
Mild: Event may be noticeable to subject; does not influence daily activities; usually does not require intervention.
Moderate: Event may make subject uncomfortable; performance of daily activities may be influenced; intervention may be needed.
Severe: Event may cause noticeable discomfort; usually interferes with daily activities; subj ect may not be able to continue in the study; treatment or intervention is usually needed.
[00303] Adverse events should be assessed by the investigators as to whether or not there is a reasonable possibility of causal relationship to the study drug and reported as either related or unrelated.
[00304] Related to study drug: This category applies to any AE (serious or not) that appears to have a reasonable possibility of causal relationship to the use of the study drug (i.e., a relationship cannot be ruled out). Guidelines to determine whether an event might be considered related include (but are not limited to) the following:
The event occurred in close temporal relationship to study drug administration. The event abated (diminished) or disappeared when treatment with the study drug was down-titrated, interrupted, or discontinued.
The event re-occurred when treatment was re-introduced.
- Environmental factors such as clinical state and other treatments could equally have caused the event.
[00305] Related adverse events should be considered as one of the following categories:
- Definite: A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (de-challenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory re-challenge procedure if necessary.
- Probable: A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information is not required to fulfill this definition.
- Possible: A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.
[00306] Unrelated to study drug: This category applies to any AE (serious or not) that does not appear to have a reasonable relationship to the use of study drug (see above guidelines).
Unrelated adverse events should be considered as one of the following categories:
- Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations.
- Unrelated: A clinical event, including laboratory test abnormality, which is clearly not related to drug administration.
Serious Adverse Events [00307] A Serious Adverse Event (SAE) is defined by the International Conference on Harmonization (ICH) guidelines as any AE fulfilling at least one of the following criteria:
- Results in death.
Is life-threatening. Life-threatening refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death if it were more severe.
- Requires subject's hospitalization or prolongation of existing hospitalization.
- Results in persistent or significant disability or incapacity.
Is a congenital anomaly or birth defect.
Is medically significant or requires intervention to prevent at least one of the outcomes listed above.
[00308] Important medical events that may not immediately result in death, be life-threatening, or require hospitalization may be considered as SAEs when, based upon appropriate medical judgment, they may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions above.
[00309] All SAEs regardless of causal relationship must be reported, including those related to study-mandated procedures. These SAEs occurring during study drug administration, i.e., between study drug initiation and EOS after study drug discontinuation, are defined as treatment emergent SAEs. New SAEs, including those related to study-mandated procedures, occurring after study drug discontinuation, i.e., between study drug discontinuation and EOS, must be reported. Serious adverse events still ongoing at the End-of-Study visit must be followed until resolution or stabilization or until the event is otherwise explained.
K. Statistical Analysis Methodology
[00310] Three different analysis sets are defined. Subjects who withdraw from the study, or who have missing data, will be included in the statistical analyses provided that they are eligible for inclusion in the analysis population as described below.
[00311] All-treated set: This analysis set includes all randomized subjects who received study drug (at least one dose). [00312] Safety set: This analysis set includes subjects from the all-treated set who had at least one safety assessment post-baseline. The safety set will be employed in the analysis of tolerability and safety variables.
[00313] Per-protocol set: This analysis set comprises all subjects included in the All-treated set who did not violate the protocol in a way that might affect the evaluation of the effect of the study drug(s) on the primary endpoint, i.e., without major protocol violations or deviations. The Per- protocol set will be employed in the analysis of PK variables.
[00314] All analyses will be performed on data available at the time point considered. In summary tables, the number of subjects with missing data will be presented unless otherwise specified. In calculation of percentages, subjects with missing data will not be considered in numerator or denominator unless otherwise specified.
Pharmacokinetic Statistical Analysis
[00315] The per-protocol analysis set will be used for all PK analyses. Individual subject listings will be provided for Compound 1. Mean and individual plasma concentration-time profiles for Compound 1 will be presented graphically for each group. PK variables will be summarized using arithmetic mean, standard deviation, geometric mean, median, minimum, maximum, and CV%. Attainment of steady-state conditions will be determined by visual inspection of the trough plasma concentrations.
Cardiodynamic Parameters
[00316] Cardiodynamic ECG evaluation may be performed for Part 1 (SAD) and Part 3 (MAD), based on observed PK and other project considerations. If this evaluation is performed, the primary analysis will be based on concentration-QTc (C-QTc) modeling of the relationship between the plasma concentrations of Compound 1 and its potential metabolites and change-from-baseline QTcF (AQTcF) with the intent to exclude an effect of placebo-corrected AQTcF (AAQTcF) > 10 msec at clinically relevant plasma concentrations. The effect of Compound 1 on the placebo- corrected AQTcF, AHR (heart rate), APR, and AQRS (AAQTcF, AAHR, AAPR, and AAQRS) will also be evaluated at each post-dosing time point ('by-time point' analysis). In addition, an analysis of categorical outliers will be performed for changes in HR, PR, QRS, QTcF, T-wave morphology and U-wave presence. Alternative Cardiodynamic Parameters
[00317] Cardiodynamic Mean hourly heart rate will be analyzed for Part 1 (SAD) and Part 3 (MAD) as described in F. Study Assessments: Mean Hourly Heartrate. The effect of Compound 1 on the placebo-corrected AQTcF, AHR (heart rate), APR, and AQRS (AAQTcF, AAHR, AAPR, and AAQRS) will also be evaluated at each post-dosing time point ('by-time point' analysis). In addition, an analysis of categorical outliers will be performed for changes in HR, PR, QRS, and QTcF, and descriptive analysis of mean hourly HR will be performed. Optional cardiodynamic evaluation and precision QT may be performed for Part 1 (SAD) and Part 3 (MAD), based on observed PK and other project considerations. The analysis will be based on concentration-QTc (C-QTc) modeling of the relationship between the plasma concentrations of Compound 1 and its potential metabolites and change-from-baseline QTcF (AQTcF) with the intent to exclude an effect of placebo-corrected AQTcF (AAQTcF) > 10 msec at clinically relevant plasma concentrations.
Pharmacodynamic Parameters
[00318] Serum tryptase levels, SCF, CTX, 4P-hydroxy cholesterol and mast cell counts will be listed. PD markers will be evaluated graphically and descriptive statistics of absolute values and change from baseline at each time point will be tabulated by treatment.
Pharmacokinetic/Pharmacodynamic Relationships
[00319] The relationship between dose and PK parameters (e.g., AUCs and Cmax) of Compound 1 with PD evaluations (e.g., serum tryptase and mast cell counts) may be evaluated graphically, using linear regressions if applicable. Additional types of relationships may be explored using nonlinear mixed-effect PK/PD modeling approaches if warranted. The relationship between dose and PK parameters (e.g., AUCs and Cmax) with safety evaluations (e.g., ECGs) may be evaluated graphically using appropriate methods.
INCORPORATION BY REFERENCE
[00320] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS
[00321] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

CLAIMS What is claimed is:
1. A method of treating a c-kit kinase mediated disease or disorder, comprising orally administering to a patient in need thereof a dose of N-(5-(5-((lR,2S)-2-fluorocyclopropyl)-l,2,4- oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3 -carboxamide, or a pharmaceutically acceptable salt thereof, in an amount of from about 10 mg to about 1,000 mg in order to treat the c-kit kinase mediated disease or disorder.
2. The method of claim 1, wherein the dose is from about 10 mg to about 200 mg of N-(5- (5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine- 3 -carboxamide, or a pharmaceutically acceptable salt thereof.
3. The method of claim 1, wherein the dose is from about 200 mg to about 400 mg of N-(5- (5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine- 3 -carboxamide, or a pharmaceutically acceptable salt thereof.
4. The method of claim 1, wherein the dose is from about 400 mg to about 800 mg of N-(5- (5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine- 3 -carboxamide, or a pharmaceutically acceptable salt thereof.
5. The method of claim 1, wherein the dose is about 30 mg of N-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, or a pharmaceutically acceptable salt thereof.
6. The method of claim 1, wherein the dose is about 100 mg of N-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, or a pharmaceutically acceptable salt thereof.
7. The method of claim 1, wherein the dose is about 200 mg ofN-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, or a pharmaceutically acceptable salt thereof.
8. The method of claim 1, wherein the dose is about 300 mg ofN-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, or a pharmaceutically acceptable salt thereof.
9. The method of claim 1, wherein the dose is about 400 mg ofN-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, or a pharmaceutically acceptable salt thereof.
10. The method of claim 1, wherein the dose is about 500 mg ofN-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, or a pharmaceutically acceptable salt thereof.
11. The method of claim 1, wherein the dose is about 800 mg ofN-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, or a pharmaceutically acceptable salt thereof.
12. The method of any one of claims 1-11, wherein the dose is orally administered two or more times per day.
13. The method of any one of claims 1-11, wherein the dose is orally administered twice per day.
14. The method of any one of claims 1-11, wherein the dose is orally administered once per day.
15. A method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a first therapeutic agent according to a first treatment cycle lasting at least 10 days, in order to treat the c-kit kinase mediated disease or disorder, wherein the first therapeutic agent is N-(5-(5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3- yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3 -carboxamide, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle.
16. The method of claim 15, wherein the first treatment cycle lasts at least 14 days.
17. The method of claim 15, wherein the first treatment cycle lasts 14 days.
18. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of from about 10 mg to about 1,000 mg on each day of the first treatment cycle.
19. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of from about 10 mg to about 200 mg on each day of the first treatment cycle.
20. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of from about 200 mg to about 400 mg on each day of the first treatment cycle.
21. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of from about 400 mg to about 800 mg on each day of the first treatment cycle.
22. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of about 30 mg on each day of the first treatment cycle.
23. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of about 100 mg on each day of the first treatment cycle.
24. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of about 200 mg on each day of the first treatment cycle.
25. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of about 300 mg on each day of the first treatment cycle.
26. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of about 400 mg on each day of the first treatment cycle.
27. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of about 500 mg on each day of the first treatment cycle.
28. The method of any one of claims 15-17, wherein the first therapeutic agent is orally administered in an amount of about 800 mg on each day of the first treatment cycle.
29. The method of any one of claims 15-28, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of at least 7 days.
30. The method of any one of claims 15-28, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of at least 14 days.
31. The method of any one of claims 15-28, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of at least 21 days.
32. The method of any one of claims 15-28, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of at least 28 days.
33. The method of any one of claims 15-28, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of 7 days.
34. The method of any one of claims 29-33, wherein after the non-treatment cycle, the first therapeutic agent is administered to the patient according to a second treatment cycle lasting at least 10 days during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
35. The method of any one of claims 29-33, wherein after the non-treatment cycle, the first therapeutic agent is administered to the patient according to a second treatment cycle lasting at least 14 days during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
36. The method of any one of claims 29-33, wherein after the non-treatment cycle, the first therapeutic agent is administered to the patient according to a second treatment cycle lasting 14 days during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
37. The method of any one of claims 34-36, wherein the first therapeutic agent is orally administered in an amount of from about 10 mg to about 1,000 mg on each day of the second treatment cycle.
38. The method of any one of claims 34-36, wherein the first therapeutic agent is orally administered in an amount of from about 10 mg to about 200 mg on each day of the second treatment cycle.
39. The method of any one of claims 34-36, wherein the first therapeutic agent is orally administered in an amount of from about 200 mg to about 400 mg on each day of the second treatment cycle.
40. The method of any one of claims 34-36, wherein the first therapeutic agent is orally administered in an amount of from about 400 mg to about 800 mg on each day of the second treatment cycle.
41. The method of any one of claims 1-40, wherein the patient is in a fasted state when N- (5-(5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2- a]pyridine-3 -carboxamide, or pharmaceutically acceptable salt thereof, is administered to the patient.
42. The method of any one of claims 1-40, wherein the patient is in a fed state when N-(5- (5-((lR,2S)-2-fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine- 3 -carboxamide, or pharmaceutically acceptable salt thereof, is administered to the patient.
43. The method of any one of claims 1-42, wherein the N-(5-(5-((lR,2S)-2- fluorocyclopropyl)-l,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[l,2-a]pyridine-3- carboxamide, or pharmaceutically acceptable salt thereof, is administered to the patient as part of a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers.
44. A method of treating a c-kit kinase mediated disease or disorder, comprising administering to a patient in need thereof a first therapeutic agent according to a first treatment cycle lasting at least 10 days, in order to treat the c-kit kinase mediated disease or disorder, wherein the first therapeutic agent is c-kit kinase inhibitor, and a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the first treatment cycle.
45. The method of claim 44, wherein the first treatment cycle lasts at least 14 days.
46. The method of claim 44, wherein the first treatment cycle lasts 14 days.
47. The method of any one of claims 44-46, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of at least 7 days.
48. The method of any one of claims 44-46, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of at least 14 days.
49. The method of any one of claims 44-46, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of at least 21 days.
50. The method of any one of claims 44-46, wherein after the first treatment cycle, there is a non-treatment cycle during which the patient does not receive the first therapeutic agent for a duration of at least 28 days.
51. The method of any one of claims 47-50, wherein after the non-treatment cycle, the first therapeutic agent is administered to the patient according to a second treatment cycle lasting at least 10 days during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
52. The method of any one of claims 47-50, wherein after the non-treatment cycle, the first therapeutic agent is administered to the patient according to a second treatment cycle lasting at least 14 days during which a therapeutically effective amount of the first therapeutic agent is administered to the patient on each day of the second treatment cycle.
53. The method of any one of claims 44-52, wherein first therapeutic agent is a small organic compound, or a pharmaceutically acceptable salt thereof.
54. The method of any one of claims 44-52, wherein first therapeutic agent is an antibody.
55. The method of any one of claims 44-52, wherein first therapeutic agent is:
(a) BLU-263, avapritinib, masitinib, HT-KIT, CGT-9846, AZD 3229, axitinib, foretinib, regorafenib, sorafenib, dasatinib, imatinib, pazopanib, pexidartinib, lenvatinib, cabozantinib, M4205, dovitinib, chiauranib, ripretinib, sitravatinib, flumatinib, amuvatinib, linifanib, telatinib, AST 487, motesanib, KΪ20227, SU14813, tandutinib, toceranib, ISCK03, OSI-930, motesanib, PLX647, DCC-3014, AC710, tyrphostin AG1296, SU14813, AZD2932, c-Kit-IN-1, c-Kit-IN-2, CHMFL- ABL-KIT -155, KG5, PD180970, JNJ-38158471, or HG-7-85-01; or a pharmaceutically acceptable salt thereof; or
(b) CDX-0159, CDX-0158, NN-2101, NN-2901, FSI-174 or JSP-191.
56. The method of any one of claims 1-55, wherein the c-kit kinase mediated disease or disorder is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrosis disease, or a dermatological disease.
57. The method of any one of claims 1-55, wherein the c-kit kinase mediated disease or disorder is a mast-cell associated disease.
58. The method of any one of claims 1-55, wherein the c-kit kinase mediated disease or disorder is an inflammatory disorder.
59. The method of any one of claims 1-55, wherein the c-kit kinase mediated disease or disorder is an autoimmune disorder.
60. The method of any one of claims 1-55, wherein the c-kit kinase mediated disease or disorder is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes or type II diabetes.
61. The method of any one of claims 1-55, wherein the c-kit kinase mediated disease or disorder is urticaria.
62. The method of any one of claims 1-55, wherein the c-kit kinase mediated disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD), or ulcerative colitis.
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