WO2020223235A1 - Formes pharmaceutiques de ponatinib du type mini-comprimés - Google Patents

Formes pharmaceutiques de ponatinib du type mini-comprimés Download PDF

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Publication number
WO2020223235A1
WO2020223235A1 PCT/US2020/030280 US2020030280W WO2020223235A1 WO 2020223235 A1 WO2020223235 A1 WO 2020223235A1 US 2020030280 W US2020030280 W US 2020030280W WO 2020223235 A1 WO2020223235 A1 WO 2020223235A1
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Prior art keywords
mini
tablets
ponatinib
tablet
administration
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PCT/US2020/030280
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English (en)
Inventor
Francis X. Muller
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Incyte Corporation
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Publication of WO2020223235A1 publication Critical patent/WO2020223235A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present application is directed to mini-tablets of ponatinib, or a pharmaceutically acceptable salt thereof, capsules and kits comprising the mini-tablets, and methods of treating pediatric or geriatric patients.
  • Ponatinib (3-(imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N- ⁇ 4-[(4- methylpiperazin-l-yl)methyl]-3-(trifluoromethyl)phenyl ⁇ benzamide) is a multi -targeted tyrosine-kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
  • CML chronic myeloid leukemia
  • Ph+ALL Philadelphia chromosome positive acute lymphoblastic leukemia
  • Ponatinib is marketed as ponatinib hydrochloride which is the 1 : 1 ponatinib HC1 salt.
  • the present application is directed to, inter alia , a mini-tablet, comprising a composition comprising ponatinib, or a pharmaceutically acceptable salt thereof, in an amount of about 0.1 mg to about 1 mg on a free base basis of ponatinib.
  • the present application further provides a capsule comprising the mini-tablets of the invention.
  • the present application further provides a kit for providing a dose of ponatinib, or a pharmaceutically acceptable salt thereof, to a pediatric patient, comprising a capsule of the invention.
  • the present application further provides a method of treating a leukemia in a patient, comprising administering a mini-tablet or capsule of the invention.
  • FIG. 1 depicts a typical dissolution profile for a capsule of Example 3.
  • FIG. 2 depicts plasma concentrations of ponatinib (mean ⁇ SE) in healthy participants following administration of ponatinib 15 mg tablet and 3 x 5 mg minitab capsules.
  • FIG. 3 depicts Table 43 which summarizes PK parameters for administration of single dose of ponatinib 15 mg tablet (Treatment A) and 3 x 5 mg MiniTab capsules
  • FIG. 4 depicts Table 45 which presents the statistical analysis summary for comparison of ponatinib PK parameters between 15 mg tablet and 3 x 5 mg MiniTab capsules.
  • FIG. 5 depicts ponatinib Cmax values for individual participants following
  • FIGS. 6A-B depict ponatinib AUC values for individual participants following administration of ponatinib 15 mg tablet and 3 x 5 mg minitab capsules (A: AUCO-t, B: AUCO-oo).
  • FIG. 7 depicts plasma concentrations of ponatinib (mean ⁇ SE) in healthy participants following administration of ponatinib 3 x 5 mg minitab capsules intact and capsules opened and sprinkled on yogurt or applesauce.
  • FIG. 8 depicts Table 5 which summarizes PK parameters following administration of a single dose of ponatinib 3 x 5 mg MiniTab capsules intact (Treatment C) and 3 x 5 mg MiniTab capsules opened and sprinkled on yogurt (Treatment D) or applesauce (Treatment E).
  • FIG. 9 depicts Table 6 which presents the statistical analysis summary for
  • FIG. 10 depicts ponatinib Cmax values for individual participants following administration of ponatinib 3 x 5 mg minitab capsules intact and capsules opened and sprinkled on yogurt or applesauce.
  • the present application provides, inter alia , a mini-tablet, comprising a composition comprising ponatinib, or a pharmaceutically acceptable salt thereof, in an amount of about 0.1 mg to about 1 mg on a free base basis of ponatinib.
  • the ponatinib, or the pharmaceutically acceptable salt thereof is ponatinib HC1.
  • the ponatinib HC1 is a polymorph designated as Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or Form K as described in U.S. Patent No. 9493470, which is incorporated herein by reference in its entirety.
  • the ponatinib HC1 is crystalline Form A.
  • the ponatinib hydrochloride is more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99% or more than 99.9% of crystalline Form A of ponatinib hydrochloride.
  • crystalline Form A is characterized by an x-ray powder diffraction pattern comprising at least five 20 values ( ⁇ 0.3) selected from 5.9, 7.1, 10.0, 12.5, 16.4, 19.3, 21.8, 23.8, and 26.1. In some embodiments, crystalline Form A is characterized by an x-ray powder diffraction pattern comprising at least five 20 values ( ⁇ 0.3) selected from 5.9, 7.1, 10.0, 12.5, 13.6, 14.1, 15.0, 16.4, 17.7, 18.6, 19.3, 20.4, 21.8, 22.3, 23.8, 24.9, 26.1, 27.0, 28.4, 30.3, 31.7, and 35.1.
  • the composition comprises from about 0.4 mg to about 0.6 mg of the ponatinib, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, the composition comprises about 0.5 mg of the ponatinib, or a
  • the composition comprises from about 0.4 mg to about 0.6 mg of ponatinib HC1 on a free base basis. In some embodiments, the composition comprises about 0.5 mg of ponatinib HC1 on a free base basis.
  • the composition comprises a filler component.
  • the composition comprises from about 70% to about 97% (w/w) of a filler component. In some embodiments, the composition comprises from about 80% to about 90% (w/w) of the filler component. In some embodiments, the composition comprises from about 85% to about 90% (w/w) of the filler component.
  • the filler component comprises two different fillers. In some embodiments, the filler component comprises two different fillers in about a 40-60 to about a 60-40 ratio. In some embodiments, the filler component comprises two different fillers in about a 50-50 ratio.
  • the filler component comprises microcrystalline cellulose, powdered cellulose, cellulose, pregelatinized starch, starch, mannitol, sorbitol, powdered sugar, compressible sucrose, sucrose, dextrose, inositol, maltodextrin, calcium phosphate (e.g., di and tri basic, hydrated or anhydrous), calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, lactose monohydrate, anhydrous lactose, polyvinylpyrrolidone, copovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and combinations thereof.
  • microcrystalline cellulose powdered cellulose, cellulose, pregelatinized starch, starch, mannitol, sorbitol, powdered sugar, compressible sucrose, sucrose, dextrose, inositol, maltodextrin, calcium phosphate (e.g., di and tri basic,
  • the filler component comprises microcrystalline cellulose, lactose monohydrate and combinations thereof.
  • the filler component comprises microcrystalline cellulose, spray-dried lactose monohydrate and combinations thereof.
  • the composition comprises a disintegrant component. In some embodiments, the composition comprises from about 1% to about 12% (w/w) of a disintegrant component. In some embodiments, the composition comprises from about 2% to about 6% (w/w) of the disintegrant component. In some embodiments, the composition comprises from about 3% to about 5% (w/w) of the disintegrant component.
  • the disintegrant component comprises corn starch, potato starch, modified com starch, croscarmellose sodium, crospovidone, carmellose calcium, sodium alginate, potassium alginate, calcium alginate, sodium starch glycolate, magnesium aluminum silicate, methyl cellulose, modified cellulose gum, agar, bentonite, montmorillonite clay, natural sponge, an ion-exchange resin (e.g., polyacrin potassium), alginic acid, and combinations thereof.
  • corn starch potato starch, modified com starch, croscarmellose sodium, crospovidone, carmellose calcium, sodium alginate, potassium alginate, calcium alginate, sodium starch glycolate, magnesium aluminum silicate, methyl cellulose, modified cellulose gum, agar, bentonite, montmorillonite clay, natural sponge, an ion-exchange resin (e.g., polyacrin potassium), alginic acid, and combinations thereof.
  • ion-exchange resin e
  • the disintegrant component comprises croscarmellose sodium, crospovidone, and sodium starch glycolate, and combinations thereof.
  • the disintegrant component is sodium starch glycolate.
  • the composition comprises a lubricant component.
  • the composition comprises from about 0.5% to about 2%
  • the composition comprises from about 0.6% to about 2% (w/w) of a lubricant component. In some embodiments, the composition comprises from about 0.7% to about 2% (w/w) of a lubricant component. In some embodiments, the composition comprises from about 0.8% to about 2% (w/w) of a lubricant component. In some embodiments, the composition comprises from about 0.9% to about 2% (w/w) of a lubricant component. In some embodiments, the composition comprises from about 1% to about 2% (w/w) of a lubricant component. In some embodiments, the composition comprises from about 0.9% to about 1.1% (w/w) of a lubricant component.
  • the lubricant component comprises a metallic stearate, glyceryl palmitostearate, stearic acid, hydrogenated vegetable oils, glyceryl behenate, polyethylene glycol, an ethylene oxide polymer, fatty acid, fatty alcohol, fatty acid ester, propylene glycol fatty acid ester, polypropylene glycol, polyalkylene glycol, mineral oil, liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL- leucine, and combinations thereof.
  • the lubricant component comprises a metallic stearate, glyceryl palmitostearate, stearic acid, and combinations thereof.
  • the lubricant component comprises a metallic stearate.
  • the metallic stearate is selected from magnesium stearate, calcium stearate, and zinc stearate. In some embodiments, the metallic stearate is magnesium stearate.
  • composition comprises:
  • composition comprises:
  • composition comprises:
  • composition comprises:
  • a disintegrant component from about 1% to about 12% (w/w) of a disintegrant component; and from about 0.6% to about 2% (w/w) of a lubricant component.
  • composition comprises:
  • composition comprises:
  • composition comprises:
  • the filler component comprises microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, mannitol, sorbitol, powdered sugar, compressible sucrose, sucrose, dextrose, inositol, maltodextrin, calcium phosphate, calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, lactose monohydrate, anhydrous lactose, polyvinylpyrrolidone, copovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, or a combination thereof;
  • the disintegrant component comprises corn starch, potato starch, modified corn starch, croscarmellose sodium, crospovidone, carmellose calcium, sodium alginate, potassium alginate, calcium alginate, sodium starch glycolate, magnesium aluminum silicate, methyl cellulose, modified cellulose gum, agar, bentonite, montmorillonite clay, natural sponge, an ion-exchange resin, alginic acid, or a combination thereof; and
  • the lubricant component comprises a metallic stearate, glyceryl palmitostearate, stearic acid, hydrogenated vegetable oils, glyceryl behenate, polyethylene glycol, an ethylene oxide polymer, fatty acid, fatty alcohol, fatty acid ester, propylene glycol fatty acid ester, polypropylene glycol, polyalkylene glycol, liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, or a combination thereof.
  • the filler component comprises microcrystalline cellulose, lactose monohydrate or a combination thereof;
  • the disintegrant component comprises croscarmellose sodium, crospovidone, sodium starch glycolate, or a combination thereof;
  • the lubricant component comprises magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, stearic acid, or a combination thereof.
  • the filler component comprises microcrystalline cellulose, spray-dried lactose monohydrate, or a combination thereof;
  • the disintegrant component is sodium starch glycolate
  • the lubricant component is magnesium stearate.
  • the composition comprises a glidant component.
  • the composition comprises from about 0.2% to about 1% of the glidant component. In some embodiments, the composition comprises from about 0.4% to about 0.5% of the glidant component.
  • the glidant component comprises talc, colloidal silicon dioxide, or a combination thereof.
  • the glidant component is colloidal silicon dioxide.
  • the mini-tablet has a diameter along the longest axis of about 1 mm to about 2.4 mm.
  • the mini-tablet has a diameter along the longest axis of about 2 mm.
  • the weight of the composition is from about 5 mg to about 10 mg.
  • the weight of the composition is about 8 mg.
  • the mini-tablet further comprises a coating on the outer surface of the composition.
  • the composition comprises from about 85% to about 98% (w/w) of said mini-tablet.
  • the composition comprises from about 90% to about 95% (w/w) of said mini-tablet.
  • the composition comprises from about 91% to about 93% (w/w) of said mini-tablet.
  • the coating comprises from about 5% to about 10% (w/w) of said mini-tablet. In some embodiments, the coating comprises from about 7% to about 9% (w/w) of said mini-tablet.
  • the mini-tablet further comprises a coating on the outer surface of the composition, wherein the composition comprises from about 85% to about 98% (w/w) of said mini -tablet; and the coating comprises from about 5% to about 10% (w/w) of said mini-tablet. In some embodiments, the mini-tablet further comprises a coating on the outer surface of the composition, wherein the composition comprises from about 90% to about 95% (w/w) of said mini -tablet; and the coating comprises from about 5% to about 10% (w/w) of said mini-tablet.
  • the mini-tablet further comprises a coating on the outer surface of the composition, wherein the composition comprises from about 90% to about 95% (w/w) of said mini-tablet; and the coating comprises from about 7% to about 9% (w/w) of said mini-tablet. In some embodiments, the mini-tablet further comprises a coating on the outer surface of the composition, wherein the composition comprises from about 91% to about 93% (w/w) of said mini-tablet; and the coating comprises from about 7% to about 9% (w/w) of said mini-tablet.
  • the coating is suitable for taste masking.
  • the coating comprises polyvinyl alcohol, polyvinyl acetate, hypomellose, polyethylene glycol, talc, or a combination thereof.
  • the present application further provides a mini-tablet comprising a composition having a coating on the outer surface of the composition, wherein the composition comprises:
  • mini-tablet has a diameter of about 2 mm.
  • the present application also provides a mini-tablet comprising a composition having a coating on the outer surface of the composition, wherein the composition comprises:
  • microcrystalline cellulose from about 43% to about 45% (w/w) of microcrystalline cellulose
  • mini-tablet has a diameter of about 2 mm.
  • the present application further provides a capsule comprising one or more of the mini-tablets of any of the embodiments described herein. In some embodiments, the capsule comprises ten of the mini-tablets.
  • a single capsule provides a dose of about 1 mg to about 10 mg of ponatinib, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, a single capsule provides a dose of about 3 mg to about 7 mg of ponatinib, or a pharmaceutically acceptable salt thereof, on a free base basis. In some embodiments, a single capsule provides a dose of about 5 mg of ponatinib, or a pharmaceutically acceptable salt thereof, on a free base basis.
  • a single capsule provides a dose of about 1 mg to about 10 mg of ponatinib HC1 on a free base basis. In some embodiments, a single capsule provides a dose of about 3 mg to about 7 mg of ponatinib HC1 on a free base basis.
  • a single capsule provides a dose of about 5 mg of ponatinib HC1 on a free base basis.
  • the present application also provides a kit for providing a dose of ponatinib, or a pharmaceutically acceptable salt thereof, to a pediatric patient, comprising the capsule of any of the embodiments described herein.
  • the capsule dissolves within 30 minutes in 500 mL of hydrochloric acid buffer having a pH of about 2.1 at 37 °C using USP Apparatus 1 (baskets) set to 100 rpm.
  • administration of one or more of the mini-tablets comprising a dose of about 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof, results in statistically equivalent bioavailability to a tablet of having a dose of about 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets comprising a dose of about 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof, results in statistically equivalent bioavailability to a tablet of having a dose of about 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets results in a statistically equivalent mean bioavailability to a tablet having the same dosage.
  • the one or more mini -tablets comprise a dosage of about 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • the one or more mini-tablets comprise a dosage of about 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more mini-tablets comprise a dosage of about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of a capsule containing one or more of the mini-tablets comprising a dose of about 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof results in statistically equivalent bioavailability to a tablet of having a dose of about 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of about 18 to about 21 ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of about 18 to about 21 ng/mL, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of about 14 to about 26 ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of about 14 to about 26 ng/mL, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of from about 10 to about 30 ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of from about 10 to about 30 ng/mL, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of from about 4.8 to about 6.3 ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of from about 4.8 to about 6.3 ng/mL, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of from about 4 to about 7ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean peak plasma concentration (Cmax) of ponatinib of from about 4 to about 7 ng/mL, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 500 to about 600 h-ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 500 to about 600 h-ng/mL, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 428 to about 739 h-ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 428 to about 739 h-ng/mL, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 400 to about 800 h-ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 400 to about 800 h-ng/mL, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 140 to about 250 h-ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 140 to about 250 h-ng/mL, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 100 to about 300 h-ng/mL. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean bioavailability (AUCo- ) of ponatinib of from about 100 to about 300 h-ng/mL, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean time to peak plasma concentration (Tmax) of ponatinib of about 5 hours to about 6 hours. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean time to peak plasma concentration (Tmax) of ponatinib of about 5 hours to about 6 hours, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean time to peak plasma concentration (Tmax) of ponatinib of about 5 hours to about 6 hours, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • Tmax mean time to peak plasma concentration
  • administration of one or more of the mini-tablets to a human results in a mean time to peak plasma concentration (Tmax) of ponatinib of from about 4 to about 8 hours. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean time to peak plasma concentration (Tmax) of ponatinib of from about 4 to about 8 hours, wherein the one or more mini-tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean time to peak plasma concentration (Tmax) of ponatinib of from about 4 to about 8 hours, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • Tmax mean time to peak plasma concentration
  • administration of one or more of the mini-tablets to a human results in a mean half-life (ti/2) of from about 30 to about 40 hours. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean half-life (ti/2) of from about 30 to about 40 hours, wherein the one or more mini-tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean half-life (ti/2) of from about 30 to about 40 hours, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean half-life (ti/2) of from about 27 to about 47 hours. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean half-life (ti/2) of from about 27 to about 47 hours, wherein the one or more mini-tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean half-life (ti/2) of from about 27 to about 47 hours, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets results in a mean half-life (ti/2) of from about 20 to about 50 hours. In some embodiments,
  • administration of one or more of the mini-tablets results in a mean half-life (ti/2) of from about 20 to about 50 hours, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets results in a mean half-life (ti/2) of from about 20 to about 50 hours, wherein the one or more mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets to a human results in a mean oral clearance (CL/F) of ponatinib of from about 22 to about 39 L/h. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean oral clearance (CL/F) of ponatinib of from about 22 to about 39 L/h, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets results in a mean oral clearance (CL/F) of ponatinib of from about 20 to about 40 L/h. In some embodiments, administration of one or more of the mini-tablets results in a mean oral clearance (CL/F) of ponatinib of from about 20 to about 40 L/h, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a
  • administration of one or more of the mini-tablets to a human results in a mean oral clearance (CL/F) of ponatinib of from about 28 to about 32 L/h. In some embodiments, administration of one or more of the mini-tablets to a human results in a mean oral clearance (CL/F) of ponatinib of from about 28 to about 32 L/h, wherein the one or more mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • administration of one or more of the mini-tablets with food results in a statistically equivalent mean bioavailability to the one or more of the mini-tablets administered without food.
  • administration of one or more of the mini-tablets with yogurt or applesauce results in a statistically equivalent a mean bioavailability to one or more of the mini-tablets administered without food.
  • the one or more mini-tablets are administered by sprinkling the one or more mini-tablets on yogurt. In some embodiments, the one or more mini-tablets are administered by sprinkling one or more mini-tablets on applesauce.
  • the mini -tablets comprise a dosage of 15 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • the mini-tablets comprise a dosage of 5 mg on a free base basis of ponatinib, or a pharmaceutically acceptable salt thereof.
  • the administration in the preceding embodiments comprises administering 30 mini-tablets.
  • the administration in the preceding embodiments comprises administering 3 capsules each comprising 10 mini -tablets.
  • the administration in the preceding embodiments comprises administering 10 mini -tablets.
  • the administration in the preceding embodiments comprises administering one capsule comprising 10 mini -tablets.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present application also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present application include the
  • non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present applicatin can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols ( e.g ., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's
  • the patient is a pediatric patient, such as a child 12 years of age or under, 6 years of age or under, 5 years of age or under, 4 years of age or under, 3 years of age or under, 2 years of age or under, or 1 year of age or under.
  • the pediatric patient’s age is about 6 months to about 5 years, about 6 months to about 4 years, about 6 months to about 3 years, about 6 months to about 2 years, or about 6 months to about 1 year.
  • the patient is a geriatric patient, for example, a geriatric patient suffering from dysphagia or other swallowing disorder.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e. dinner arresting further development of the pathology and/or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e. termed reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • preventing refers to preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • glidant component refers to one or more substances that improve flow characteristics of the formulation during processing.
  • the term“filler component” refers to one or more substances that act to dilute the active compound to the desired dosage and/or that act as a carrier for the active compound.
  • the filler acts as a binder to increase the mechanical strength and/or compressibility of a composition.
  • disintegrant component refers to one or more substances that encourage disintegration in water (or water containing fluid in vivo ) of the composition.
  • lubricant component refers to one or more substances that aids in preventing sticking to the equipment of the formulation during processing and/or that improves powder flow of the formulation during processing.
  • the term“fatty alcohol” refers to an aliphatic alcohol that is saturated or unsaturated. In some embodiments, the fatty alcohol in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has between about eight to about thirty carbons on average. In some embodiments, the fatty alcohol has about eight to about twenty- four carbons on average. In some embodiments, the fatty alcohol has about twelve to about eighteen carbons on average.
  • Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, palmitolyl acid, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleyl alcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol, isobehenyl alcohol, selachyl alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.
  • fatty ester refers to an ester compound formed between a fatty acid and an organic compound containing a hydroxyl group.
  • hydroxyl group containing compound is a carbohydrate, such as, but not limited to, glucose, lactose, sucrose, dextrose, mannitol, xylitol, sorbitol, maltodextrin and the like.
  • the hydroxyl containing compound is a fatty alcohol.
  • the fatty ester comprises lanolin.
  • the fatty ester comprises capric ester or caprylic esters, or mixtures thereof.
  • the fatty ester comprises about 95% or greater of saturated fatty esters.
  • Suitable fatty acids and fatty alcohols for deriving the fatty esters include, but are not limited to, those defined herein.
  • Suitable fatty esters include, but are not limited to sucrose fatty acid esters (such as those available from
  • Medium chain fatty esters include, but are not limited, LabrafacTM CC (available from Gattefosse), MiglyolTM 810 and 812 (available from Multi Chem), the MyritolTM series (available from Cognis), CaptexTM 300 and 355 (available from Abitec), and CrodamolTM GTC/C (available from Croda).
  • the term“polyalkylene glycol”, employed alone or in combination with other terms, refers to a polymer containing oxyalkylene monomer units, or copolymer of different oxyalkylene monomer units.
  • the term“oxyalkylene”, employed alone or in combination with other terms refers to a group of formula -O-alkylene-.
  • the polyalkylene glycol is polytetrahydrofuran.
  • the polyalkylene glycol is polybutylene glycol.
  • polyethylene glycol refers to a polymer containing ethylene glycol monomer units of formula -O-CH2-CH2-.
  • Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., a methyl group.
  • derivatives of polyethylene glycols having esterifiable carboxy groups are also suitable.
  • Polyethylene glycols useful in the present application can be polymers of any chain length or molecular weight, and can include branching. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 9000.
  • the average molecular weight of the polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400.
  • Suitable polyethylene glycols include, but are not limited to polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol -400, polyethylene glycol-600, and polyethylene glycol-900. The number following the dash in the name refers to the average molecular weight of the polymer. In some embodiments, the polyethylene glycol is polyethylene glycol-400.
  • Suitable polyethylene glycols include, but are not limited to the CarbowaxTM and CarbowaxTM Sentry series (available from Dow), the LipoxolTM series (available from Brenntag), the LutrolTM series (available from BASF), and the PluriolTM series (available from BASF).
  • polypropylene glycol refers to a polymer containing propylene glycol monomer units of formula -0-C(CH3)-CH2-.
  • the polypropylene glycols can be formed from the ring-opening polymerization of propylene oxide.
  • Suitable polypropylene glycols for use in the invention can be of any chain length or molecular weight, and can include branching.
  • the polypropylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., a methyl group. Also suitable are derivatives of
  • polypropylene glycols having esterifiable carboxy groups having esterifiable carboxy groups.
  • polyvinylpyrrolidone refers to a polymer of
  • the polyvinylpyrrolidone contains one or more additional polymerized monomers. In some embodiments, the additional polymerized monomer is a carboxy containing monomer. In some embodiments, the polyvinylpyrrolidone is povidone. In some embodiments, the polyvinylpyrrolidone has a molecular weight between 2500 and 3 million. In some embodiments, the polyvinylpyrrolidone is povidone K12, K17, K25, K30, K60, K90, or K120. In some embodiments, the polyvinylpyrrolidone is povidone K25. Suitable polyvinylpyrrolidone polymers include, but are not limited to, the KollidoneTM series (available from BASF) and the PlasdoneTM series (available from ISP).
  • “statistically equivalent bioavailability” in terms of comparing mini tablets to tablets means that the AUC values are within 80% to 125% of each other.
  • mean when preceding a pharmacokinetic value (e.g. mean Cmax) represents the arithmetic mean value of the pharmacokinetic value taken from a population of patients unless otherwise specified.
  • Cmax means the maximum observed plasma concentration
  • Ci2h refers to the plasma concentration measured at 12 hours from administration.
  • Tmax refers to the time at which the maximum blood plasma concentration is observed.
  • T1/2 refers to the time at which the plasma concentration is half of the observed maximum.
  • AUC refers to the area under the plasma concentration-time curve which is a measure of total bioavailability.
  • AUCo- refers to the area under the plasma concentration-time curve extrapolated to infinity.
  • AUCo-t refers to the area under the plasma concentration-time curve from time 0 to the last time point with a quantifiable plasma concentration, usually about 12- 36 hours.
  • CL/F refers to oral clearance
  • “food” refers to material which is typically acceptable as consumable by most humans safely.
  • Ponatinib and ponatinib HC1 can be made by the processes described in U.S. Patent No. 8114874 (particularly the procedure in Example 16), which is incorporated herein by reference in its entirety. Further, various polymorphic forms of ponatinib HC1 can be prepared as described in U.S. Patent No. 9493470, which is incorporated herein by reference in its entirety. In particular, the‘470 patent discloses methods of making polymorphs of ponatinib HC1 designated as Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, and Form K.
  • reaction for preparing compound or salts can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g ., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. , 3 ⁇ 4 or 13 C), infrared spectroscopy, spectrophotometry (e.g, UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography -mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. , 3 ⁇ 4 or 13 C), infrared spectroscopy, spectrophotometry (e.g, UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography -mass spectroscopy (LCMS), or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography -mass
  • ponatinib may be useful in the treatment of cancers, including both primary and metastatic cancers, including solid tumors as well as lymphomas and leukemias (including CML, AML and ALL), and including cancers which are resistant to other therapies, including other therapies involving the administration of kinase inhibitors such as Gleevec, Tarceva or Iressa.
  • cancers including both primary and metastatic cancers, including solid tumors as well as lymphomas and leukemias (including CML, AML and ALL), and including cancers which are resistant to other therapies, including other therapies involving the administration of kinase inhibitors such as Gleevec, Tarceva or Iressa.
  • Such cancers include, among others, cancers of the breast, cervix, colon and rectum, lung, ovaries, pancreas, prostate, head and neck, gastrointestinal stroma, as well as diseases such as melanoma, multiple myeloma, non-Hodgkin's lymphoma, melanoma, gastric cancers and leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) including cases which are resistant to one or more other therapies, including among others, Gleevec, Tarceva or Iressa.
  • diseases such as melanoma, multiple myeloma, non-Hodgkin's lymphoma, melanoma, gastric cancers and leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) including cases which are resistant to one or more other therapies, including among others, Glee
  • Resistance to various anticancer agents can arise from one or more mutations in a mediator or effector of the cancer (e.g., mutation in a kinase such as Src or Abl) which correlate with alteration in the protein's drug binding properties, phosphate binding properties, protein binding properties, autoregulation or other characteristics.
  • a mediator or effector of the cancer e.g., mutation in a kinase such as Src or Abl
  • kinase such as Src or Abl
  • BCR- Abl the kinase associated with chronic myeloid leukemia
  • Gleevec has been mapped to a variety of BCR/ Abl mutations which are linked to a variety of functional consequences, including among others, steric hindrance of drug occupancy at the kinase's active site, alteration in deformability of the phosphate binding P loop, effects on the conformation of the activation loop surrounding the active site, and others.
  • steric hindrance of drug occupancy at the kinase's active site alteration in deformability of the phosphate binding P loop, effects on the conformation of the activation loop surrounding the active site, and others.
  • Shah et al, 2002, Cancer Cell 2, 117-125 and Azam et al, 2003, Cell 112, 831-843 and references cited therein for representative examples of such mutations in Bcr/Abl which correlate with drug resistance. See also the following references for additional background information on
  • Ponatinib is particularly useful against leukemias and other cancers, including those which are resistant in whole or part to other anticancer agents, specifically including Gleevec and other kinase inhibitors, and specifically including leukemias involving one or more mutations in BCR/Abl, within or outside the kinase domain, including but not limited to those noted in any of the foregoing publications.
  • the present application also provides a method of treating cancer in a patient, comprising administering the mini-tablets of any of the embodiments described herein.
  • the present application provides a method of treating cancer in a patient, comprising administering the capsule of any of the embodiments described herein.
  • the present application also provides a method of treating cancer in a patient, comprising administering the mini-tablets removed from a single capsule as described in any of the embodiments herein.
  • the present disclosure further provides a method of treating a leukemia in a patient, comprising administering one or more of the mini-tablets described herein, or one or more of the capsules described herein. In some embodiments, the present disclosure further provides a method of treating a leukemia in a patient, comprising administering one or more mini-tablets removed from one or more of the capsules described herein.
  • the cancer is leukemia.
  • the leukemia is chronic myeloid leukemia.
  • the leukemia is acute lymphoblastic leukemia.
  • the leukemia is chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
  • the leukemia is Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
  • the cancer is a non-hemotological cancer such as endometrial cancer, lung cancer, head and neck cancer, gastrointestinal stromal tumor (GIST), glioblastoma, thyroid cancer, hepatobiliary cancer, or any other solid tumors such as solid tumors characterized by mutations in one or more of the genes for FGFR1, FGFR2, FGFR3, FGFR4, RET, and KIT.
  • GIST gastrointestinal stromal tumor
  • glioblastoma glioblastoma
  • thyroid cancer hepatobiliary cancer
  • KIT KIT
  • the patient is a pediatric patient. In some embodiments, the patient is a geriatric patient.
  • the compounds of the invention can be provided with or used in combination with a companion diagnostic.
  • a companion diagnostic refers to a diagnostic device useful for determining the safe and effective use of a therapeutic agent.
  • a companion diagnostic may be used to customize dosage of a therapeutic agent for a given subject, identify appropriate subpopulations for treatment, or identify populations who should not receive a particular treatment because of an increased risk of a serious side effect.
  • the companion diagnostic is used to monitor treatment response in a patient. In some embodiments, the companion diagnostic is used to identify a subject that is likely to benefit from a given compound or therapeutic agent. In some embodiments, the companion diagnostic is used to identify a subject having an increased risk of adverse side effects from administration of a therapeutic agent, compared to a reference standard. In some embodiments, the companion diagnostic is an in vitro diagnostic or imaging tool selected from the list of FDA cleared or approved companion diagnostic devices. In some embodiments, the companion diagnostic is selected from the list of tests that have been cleared or approved by the Center for Devices and Radiological Health.
  • the compounds of the invention can be used in combination treatments where the compound of the invention is administered in conjunction with other treatments such as the administration of one or more additional therapeutic agents.
  • the one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
  • the additional therapeutic agents include one or more of the following anti-cancer therapies or agents: radiation therapy, cytostatic agents, cytotoxic agents, other anti-cancer agents and other drugs to amerliorate symptoms of the cancer or side effects of any of the drugs.
  • the additional therapeutic agents can include, for example, an agent such as an antibiotic-type agent, alkylating agent, antimetabolite agent, hormonal agent, immunological agent, or interferon-type agent.
  • Suitable antimetabolite antineoplastic agents may be selected from but not limited to
  • CibaGeigy CGP-30694 cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine,
  • EX-015 benzrabine, floxuridine, fludarabine phosphate, 5fluorouracil, N-(21-furanidyl) fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-1 88011, Lilly LY- 264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC- 127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricytin.
  • Suitable alkylating-type antineoplastic agents may be selected from but not limited to Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin- 139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL- 286558, Sanofi CY-233, cyplatate, Degussa D 384, Sumimoto DACHP(Myr)2,
  • diphenylspiromustine diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA- 2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G M, Chinoin GYKI-17230, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactolf Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC- 342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
  • Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont
  • ADR-456 aeroplysinin derivative, Ajinomoto AN II, Ajinomoto AN3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-
  • Hakko DC-79 Kyowa Hakko DC-88A, Kyowa Hakko, DC89-AI, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-AI, esperamicin-Alb, Erbamont FCE21954,
  • NKT-01 SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.
  • anticancer agents that may be used in combination with ponatinib according to the present invention include, for example, tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to xcarotene, X-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1F Henkel
  • APD aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, BristoMyers BNY-40481, Vestar boron-
  • Tsumura EPMTC the epothilones, ergotamine, etoposide, etretinate, fenretinide, Fujisawa
  • NMF5N hexadecylphosphocholine
  • Green Cross HO-221 homoharringtonine
  • hydroxyurea
  • K-76COONa Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU 1121 Lilly LY- 186641, NCI (US) MAP, marycin,
  • the present compounds may also be used in co-therapies with other anti neoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong- A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol,
  • Maruyama vaccine Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfm, vinorelbine,
  • VIRULIZIN zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aetema), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinidel filgrastim SDOl (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin iproxifene, LDI 200 (M
  • the additional therapeutic agent is a chemotherapeutic agent such as cytarabine.
  • the additional therapeutic agent is a kinase inhibitor such as, for example, trametinib.
  • the additional therapeutic agent is an antibody such as, for example, blinatumomab.
  • the mini-tablets of the present application can be administered orally.
  • the compound or salt is administered by a process comprising adding the mini -tablets as described herein to the patient’s food and instructing the patient to ingest the food.
  • the mini-tablets from a single capsule are administered to the patient.
  • compositions described herein can be prepared in a manner well known in the pharmaceutical art.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. , about 40 mesh.
  • compositions may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g. , see International App. No. WO 2002/000196.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non- critical parameters which can be changed or modified to yield essentially the same results.
  • Ponatinib mini-tabs were prepared using a blend-mill-blend-compression-coating process.
  • the scale of manufacture ranged from 100 grams (12,000 Tablets) to 2000 grams (250,000 Tablets).
  • Step 1 All excipients in Tables 1 or 2 (the amounts being scaled according to the desired batch size), other than the lubricant, were first blended for 10 minutes at 10 RPM’s in an appropriate blender, such as a Blendmaster bin blender.
  • an appropriate blender such as a Blendmaster bin blender.
  • Step 2 The blend was then passed through an appropriate screen, such as a Flexsift with a 30 mesh screen.
  • an appropriate screen such as a Flexsift with a 30 mesh screen.
  • Step 3 The screened blend is then blended for 10 minutes at 10 RPM’s in an appropriate blender, such as a Blendmaster bin blender.
  • Step 4 The lubricant is then added to the resultant blend, and blended for 3 minutes at 10 RPM’s in an appropriate blender, such as a Blendmaster bin blender.
  • Step 5 The lubricated blend was then compressed into 2 mm mini-tablets on an appropriate tablet press, such as a Minipress IIB.
  • Step 6 An 8% aqueous film coat was applied to the mini-tablets using an appropriate coating machine, such a Compu-lab coater. Table 1
  • Ponatinib mini -tabs were prepared according to the procedure in Example 1, except that the excipients and ponatinib loading levels were adjusted as shown in Table 2.
  • a capsule was made by encapsulating ten mini-tablets made via Example 1 into a size 2 HPMC capsules using an appropriate capsule filling machine.
  • Example 4 Preparation of Capsules
  • a capsule was made by encapsulating 19 mini -tablets made via Example 2 into a size 2 HPMC capsules using an appropriate capsule filling machine.
  • FIG. 1 shows the resultant dissolution curve 100 indicating that the capsule rapidly dissolves with complete dissolution at approximately 30 minutes.
  • an open-label, single-agent, dose-escalation, multicenter, Phase 1/2 study is planned to investigate tolerability, safety, and activity of ponatinib in the pediatric population from 1 year to less than 18 years of age with malignant disease for which no effective treatment is known, and with an expansion cohort (A) including the pediatric population with a chronic phase CML.
  • the dose-escalation and expansion Cohort B will include pediatric participants, ages 1 year to less than 18 years old, with histological diagnosis of advanced leukemias and solid tumors, including lymphoma and tumors of the central nervous system, for whom no effective therapy is known; Karnofsky or Lansky scale at least 40%.
  • Ponatinib 5 mg capsules, 15 mg tablets, 30 mg tablets, and 45 mg tablets will be used in this upcoming Phase 1/2 study. Preliminary PK results from a prior study indicated that the tested formulation was viable. A new 5 mg MiniTab capsule formulation for use in the pediatric population that will be assessed in this healthy adult participant relative
  • ponatinib Considering the planned dose range for the pediatric clinical development of ponatinib, it is expected that multiples of a 5 mg strength dose (ie, 5, 10, 15, and 30 mg) should be sufficient for dose flexibility in a given patient across the pediatric patient population > 1 year old. Based on the dose-linear PK of ponatinib established in adults, the 15 mg dose was selected for this relative BA study as an adult reference tablet formulation is currently available at this dose.
  • Treatment A Ponatinib 15 mg tablet (reference formulation) administered orally after an overnight fast of > 10 hours.
  • Treatment B Ponatinib 5 mg c 3 capsules (test formulation) administered orally after an overnight fast of > 10 hours.
  • Treatment C Ponatinib 5 mg x 3 intact MiniTab capsules (reference formulation) administered orally after an overnight fast of > 10 hours.
  • Treatment D Ponatinib 5 mg x 3 MiniTab capsule opened and sprinkled on yogurt (test formulation 1) administered orally after an overnight fast of
  • the study will consist of a screening period, a treatment period, and a post-treatment period.
  • Study drug will be administered on Days 1 and 8 in Cohort 1 and on Days 1, 8, and 15 in Cohort 2.
  • participants will sign an informed consent form (ICF) and will be assessed for eligibility with screening assessments.
  • Participants will be admitted to the CRU in the afternoon or evening before study drug administration and confined through 120 hours after the last study drug administration.
  • Blood samples for determination of plasma concentrations of ponatinib will be collected at the following scheduled times after administration of each treatment on Days 1, 8, and 15 (Day 15 for Cohort 2 only): at predose (0 h) and at 1, 2, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours postdose.
  • study drug administration days will be separated by a washout period of at least 7 days. Participants will remain in the clinical research unit (CRU) until the last PK sample has been taken. Participants will return for a safety follow-up visit 33 ⁇ 3 days after the last study drug administration.
  • CRU clinical research unit
  • the study begins when the first participant signs the ICF.
  • the end of the study is defined as the date of the last visit of the last participant in the study, which is usually the follow-up visit, unless there is an early termination (ET).
  • ET early termination
  • a participant is considered to have completed the study if he/she has completed all visits of the study, including the follow-up visit.
  • Women of nonchildbearing potential ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR > 12 months of amenorrhea and at least 51 years of age and FSH compatible with postmenopausal status
  • Women of nonchildbearing potential ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR > 12 months of amenorrhea and at least 51 years of age and FSH compatible with postmenopausal status
  • ALT and AST Hepatic transaminases
  • ALP ALP
  • total bilirubin > 1.25 x the laboratory defined ULN at screening or check-in, confirmed by repeat testing (except participants with Gilbert’s disease, for which total bilirubin must be ⁇ 2.0 c ULN).
  • Ponatinib MiniTab capsules are presented as 10 film-coated 2 mm MiniTabs in a size 2, white, opaque HPMC capsule. Each capsule contains 5 mg of ponatinib as the free base.
  • Each MiniTab contains the active ingredient with microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, silicon dioxide, and magnesium stearate.
  • each MiniTab has a white, nonfunctional PVA-based film coat. See Examples 1 and 2.
  • Iclusig (ponatinib) tablets are commercially available as 15 mg (free base equivalent) tablets. These tablets contain the active ingredient with microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The tablets are coated with a white, nonfunctional film coat. Study Treatment Information
  • Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA 2007).
  • the participant has a confirmed decline in eGFR (confirmed by repeat testing) of 35% or greater compared with the baseline value on Day -1.
  • the assessment is based on measurements of serum creatinine and subsequent calculation of eGFR using the site’s standard formula.
  • baseline is defined as Day 1 predose safety ECG.
  • All concomitant medications and treatments must be recorded in the eCRF, including any prior medication received up to 14 days before the first dose of study treatment. Any addition, deletion, or change in the dose of these medications will also be recorded.
  • Concomitant treatments/procedures that are required to manage a participant’s medical condition during the study will also be recorded in the eCRF. The medical monitor should be contacted if there are any questions regarding concomitant or prior therapy.
  • Paracetamol acetaminophen is permitted up to 2000 mg per 24 hours as needed.
  • PK parameters For each participant receiving treatment, the following PK parameters will be calculated from the plasma concentrations of ponatinib using standard noncompartmental (model -independent) PK methods:
  • Venous blood samples will be collected to assess the PK of ponatinib. Collection tubes and sample collection as well as processing and shipment instructions will be provided in the Laboratory Manual. Timing of blood PK assessments is outlined below. After the predose PK sample is drawn, participants will begin the study treatment. Predose is defined as within 1 hour before administration of study treatment.
  • Cohort 2 was a 3 -sequence, 3 -period crossover with 24 participants who were randomly assigned to 1 of 3 treatment sequences (3 x 5 mg MiniTab capsules intact, 3 x 5 mg MiniTab capsules opened and sprinkled on yogurt and 3 x 5 mg MiniTab capsules opened and sprinkled on applesauce).
  • the relative bioavailability (AUCo- ratio) was 103% with a 90% confidence interval (Cl) of 97.8% to 109%, indicating that the formulations are bioequivalent.
  • the relative bioavailability (AUCo- ratio) was 93.0% with a 90% Cl of 88.8% to 97.4%.
  • FIG. 3 depicts Table 3 which summarizes PK parameters for administration of single dose of ponatinib 15 mg tablet (Treatment A) and 3 x 5 mg MiniTab capsules (Treatment B).
  • FIG. 4 depicts Table 4 which presents the statistical analysis summary for comparison of ponatinib PK parameters between 15 mg tablet and 3 x 5 mg MiniTab capsules.
  • FIG. 2 presents plasma concentrations (mean ⁇ SE) of ponatinib in healthy participants following administration of ponatinib 15 mg tablet (200 reference formulation) and 3 x 5 mg MiniTab capsules (210 reference formulation).
  • FIG. 3 depicts Table 3 which summarizes PK parameters for administration of single dose of ponatinib 15 mg tablet (Treatment A) and 3 x 5 mg MiniTab capsules (Treatment B).
  • FIG. 4 depicts Table 4 which presents the statistical analysis summary for comparison of ponatinib PK parameters between 15 mg tablet and 3 x 5 mg MiniTa
  • FIGS. 6A-B compare the ponatinib AUC values for individual participants following administration of ponatinib 15 mg tablet (data sets 400 and 430 respectively) and 3 x 5 mg MiniTab capsules (data sets 410 and 440 respectively) with the geometric means (420 and 450).
  • ponatinib reached maximum concentration with median T max of 6.0 hours for tablet and 6.0 hours for MiniTab capsules.
  • the geometric mean terminal half-life of ponatinib after administration of tablet was 30.5 hours, which was similar to that for MiniTab capsule (30.4 hours).
  • the ponatinib geometric mean ratio (90% Cl) of Cmax, AUCo- t (FIG. 6 A) and AUCo- (FIG. 6B) (calculated as 3 c 5 mg MiniTab capsules versus 15 mg tablet) was 104% (97.2%-110%), 104% (98.3%-l 10%) and 103% (97.8%- 109%), respectively.
  • FIG. 8 depicts Table 5 which summarizes PK parameters following administration of a single dose of ponatinib 3 x 5 mg MiniTab capsules intact (Treatment C) and 3 x 5 mg MiniTab capsules opened and sprinkled on yogurt (Treatment D) or applesauce (Treatment E).
  • FIG. 7 presents plasma concentrations (mean ⁇ SE) of ponatinib in healthy participants following administration of ponatinib 3 x 5 mg MiniTab capsules intact (500) versus 3 x 5 mg MiniTab capsules opened and sprinkled on yogurt (510) or applesauce (520).
  • FIG. 8 depicts Table 5 which summarizes PK parameters following administration of a single dose of ponatinib 3 x 5 mg MiniTab capsules intact (Treatment C) and 3 x 5 mg MiniTab capsules opened and sprinkled on yogurt (Treatment D) or applesauce (Treatment E).
  • FIG. 7 presents plasma concentrations (
  • FIG. 9 depicts Table 6 which presents the statistical analysis summary for comparison of ponatinib PK parameters among 3 x 5 mg MiniTab capsules intact and 3 x 5 mg MiniTab capsules opened and sprinkled on yogurt or applesauce.
  • FIG. 10 compares the ponatinib Cmax values for individual participants following administration of ponatinib 3 x 5 mg MiniTab capsules intact (data set 600) and 3 x 5 mg MiniTab capsules opened and sprinkled on yogurt (data set 610) or applesauce (data set 620) and the geometric mean (630).
  • FIGS. 11 A-B compare the ponatinib AUC values (AUCo-t (FIG. 11 A) and AUCo- (FIG.
  • the geometric mean terminal half-life of ponatinib after administration of MiniTab capsules intact was 33.5 hours, which was similar to that for MiniTab capsules opened and sprinkled on yogurt (34.1 hours) or applesauce (33.7 hours).
  • the ponatinib geometric mean ratio (90% Cl) of Cmax, AUCo- t , and AUCo- ⁇ was 89.6% (84.3%-95.1%), 93.4% (89.0%-98.1%) and 93.0% (88.8%-97.4%), respectively.
  • the ponatinib geometric mean ratio (90% Cl) of Cmax, AUCo-t, and AUCo- was 89.5% (84.2%-95.1%), 96.2% (91.5%- 101%), and 95.9% (91 5%-101%), respectively.

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Abstract

La présente invention concerne des mini-comprimés de ponatinib, ou un sel pharmaceutiquement acceptable associé, des gélules et des kits comprenant les mini-comprimés et des méthodes de traitement de patients pédiatriques ou gériatriques.
PCT/US2020/030280 2019-04-29 2020-04-28 Formes pharmaceutiques de ponatinib du type mini-comprimés WO2020223235A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000196A2 (fr) 2000-06-28 2002-01-03 Smithkline Beecham P.L.C. Procede de broyage par voie humide
US8114874B2 (en) 2005-12-23 2012-02-14 Ariad Pharmaceuticals, Inc. Substituted acetylenic imidazo[1,2-B]pyridazine compounds as kinase inhibitors
WO2012139027A1 (fr) * 2011-04-07 2012-10-11 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement de maladies neurodégénératives
CN104650086A (zh) * 2013-11-22 2015-05-27 天津市汉康医药生物技术有限公司 盐酸帕纳替尼化合物
WO2015085972A1 (fr) * 2013-12-09 2015-06-18 Zentiva, K.S. Nouveaux sels de 3-(2-imidazo[1,2-b]pyridazin-3-yl-éthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl]benzamide
US9493470B2 (en) 2012-12-12 2016-11-15 Ariad Pharmaceuticals, Inc. Crystalline forms of 3-(imidazo[1,2-B] pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl) methyl]-3-(trifluoromethyl)phenyl}benzamide and its mono hydrochloride salt
WO2018232501A1 (fr) * 2017-06-20 2018-12-27 Apotex Inc. Formes cristallines du chlorhydrate de ponatinib

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000196A2 (fr) 2000-06-28 2002-01-03 Smithkline Beecham P.L.C. Procede de broyage par voie humide
US8114874B2 (en) 2005-12-23 2012-02-14 Ariad Pharmaceuticals, Inc. Substituted acetylenic imidazo[1,2-B]pyridazine compounds as kinase inhibitors
WO2012139027A1 (fr) * 2011-04-07 2012-10-11 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement de maladies neurodégénératives
US9493470B2 (en) 2012-12-12 2016-11-15 Ariad Pharmaceuticals, Inc. Crystalline forms of 3-(imidazo[1,2-B] pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl) methyl]-3-(trifluoromethyl)phenyl}benzamide and its mono hydrochloride salt
CN104650086A (zh) * 2013-11-22 2015-05-27 天津市汉康医药生物技术有限公司 盐酸帕纳替尼化合物
WO2015085972A1 (fr) * 2013-12-09 2015-06-18 Zentiva, K.S. Nouveaux sels de 3-(2-imidazo[1,2-b]pyridazin-3-yl-éthynyl)-4-méthyl-n-[4-[(4-méthyl-1-pipérazinyl)méthyl]-3-(trifluorométhyl)phényl]benzamide
WO2018232501A1 (fr) * 2017-06-20 2018-12-27 Apotex Inc. Formes cristallines du chlorhydrate de ponatinib

Non-Patent Citations (28)

* Cited by examiner, † Cited by third party
Title
"Drug Interaction Database Program", 2002, UNIVERSITY OF WASHINGTON SCHOOL OF PHARMACY
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
"Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials", 2007, FDA
AZAM ET AL., CELL, vol. 112, 2003, pages 831 - 843
BERGE ET AL., J. PHARM. SCI., vol. 66, no. 1, 1977, pages 1 - 19
BHAT ET AL.: "Interactions of p62(dok) with p210(bcr-abl) and Bcr-Abl-associated proteins", J BIOL CHEM., vol. 273, no. 48, 27 November 1998 (1998-11-27), pages 32360 - 8
BRAZIEL ET AL.: "Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months' experience", BLOOD, vol. 100, no. 2, 15 July 2002 (2002-07-15), pages 435 - 41
CARLESSO ET AL.: "Use of a temperature-sensitive mutant to define the biological effects of the p210BCR-ABL tyrosine kinase on proliferation of a factor-dependent murine myeloid cell line", ONCOGENE, vol. 9, no. 1, January 1994 (1994-01-01), pages 149 - 56
CORBIN ET AL.: "Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571", J BIOL CHEM., vol. 277, no. 35, 30 August 2002 (2002-08-30), pages 32214 - 9, XP002429304, DOI: 10.1074/jbc.M111525200
DRUKER ET AL.: "Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome", N ENGL J MED., vol. 344, no. 14, 5 April 2001 (2001-04-05), pages 1038 - 42, XP009053343, DOI: 10.1056/NEJM200104053441402
HALLEK ET AL.: "Interaction of the receptor tyrosine kinase pl45c-kit with the p2100bcr/abl kinase in myeloid cells", BR J HAEMATOL., vol. 94, no. 1, July 1996 (1996-07-01), pages 5 - 16
HEANEY ET AL.: "Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation", BLOOD, vol. 89, no. 1, 1 January 1997 (1997-01-01), pages 297 - 306
HOCHHAUS ET AL.: "Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy", LEUKEMIA, vol. 16, no. 11, November 2002 (2002-11-01), pages 2190 - 6, XP002636110, DOI: 10.1038/sj.leu.2402741
HOCHHAUS ET AL.: "Roots of clinical resistance to STI-571 cancer therapy", SCIENCE, vol. 293, no. 5538, 21 September 2001 (2001-09-21), pages 2163, XP002229885, DOI: 10.1126/science.293.5538.2163a
KANTARJIAN ET AL.: "Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia", N ENGL J MED., vol. 346, no. 9, 28 February 2002 (2002-02-28), pages 645 - 52
KOLIBABA ET AL.: "CRKL binding to BCR-ABL and BCR-ABL transformation", LEUK LYMPHOMA, vol. 33, no. 1-2, March 1999 (1999-03-01), pages 119 - 26, XP009028304
KOLIBABA ET AL.: "Protein tyrosine kinases and cancer", BIOCHIM BIOPHYS ACTA, vol. 1333, no. 3, 9 December 1997 (1997-12-09), pages F217 - 48, XP004281804, DOI: 10.1016/S0304-419X(97)00022-X
KURZROCK ET AL.: "Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics", ANN INTERN MED., vol. 138, no. 10, 20 May 2003 (2003-05-20), pages 819 - 30, XP009164345, DOI: 10.7326/0003-4819-138-10-200305200-00010
MAURO ET AL.: "Chronic myelogenous leukemia", CURR OPIN ONCOL., vol. 13, no. 1, January 2001 (2001-01-01), pages 3 - 7
N ENGL J MED, vol. 345, no. 3, 19 July 2001 (2001-07-19), pages 232
N ENGL J MED, vol. 346, no. 24, 13 June 2002 (2002-06-13), pages 1923
ODA ET AL.: "The SH2 domain of ABL is not required for factor-independent growth induced by BCR-ABL in a murine myeloid cell line", LEUKEMIA, vol. 9, no. 2, February 1995 (1995-02-01), pages 295 - 301
O'DWYER ET AL.: "Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate", LEUKEMIA, vol. 17, no. 3, March 2003 (2003-03-01), pages 481 - 7
O'DWYER ET AL.: "The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML", BLOOD, vol. 100, no. 5, 1 September 2002 (2002-09-01), pages 1628 - 33
P. G. M. WUTST. W. GREENE: "Protective Groups in Organic Synthesis", 2006, WILEY & SONS, INC.
SENECHAL ET AL.: "Structural requirements for function of the Crkl adapter protein in fibroblasts and hematopoietic cells", MOL CELL BIOL., vol. 18, no. 9, September 1998 (1998-09-01), pages 5082 - 90
SHAH ET AL., CANCER CELL, vol. 2, 2002, pages 117 - 125
WERTHEIM ET AL.: "BCR-ABL-induced adhesion defects are tyrosine kinase-independent", BLOOD, vol. 99, no. 11, 1 June 2002 (2002-06-01), pages 4122 - 30, XP055332826, DOI: 10.1182/blood.V99.11.4122

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