WO2022179592A1 - Médicament thérapeutique combiné pour leucémie myéloïde aiguë - Google Patents

Médicament thérapeutique combiné pour leucémie myéloïde aiguë Download PDF

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Publication number
WO2022179592A1
WO2022179592A1 PCT/CN2022/077828 CN2022077828W WO2022179592A1 WO 2022179592 A1 WO2022179592 A1 WO 2022179592A1 CN 2022077828 W CN2022077828 W CN 2022077828W WO 2022179592 A1 WO2022179592 A1 WO 2022179592A1
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mutation
compound
pharmaceutically acceptable
trihydrochloride
daunorubicin
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PCT/CN2022/077828
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English (en)
Chinese (zh)
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夏雪芳
郝春颜
范丽雪
束云
柴晓玲
杨晓旭
张笑
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石药集团中奇制药技术（石家庄）有限公司
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Publication of WO2022179592A1 publication Critical patent/WO2022179592A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a combined therapeutic drug for treating acute myeloid leukemia.
  • AML Acute myeloid leukemia
  • AML is a hematological malignancy in which abnormal proliferation, differentiation and cloning of hematopoietic stem cells invade the bone marrow, blood and extramedullary tissues.
  • AML has the highest mortality rate, with a 5-year survival of approximately 24%.
  • AML accounts for about 70% of adult leukemias. After treatment, 35% to 40% of adult AML patients aged 60 and below can achieve long-term survival, while only 5% to 15% of patients over 60 years old can achieve long-term survival.
  • Elderly AML patients who tolerate intensive chemotherapy have a median survival time of only 5 to 10 months.
  • FLT3 FMS-like tyrosine kinase
  • FLT3 is a member of the class III receptor tyrosine kinase (TK) family and is normally expressed on the surface of hematopoietic progenitor cells. FLT3 and its ligands play important roles in the proliferation, survival and differentiation of pluripotent stem cells.
  • TKD juxtamembrane domain tyrosine kinase domain
  • ITD internal tandem repeats
  • Compound I is a novel multi-target protein kinase inhibitor, the main targets include FLT3, etc., and the structure is shown in the following formula (I):
  • WO 2011/147066A1 discloses the compound and its preparation method and medical use.
  • PCT/CN2021/073285 further studies the pharmaceutically acceptable salts of compound I and their uses. The entire contents of the above-mentioned patents are incorporated herein by reference.
  • In vitro and in vivo studies have shown that Compound I or its pharmaceutically acceptable salts have a strong growth inhibitory effect on FLT3-ITD mutant acute myeloid leukemia cell lines.
  • compound I or its pharmaceutically acceptable salts combined with DNR and Ara-C in the treatment of newly diagnosed AML younger than 60 years old can further improve the efficacy, and whether it has advantages in safety and tolerance compared with similar drugs, it is not yet known. .
  • the present invention provides the use of compound I or a pharmaceutically acceptable salt thereof, daunorubicin and cytarabine in preparing a medicine for treating acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • the acute myeloid leukemia is preferably a FLT3 mutation-positive acute myeloid leukemia, more preferably an untreated FLT3 mutation-positive acute myeloid leukemia.
  • the FLT3 mutation-positive comprises FLT3 internal tandem repeat (ITD) mutation-positive, FLT3 tyrosine kinase domain (TKD)/D835 mutation-positive, and/or FLT3 tyrosine kinase domain (TKD) /I836 mutation positive.
  • the acute myeloid leukemia is FLT3 mutation-positive acute myeloid leukemia accompanied by one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 Mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation, U2AF2 mutation, SF1 mutation, etc., preferably BCORL1 mutation, CEBPA mutation, CBL mutation, TP53 mutation.
  • the acute myeloid leukemia is FLT3 mutation-negative acute myeloid leukemia.
  • the FLT3 mutation-negative acute myeloid leukemia is accompanied by one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation , IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation, U2AF2 mutation, SF1 mutation, etc.
  • BCORL1 mutation is preferred , CEBPA mutation, CBL mutation, TP53 mutation.
  • the pharmaceutically acceptable salt of compound I is not particularly limited, and is prepared from the free base of compound I and acid. Those skilled in the art can select suitable salt forms by conventional methods. Specific examples of pharmaceutically acceptable salts of Compound 1 include, but are not limited to, the hydrochloride, mesylate, malate, tartrate, oxalate, succinate, acetate, sulfate, and the like of Compound 1; Hydrochloride, malate, tartrate, oxalate, succinate, acetate are preferred; hydrochloride is further preferred.
  • the hydrochloride is more preferably trihydrochloride.
  • the trihydrochloride includes the corresponding anhydrate, hydrate, solvate, etc., more preferably trihydrochloride pentahydrate.
  • the molar ratio of cytarabine to daunorubicin is 1-100:1, preferably 1-25:1, more preferably 2-10:1, such as 5:1.
  • the molar ratio of compound I or its pharmaceutically acceptable salt and daunorubicin is 100:1-1:100, preferably 2:1-1:70, more preferably 4:1-1:50 (with compound I content calculation).
  • Compound I or a pharmaceutically acceptable salt thereof, daunorubicin and cytarabine can be contained in the same pharmaceutical preparation, or can be separately prepared into clinically acceptable preparations, and the medicine can be prepared in a combined packaging manner.
  • the clinically accepted preparations include oral preparations, injection preparations, topical preparations, external preparations and the like.
  • the medicament is in a single-dose or divided-dose form.
  • the dosage form contains a therapeutically effective amount of daunorubicin, cytarabine, compound I or a pharmaceutically acceptable salt thereof.
  • the formulation of the accepted salt is preferably an oral formulation, such as tablets, capsules, pills, etc.; each formulation unit contains about 0.001 mg to about 1000 mg of Compound I or a pharmaceutically acceptable salt thereof (calculated as Compound I), preferably about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 330 mg, or about 20 mg to about 300 mg, or about 20 mg to about 250 mg, or about 20 mg to about 210 mg, or about 20 mg to about 180 mg, or about 20 mg - about 160 mg, or about 20 mg to about 140 mg, or about 20 mg to about 120 mg, or about 20 mg to about 100 mg.
  • Compound I preferably about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 330 mg, or about 20 mg to about 300 mg, or about 20 mg to about 250 mg, or about 20 mg to about 210 mg, or about 20 mg to about 180 mg, or about 20 mg - about 160 mg, or about 20 mg to about 140 mg, or about
  • Exemplary amounts are, for example, 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 110 mg, about 120 mg, about 125 mg, about 130 mg, About 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 310 mg, about 320 mg, about 360 mg, about 400 mg.
  • the daunorubicin preparation is preferably daunorubicin hydrochloride for injection, such as daunorubicin hydrochloride lyophilized powder for injection; each preparation unit contains about 10 mg to about 30 mg of active ingredient, preferably about 20 mg.
  • the cytarabine preparation is preferably cytarabine hydrochloride for injection, such as cytarabine hydrochloride lyophilized powder for injection; each preparation unit contains about 0.1g to about 0.5g of active ingredients, such as about 0.1g, about 0.3 g or about 0.5 g.
  • the pharmaceutically acceptable salt of Compound I is the hydrochloride salt, preferably the trihydrochloride salt, more preferably the trihydrochloride pentahydrate.
  • Each dosage unit contains about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 350 mg, or about 20 mg to about 310 mg, or about 25 mg to about 300 mg, or about 25 mg to about 250 mg, or about 50 mg to about 250 mg, or about 50 mg to about 200 mg, or about 50 mg to about 175 mg, or about 50 mg to about 160 mg, or about 50 mg to about 150 mg, or about 50 mg to about 125 mg, or about 50 mg to about 100 mg; exemplary amounts such as about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 310 mg, about 350 mg, about 400
  • the present invention provides the use of compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving the curative effect of daunorubicin and cytarabine in the treatment of acute myeloid leukemia.
  • the acute myeloid leukemia is preferably FLT3 mutation-positive acute myeloid leukemia. More preferred is untreated FLT3 mutation-positive acute myeloid leukemia.
  • the FLT3 mutation-positive comprises FLT3 internal tandem repeat (ITD) mutation-positive, FLT3 tyrosine kinase domain (TKD)/D835 mutation-positive, and/or FLT3 tyrosine kinase domain (TKD) /I836 mutation positive.
  • the acute myeloid leukemia refers to FLT3 mutation-positive acute myeloid leukemia with one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation , U2AF2 mutation, SF1 mutation, etc., preferably BCORL1 mutation, CEBPA mutation, CBL mutation, TP53 mutation.
  • the acute myeloid leukemia is FLT3 mutation-negative acute myeloid leukemia.
  • these FLT3 mutation-negative acute myeloid leukemias are accompanied by one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation, U2AF2 mutation, SF1 mutation, etc.
  • the pharmaceutically acceptable salt of compound I is not particularly limited, and is prepared from the free base of compound I and acid. Those skilled in the art can select suitable salt forms by conventional methods. Specific examples of pharmaceutically acceptable salts of Compound 1 include, but are not limited to, the hydrochloride, mesylate, malate, tartrate, oxalate, succinate, acetate, sulfate, and the like of Compound 1; Hydrochloride, malate, tartrate, oxalate, succinate, acetate are preferred; hydrochloride is further preferred.
  • the hydrochloride is more preferably trihydrochloride.
  • the trihydrochloride includes the corresponding anhydrate, hydrate, solvate, etc., more preferably trihydrochloride pentahydrate.
  • the medicament is formulated into a clinically acceptable formulation, such as an oral formulation, an injection formulation, a topical formulation, a topical formulation, and the like.
  • the medicament is in a single-dose or divided-dose form.
  • the dosage form contains a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof.
  • each formulation unit contains about 0.001 mg to about 1000 mg of Compound I or a pharmaceutically acceptable salt thereof (based on Compound I), preferably about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 330 mg, or about 20 mg to about 300 mg, or about 20 mg to about 250 mg, or about 20 mg to about 210 mg, or about 20 mg to about 180 mg, or about 20 mg to about 160 mg, or about 20 mg to about 140 mg, or about 20 mg to about 120 mg, or about 20 mg to about 100 mg.
  • Exemplary amounts are, for example, 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 110 mg, about 120 mg, about 125 mg, about 130 mg, About 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 310 mg, about 320 mg, about 360 mg, about 400 mg.
  • the pharmaceutically acceptable salt of Compound I is the hydrochloride salt, preferably the trihydrochloride salt, more preferably the trihydrochloride pentahydrate.
  • Each dosage unit contains about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 350 mg, or about 20 mg to about 310 mg, or about 25 mg to about 300 mg, or about 25 mg to about 250 mg, or about 50 mg to about 250 mg, or about 50 mg to about 200 mg, or about 50 mg to about 175 mg, or about 50 mg to about 160 mg, or about 50 mg to about 150 mg, or about 50 mg to about 125 mg, or about 50 mg to about 100 mg; exemplary amounts such as about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 310 mg, about 350 mg, about 400
  • the present invention also provides a method for treating acute myeloid leukemia, the method comprising administering to a subject or patient a therapeutically effective amount of daunorubicin, cytarabine and compound I or a pharmaceutically acceptable salt thereof.
  • Daunorubicin, cytarabine and Compound I or a pharmaceutically acceptable salt thereof can be administered simultaneously or separately.
  • the administration may be oral administration, injection administration, topical administration or in vitro administration.
  • the therapeutically effective amount can treat or alleviate acute myeloid leukemia in the subject or patient.
  • the acute myeloid leukemia is preferably FLT3 mutation-positive acute myeloid leukemia. More preferred is untreated FLT3 mutation-positive acute myeloid leukemia.
  • the acute myeloid leukemia refers to FLT3 mutation-positive acute myeloid leukemia with one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 Mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation, U2AF2 mutation, SF1 mutation, etc., preferably BCORL1 mutation, CEBPA mutation, CBL mutation, TP53 mutation.
  • the FLT3 mutation-positive comprises FLT3 internal tandem repeat (ITD) mutation-positive, FLT3 tyrosine kinase domain (TKD)/D835 mutation-positive, and/or FLT3 tyrosine kinase domain (TKD) /I836 mutation positive.
  • the acute myeloid leukemia is FLT3 mutation-negative acute myeloid leukemia.
  • these FLT3 mutation-negative acute myeloid leukemias are accompanied by one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation, U2AF2 mutation, SF1 mutation, etc.
  • the pharmaceutically acceptable salt of compound I is not particularly limited, and is prepared from compound I free base plus acid. Those skilled in the art can select suitable salt forms by conventional methods. Specific examples of pharmaceutically acceptable salts of Compound 1 include, but are not limited to, the hydrochloride, mesylate, malate, tartrate, oxalate, succinate, acetate, sulfate, and the like of Compound 1; Hydrochloride, malate, tartrate, oxalate, succinate, acetate are preferred; hydrochloride is further preferred.
  • the hydrochloride is more preferably trihydrochloride.
  • the trihydrochloride includes the corresponding anhydrate, hydrate, solvate, etc., more preferably trihydrochloride pentahydrate.
  • the method of treatment comprises:
  • Induction therapy one cycle every 28 days, up to two cycles.
  • the treatments for each cycle are as follows:
  • Days 1-7 Cytarabine approximately 100 mg/m 2 by continuous intravenous infusion (CIVI) for 7 days (168 h in total).
  • Days 1-3 daunorubicin about 60 mg/m 2 or about 45 mg/m 2 intravenously (IVP) or short infusion;
  • Days 8-21 Compound I or a pharmaceutically acceptable salt thereof about 20 mg/time to about 160 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Days 8-21 Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), for 14 consecutive days. Preferably, from about 50 mg to about 175 mg, more preferably from about 50 mg to about 150 mg, per oral administration. Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • cytarabine about 1g/m 2 to about 5g/m 2 is continuously infused, q12h.
  • cytarabine is administered at a dose of from about 1 g/m 2 to about 4 g/m 2 , more preferably from about 1.5 g/m 2 to about 3 g/m 2 .
  • Specific examples of the administered dose are, for example, about 3 g/m 2 or about 2 g/m 2 or about 1.5 g/m 2 .
  • Days 8-21 Compound I or a pharmaceutically acceptable salt thereof about 20 mg/time to about 160 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Days 8-21 Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), for 14 consecutive days. Preferably, from about 50 mg to about 175 mg, more preferably from about 50 mg to about 150 mg, per oral administration. Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • Compound I or a pharmaceutically acceptable salt thereof is about 20 mg/time to about 160 mg/time, orally, twice a day (BID), daily.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), daily.
  • BID twice a day
  • each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • the present invention also provides a method for improving the curative effect of daunorubicin and cytarabine in the treatment of acute myeloid leukemia, the method comprising: using compound I in combination with cytarabine and daunorubicin for treatment or a pharmaceutically acceptable salt thereof.
  • Daunorubicin, cytarabine and Compound I or a pharmaceutically acceptable salt thereof can be administered simultaneously or separately.
  • the administration may be oral administration, injection administration, topical administration or in vitro administration.
  • the therapeutically effective amount can treat or alleviate acute myeloid leukemia in the subject or patient.
  • the acute myeloid leukemia is preferably FLT3 mutation-positive acute myeloid leukemia. More preferred is untreated FLT3 mutation-positive acute myeloid leukemia.
  • the FLT3 mutation-positive comprises FLT3 internal tandem repeat (ITD) mutation-positive, FLT3 tyrosine kinase domain (TKD)/D835 mutation-positive, and/or FLT3 tyrosine kinase domain (TKD) /I836 mutation positive.
  • the acute myeloid leukemia refers to FLT3 mutation-positive acute myeloid leukemia with one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation , U2AF2 mutation, SF1 mutation, etc., preferably BCORL1 mutation, CEBPA mutation, CBL mutation, TP53 mutation.
  • the acute myeloid leukemia is FLT3 mutation-negative acute myeloid leukemia.
  • these FLT3 mutation-negative acute myeloid leukemias are accompanied by other gene mutations, including but not limited to KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL Mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation, U2AF2 mutation, SF1 mutation, etc., preferably BCORL1 mutation, CEBPA mutation, CBL mutation, TP53 mutation.
  • the pharmaceutically acceptable salt of compound I is not particularly limited, and is prepared from compound I free base plus acid. Those skilled in the art can select suitable salt forms by conventional methods. Specific examples of pharmaceutically acceptable salts of Compound 1 include, but are not limited to, the hydrochloride, mesylate, malate, tartrate, oxalate, succinate, acetate, sulfate, and the like of Compound 1; Hydrochloride, malate, tartrate, oxalate, succinate, acetate are preferred; hydrochloride is further preferred.
  • the hydrochloride is more preferably trihydrochloride.
  • the trihydrochloride includes the corresponding anhydrate, hydrate, solvate, etc., more preferably trihydrochloride pentahydrate.
  • the method includes:
  • Induction therapy one cycle every 28 days, up to two cycles.
  • the treatments for each cycle are as follows:
  • Days 1-7 Cytarabine approximately 100 mg/m 2 by continuous intravenous infusion (CIVI) for 7 days (168 h in total).
  • Days 1-3 daunorubicin about 60 mg/m 2 or about 45 mg/m 2 intravenously (IVP) or short infusion;
  • Days 8-21 Compound I or a pharmaceutically acceptable salt thereof about 20 mg/time to about 160 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Days 8-21 Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), for 14 consecutive days. Preferably, from about 50 mg to about 175 mg, more preferably from about 50 mg to about 150 mg, per oral administration. Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • cytarabine about 1g/m 2 to about 5g/m 2 is continuously infused, q12h.
  • cytarabine is administered at a dose of from about 1 g/m 2 to about 4 g/m 2 , more preferably from about 1.5 g/m 2 to about 3 g/m 2 .
  • Specific examples of the administered dose are, for example, about 3 g/m 2 or about 2 g/m 2 or about 1.5 g/m 2 .
  • Days 8-21 Compound I or a pharmaceutically acceptable salt thereof about 20 mg/time to about 160 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Days 8-21 Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), for 14 consecutive days. Preferably, from about 50 mg to about 175 mg, more preferably from about 50 mg to about 150 mg, per oral administration. Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • Compound I or a pharmaceutically acceptable salt thereof is about 20 mg/time to about 160 mg/time, orally, twice a day (BID), daily.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), daily.
  • BID twice a day
  • each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • the present invention also provides a composition
  • a composition comprising (1) daunorubicin; (2) cytarabine; (3) compound I or a pharmaceutically acceptable salt thereof, which is used for the treatment of acute myeloid leukemia.
  • Daunorubicin, cytarabine and Compound I or a pharmaceutically acceptable salt thereof can be administered simultaneously or separately.
  • the administration may be oral administration, injection administration, topical administration or in vitro administration.
  • the molar ratio of cytarabine to daunorubicin is 1-100:1, preferably 1-25:1, more preferably 2-10:1, such as 5:1.
  • the molar ratio of compound I or its pharmaceutically acceptable salt and daunorubicin is 100:1-1:100, preferably 2:1-1:70, more preferably 4:1-1:50 (with compound I content calculation).
  • the pharmaceutically acceptable salt of compound I is not particularly limited, and is prepared from compound I free base plus acid. Those skilled in the art can select suitable salt forms by conventional methods. Specific examples of pharmaceutically acceptable salts of Compound 1 include, but are not limited to, the hydrochloride, mesylate, malate, tartrate, oxalate, succinate, acetate, sulfate, and the like of Compound 1; Hydrochloride, malate, tartrate, oxalate, succinate, acetate are preferred; hydrochloride is further preferred.
  • the hydrochloride is more preferably trihydrochloride.
  • the trihydrochloride includes the corresponding anhydrate, hydrate, solvate, etc., more preferably trihydrochloride pentahydrate.
  • the treatment is:
  • Induction therapy one cycle every 28 days, up to two cycles.
  • the treatments for each cycle are as follows:
  • Days 1-7 Cytarabine approximately 100 mg/m 2 by continuous intravenous infusion (CIVI) for 7 days (168 h in total).
  • Days 1-3 daunorubicin about 60 mg/m 2 or about 45 mg/m 2 intravenously (IVP) or short infusion;
  • Days 8-21 Compound I or a pharmaceutically acceptable salt thereof about 20 mg/time to about 160 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Days 8-21 Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), for 14 consecutive days. Preferably, from about 50 mg to about 175 mg, more preferably from about 50 mg to about 150 mg, per oral administration. Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • cytarabine about 1g/m 2 to about 5g/m 2 is continuously infused, q12h.
  • cytarabine is administered at a dose of from about 1 g/m 2 to about 4 g/m 2 , more preferably from about 1.5 g/m 2 to about 3 g/m 2 .
  • Specific examples of the administered dose are, for example, about 3 g/m 2 or about 2 g/m 2 or about 1.5 g/m 2 .
  • Days 8-21 Compound I or a pharmaceutically acceptable salt thereof about 20 mg/time to about 160 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Days 8-21 Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), for 14 consecutive days. Preferably, from about 50 mg to about 175 mg, more preferably from about 50 mg to about 150 mg, per oral administration. Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • Compound I or a pharmaceutically acceptable salt thereof is about 20 mg/time to about 160 mg/time, orally, twice a day (BID), daily.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), daily.
  • BID twice a day
  • Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • the acute myeloid leukemia refers to FLT3 mutation-positive acute myeloid leukemia. More preferred is untreated FLT3 mutation-positive acute myeloid leukemia.
  • the FLT3 mutation-positive comprises FLT3 internal tandem repeat (ITD) mutation-positive, FLT3 tyrosine kinase domain (TKD)/D835 mutation-positive, and/or FLT3 tyrosine kinase domain (TKD) /I836 mutation positive.
  • the acute myeloid leukemia refers to FLT3 mutation-positive acute myeloid leukemia with one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation , U2AF2 mutation, SF1 mutation, etc., preferably BCORL1 mutation, CEBPA mutation, CBL mutation, TP53 mutation.
  • the acute myeloid leukemia is FLT3 mutation-negative acute myeloid leukemia.
  • these FLT3 mutation-negative acute myeloid leukemias are accompanied by one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation, U2AF2 mutation, SF1 mutation, etc.
  • Compound I or a pharmaceutically acceptable salt thereof, daunorubicin and cytarabine can be contained in the same pharmaceutical preparation, or can be separately prepared into clinically acceptable preparations, and the medicine can be prepared in a combined packaging manner.
  • the clinically accepted preparations include oral preparations, injection preparations, topical preparations, external preparations and the like.
  • the medicament is in a single-dose or divided-dose form.
  • the dosage form contains a therapeutically effective amount of daunorubicin, cytarabine, Compound I, or a pharmaceutically acceptable salt thereof.
  • the formulation of the accepted salt is preferably an oral formulation, such as tablets, capsules, pills, etc.; each formulation unit contains about 0.001 mg to about 1000 mg of Compound I or a pharmaceutically acceptable salt thereof (calculated as Compound I), preferably about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 330 mg, or about 20 mg to about 300 mg, or about 20 mg to about 250 mg, or about 20 mg to about 210 mg, or about 20 mg to about 180 mg, or about 20 mg - about 160 mg, or about 20 mg to about 140 mg, or about 20 mg to about 120 mg, or about 20 mg to about 100 mg.
  • Compound I preferably about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 330 mg, or about 20 mg to about 300 mg, or about 20 mg to about 250 mg, or about 20 mg to about 210 mg, or about 20 mg to about 180 mg, or about 20 mg - about 160 mg, or about 20 mg to about 140 mg, or about
  • Exemplary amounts are, for example, 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 110 mg, about 120 mg, about 125 mg, about 130 mg, About 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 310 mg, about 320 mg, about 360 mg, about 400 mg.
  • the daunorubicin preparation is preferably daunorubicin hydrochloride for injection, such as daunorubicin hydrochloride lyophilized powder for injection; each preparation unit contains about 10 mg to about 30 mg of active ingredient, preferably about 20 mg.
  • the cytarabine preparation is preferably cytarabine hydrochloride for injection, such as cytarabine hydrochloride lyophilized powder for injection; each preparation unit contains about 0.1g to about 0.5g of active ingredients, such as about 0.1g, about 0.3 g or about 0.5 g.
  • the pharmaceutically acceptable salt of Compound I is the hydrochloride salt, preferably the trihydrochloride salt, more preferably the trihydrochloride pentahydrate.
  • Each dosage unit contains about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 350 mg, or about 20 mg to about 310 mg, or about 25 mg to about 300 mg, or about 25 mg to about 250 mg, or about 50 mg to about 250 mg, or about 50 mg to about 200 mg, or about 50 mg to about 175 mg, or about 50 mg to about 160 mg, or about 50 mg to about 150 mg, or about 50 mg to about 125 mg, or about 50 mg to about 100 mg; exemplary amounts such as about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 310 mg, about 350 mg, about 400
  • the present invention also provides a medicament containing Compound I or a pharmaceutically acceptable salt thereof, which is used to improve the curative effect of cytarabine and daunorubicin in the treatment of acute myeloid leukemia.
  • the improved method is: combined use of compound I or a pharmaceutically acceptable salt thereof on the basis of treatment with cytarabine and daunorubicin.
  • Daunorubicin, cytarabine and Compound I or a pharmaceutically acceptable salt thereof may be administered simultaneously or separately.
  • the administration may be oral administration, injection administration, topical administration or in vitro administration.
  • the pharmaceutically acceptable salt of compound I is not particularly limited, and is prepared from compound I free base plus acid. Those skilled in the art can select suitable salt forms by conventional methods. Specific examples of pharmaceutically acceptable salts of Compound 1 include, but are not limited to, the hydrochloride, mesylate, malate, tartrate, oxalate, succinate, acetate, sulfate, and the like of Compound 1; Hydrochloride, malate, tartrate, oxalate, succinate, acetate are preferred; hydrochloride is further preferred.
  • the hydrochloride is more preferably trihydrochloride.
  • the trihydrochloride includes the corresponding anhydrate, hydrate, solvate, etc., more preferably trihydrochloride pentahydrate.
  • the method of improvement is:
  • Induction therapy one cycle every 28 days, up to two cycles.
  • the treatments for each cycle are as follows:
  • Days 1-7 Cytarabine approximately 100 mg/m 2 by continuous intravenous infusion (CIVI) for 7 days (168 h in total).
  • Days 1-3 daunorubicin about 60 mg/m 2 or about 45 mg/m 2 intravenously (IVP) or short infusion;
  • Days 8-21 Compound I or a pharmaceutically acceptable salt thereof about 20 mg/time to about 160 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Days 8-21 Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), for 14 consecutive days. Preferably, from about 50 mg to about 175 mg, more preferably from about 50 mg to about 150 mg, per oral administration. Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • cytarabine about 1g/m 2 to about 5g/m 2 is continuously infused, q12h.
  • cytarabine is administered at a dose of from about 1 g/m 2 to about 4 g/m 2 , more preferably from about 1.5 g/m 2 to about 3 g/m 2 .
  • Specific examples of the administered dose are, for example, about 3 g/m 2 or about 2 g/m 2 or about 1.5 g/m 2 .
  • Days 8-21 Compound I or a pharmaceutically acceptable salt thereof about 20 mg/time to about 160 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Days 8-21 Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), for 14 consecutive days. Preferably, from about 50 mg to about 175 mg, more preferably from about 50 mg to about 150 mg, per oral administration. Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • Compound I or a pharmaceutically acceptable salt thereof is about 20 mg/time to about 160 mg/time, orally, twice a day (BID), daily.
  • BID twice a day
  • Examples of each oral dose include about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg.
  • Compound I is administered in the form of a hydrochloride salt, preferably trihydrochloride, more preferably trihydrochloride pentahydrate.
  • Oral administration of Compound I trihydrochloride about 25 mg/time to about 200 mg/time, twice a day (BID), daily.
  • BID twice a day
  • Examples of each oral dose include about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg or about 175 mg, or about 200 mg.
  • the dosage of the trihydrochloride salt is in anhydrous form.
  • the acute myeloid leukemia refers to FLT3 mutation-positive acute myeloid leukemia. More preferred is untreated FLT3 mutation-positive acute myeloid leukemia.
  • the FLT3 mutation-positive comprises FLT3 internal tandem repeat (ITD) mutation-positive, FLT3 tyrosine kinase domain (TKD)/D835 mutation-positive, and/or FLT3 tyrosine kinase domain (TKD) /I836 mutation positive.
  • the acute myeloid leukemia refers to FLT3 mutation-positive acute myeloid leukemia with one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation , U2AF2 mutation, SF1 mutation, etc., preferably BCORL1 mutation, CEBPA mutation, CBL mutation, TP53 mutation.
  • the acute myeloid leukemia is FLT3 mutation-negative acute myeloid leukemia.
  • these FLT3 mutation-negative acute myeloid leukemias are accompanied by one, two or more of the following gene mutations: KIT mutation, CEBPA mutation, NPM1 mutation, PHF6 mutation, ASXL1 mutation, DNMT3A mutation, IDH1 mutation, IDH2 mutation, TET2 mutation, CBL mutation, TP53 mutation, BCORL1 mutation, EZH2 mutation, MLL mutation, SRSF2 mutation, SF3B1 mutation, U2AF1 mutation, ZRSR2 mutation, SF3A1 mutation, PRPF40B mutation, U2AF2 mutation, SF1 mutation, etc.
  • the medicament is prepared into clinically acceptable formulations, such as oral formulations, injection formulations, topical formulations, topical formulations, etc., using conventional excipients and conventional preparation methods in the art.
  • Oral formulations such as tablets, capsules, pills and the like are preferred.
  • each formulation unit contains about 0.001 mg to about 1000 mg of Compound I or a pharmaceutically acceptable salt thereof (based on Compound I), preferably about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 330 mg, or about 20 mg to about 300 mg, or about 20 mg to about 250 mg, or about 20 mg to about 210 mg, or about 20 mg to about 180 mg, or about 20 mg to about 160 mg, or about 20 mg to about 140 mg, or about 20 mg to about 120 mg, or about 20 mg to about 100 mg.
  • Exemplary amounts are, for example, 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 110 mg, about 120 mg, about 125 mg, about 130 mg, About 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 310 mg, about 320 mg, about 360 mg, about 400 mg.
  • the pharmaceutically acceptable salt of Compound I is the hydrochloride salt, preferably the trihydrochloride salt, more preferably the trihydrochloride pentahydrate.
  • Each dosage unit contains about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 350 mg, or about 20 mg to about 310 mg, or about 25 mg to about 300 mg, or about 25 mg to about 250 mg, or about 50 mg to about 250 mg, or about 50 mg to about 200 mg, or about 50 mg to about 175 mg, or about 50 mg to about 160 mg, or about 50 mg to about 150 mg, or about 50 mg to about 125 mg, or about 50 mg to about 100 mg; exemplary amounts such as about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 310 mg, about 350 mg, about 400
  • the present invention also provides a kit, which can be used in the aforementioned method.
  • the kit includes (1) daunorubicin; (2) cytarabine; (3) compound I or a pharmaceutically acceptable salt thereof.
  • the kit comprises one or more containers comprising (1) daunorubicin; (2) cytarabine; (3) Compound I or a pharmaceutically acceptable of salt.
  • the kit includes the composition: (1) daunorubicin; (2) cytarabine; (3) Compound I or a pharmaceutically acceptable salt thereof.
  • the kit further includes instructions for use according to any of the methods described herein.
  • the kit may also include instructions for selecting an individual suitable for treatment.
  • the instructions provided in the kits of the invention are typically written instructions on a label or package insert (eg, a sheet of paper included in the kit), but machine-readable instructions (eg, instructions carried on a magnetic disk or compact disc) Also acceptable.
  • the molar ratio of cytarabine to daunorubicin is 1-100:1, preferably 1-25:1, more preferably 2-10:1, such as 5:1.
  • the molar ratio of compound I or its pharmaceutically acceptable salt and daunorubicin is 100:1-1:100, preferably 2:1-1:70, more preferably 4:1-1:50 (with compound I content calculation).
  • daunorubicin, cytarabine, compound I, or a pharmaceutically acceptable salt thereof are separately formulated into a clinically acceptable formulation and are present in the kit in a combined package.
  • the preparation containing Compound I or a pharmaceutically acceptable salt thereof is preferably an oral preparation, such as tablets, capsules, pills, etc.; each preparation unit contains about 0.001 mg to about 1000 mg of Compound I or its pharmaceutically acceptable salts Accepted salts (based on Compound I), preferably about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 330 mg, or about 20 mg to about 300 mg, or about 20 mg to about 250 mg, or about 20 mg to about 210 mg, or about 20 mg to about 180 mg, or about 20 mg to about 160 mg, or about 20 mg to about 140 mg, or about 20 mg to about 120 mg, or about 20 mg to about 100 mg.
  • Exemplary amounts are, for example, 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 110 mg, about 120 mg, about 125 mg, about 130 mg, About 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 310 mg, about 320 mg, about 360 mg, about 400 mg.
  • the daunorubicin preparation is preferably daunorubicin hydrochloride for injection, such as daunorubicin hydrochloride lyophilized powder for injection; each preparation unit contains about 10 mg to about 30 mg of active ingredient, preferably about 20 mg.
  • the cytarabine preparation is preferably cytarabine hydrochloride for injection, such as cytarabine hydrochloride lyophilized powder for injection; each preparation unit contains about 0.1g to about 0.5g of active ingredients, such as about 0.1g, about 0.3 g or about 0.5 g.
  • the pharmaceutically acceptable salt of Compound I is the hydrochloride salt, preferably the trihydrochloride salt, more preferably the trihydrochloride pentahydrate.
  • Each dosage unit contains about 1 mg to about 500 mg, or about 10 mg to about 400 mg, or about 15 mg to about 350 mg, or about 20 mg to about 310 mg, or about 25 mg to about 300 mg, or about 25 mg to about 250 mg, or about 50 mg to about 250 mg, or about 50 mg to about 200 mg, or about 50 mg to about 175 mg, or about 50 mg to about 160 mg, or about 50 mg to about 150 mg, or about 50 mg to about 125 mg, or about 50 mg to about 100 mg; exemplary amounts such as about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 310 mg, about 350 mg, about 400
  • the (1) daunorubicin; (2) cytarabine; (3) Compound I, or a pharmaceutically acceptable salt thereof, may be present in separate containers or in a single container.
  • kits of the present invention are in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (eg, seled Mylar or plastic bags) and the like.
  • the kit may optionally provide other components such as buffers and instructional information.
  • Compound I or a pharmaceutically acceptable salt thereof has a strong growth inhibitory effect on FLT3-ITD-mutated acute myeloid leukemia cells.
  • Preliminary clinical studies have shown that Compound I or its pharmaceutically acceptable salts have a certain curative effect on FLT3-mutated relapsed/refractory AML, which is close to the early trial data of similar product Gilteritinib; Cardiac, liver, hematological adverse reactions, and the incidence of adverse reactions above grade 3 is low.
  • Example 1 Inhibitory effect of compound I combined with daunorubicin and cytarabine on the proliferation of human leukemia cells MV-4-11 and MOLM-13
  • Compound I provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Weigh an appropriate amount of compound I, dissolve it completely with an appropriate amount of DMSO, and prepare a 10 mM stock solution; before use, it is gradiently diluted to 1.25nM, 2.5nM, 5nM, 10nM or 20nM with complete medium as the test solution. And take the complete medium as the test solution containing compound 10nM.
  • the medium was serially diluted to 3.9nM, 7.8nM, 15.625nM, 31.25nM and 62.5nM (calculated as daunorubicin) as a mixed test solution. And take the complete medium as a mixed test solution containing cytarabine and daunorubicin at 0 nM.
  • Inhibition rate (%) (well with normal OD value - well with OD value administration)/(well with normal OD value - blank well with OD value) ⁇ 100;
  • IC50 (1) is the concentration corresponding to the inhibition of half cell proliferation by compound I alone
  • IC50 (2) is the concentration corresponding to half cell inhibition by only daunorubicin and cytarabine
  • IC50 (C1) is the concentration of compound I corresponding to half cell inhibition after compound I combined with daunorubicin and cytarabine
  • IC50 (C2) is the half of compound I produced by combined use of daunorubicin and cytarabine Cell inhibition corresponding to daunorubicin and cytarabine concentrations.
  • the CI value is calculated according to the above formula, and the meanings are as follows: CI>1.1 is an antagonistic effect; 0.9 ⁇ CI ⁇ 1.1 is an additive effect; CI ⁇ 0.9 is a synergistic effect, and the smaller the CI value, the higher the synergistic effect of the two drugs.
  • Example 2 A single-arm, multi-center, open-label, dose-escalation/expansion phase I/II study of compound I or its pharmaceutically acceptable salt in combination with "7+3" standard chemotherapy in the treatment of FLT3-mutated newly diagnosed AML patients
  • This study is a single-arm, open-label, multicenter trial designed to evaluate oral administration of Compound I or a pharmaceutically acceptable salt thereof in combination with daunorubicin and cytarabine for the treatment of FLT3 in subjects with newly diagnosed FLT3-mutated AML. Safety, tolerability, and pharmacokinetics in subjects with newly diagnosed AML mutations and to explore optimal dosing regimens.
  • Phase I phase 3+3 dose escalation, planned to enroll 9-18 subjects;
  • Phase II phase in the safe, tolerated and effective dose group, the number of cases in each group will be expanded to 20 cases.
  • the specific experimental design is as follows:
  • Compound I trihydrochloride started to climb from the 100 mg BID dose group, and 3 subjects were enrolled first. If no DLT occurs during the first cycle of the induction period, continue with dose escalation. If there is 1 case of DLT in this dose group, 3 subjects should be added in this dose group; if no DLT occurs in these 3 subjects, enter the next dose group; if there is 1 case or more cases DLT, or if 2 or more patients in a dose cohort developed DLT, consider discontinuing dose escalation for that cohort.
  • Non-hematological toxicity DLT Any ⁇ grade 3 non-hematological toxicity or non-hematological toxicity that is definitely related, likely related, possibly related to the study drug occurring in the Phase I period from the first dose of the induction period to the end of the first induction period (within 42 days) Unexpected extramedullary toxicity. But exclude the following cases:
  • Grade 3 diarrhea can be controlled after symptomatic treatment
  • Hematological toxicity DLT Long-term myelosuppression, if there is no evidence of leukemia (blasts ⁇ 5%), persistent myelosuppression after the initiation of the first induction phase therapy (including at least one of the following: ⁇ Grade 4 leukopenia , ⁇ Grade 4 neutropenia, ⁇ Grade 4 thrombocytopenia), if not resolved within 42 days of the first induction phase treatment or before the start of the consolidation phase, will be considered a DLT.
  • Serum AST and ALT ⁇ 3 ⁇ ULN a. Serum AST and ALT ⁇ 3 ⁇ ULN; b. Total serum bilirubin ⁇ 2.5 ⁇ ULN; c. Serum creatinine ⁇ 3 ⁇ ULN or glomerular filtration rate>30mL/min.
  • the subject can take the test drug orally;
  • Female/male subjects of childbearing age should take adequate non-drug contraceptive measures from the signing of the informed consent form until 180 days after the last dose, and should not donate sperm or eggs.
  • AML with central nervous system involvement defined as cases with clinical symptoms highly suspected of central involvement, or imaging evidence supporting the judgment
  • GVHD graft-versus-host disease
  • coagulation abnormalities such as disseminated intravascular coagulation (DIC), hemophilia A, hemophilia B, and von Willebrand disease;
  • the subject has received prior therapy for AML, except for the following: a. Emergency leukocytosis; b. Hydroxyurea for emergency treatment of leukocytosis ⁇ 10 days; c. Growth factor or cytokine support; d. Steroid use for allergic reactions or blood transfusion reactions;
  • NYHA New York Heart Association
  • the heart rate is less than 50 beats/min, except for subjects using pacemakers;
  • the subject has taken a strong inducer or inhibitor of CYP2C8 and CYP3A4 enzymes within two weeks before taking the test drug;
  • Compound I trihydrochloride administered in the form of compound I trihydrochloride pentahydrate, provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. The drug doses described in this clinical study were calculated as the trihydrochloride anhydrate.
  • Cytarabine hydrochloride injection freeze-dried powder preparation provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
  • Daunorubicin Daunorubicin hydrochloride injection freeze-dried powder preparation, provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. 5. Treatment
  • Days 1-7 Cytarabine 100 mg/m 2 continuous intravenous infusion (CIVI) for 7 days (total 168 h).
  • Days 8-21 Compound I trihydrochloride 100 mg/time or 125 mg/time or 150 mg/time, orally, twice a day (BID) for 14 consecutive days.
  • Efficacy evaluation after the first induction therapy On the 28th day, the bone marrow and blood images were checked to evaluate the efficacy to determine the next treatment. If bone marrow aspirate is insufficient for evaluation, repeat bone marrow evaluation within one week. If CRc is obtained, enter into post-remission consolidation therapy; if CRc is not obtained, enter into the second induction therapy. In either case, a bone marrow examination to demonstrate CRc must be performed on or before day 42 after the first induction therapy.
  • the treatment regimen is the same as the first induction treatment, unless the dose is reduced due to safety.
  • Efficacy evaluation after the second induction therapy On the 28th day, the bone marrow and blood images were checked to evaluate the efficacy to determine the next treatment. If bone marrow aspirate is insufficient for evaluation, repeat bone marrow evaluation within one week. If CRc is obtained, consolidation therapy is performed after remission; if CRc is not obtained after the second induction therapy, the induction therapy fails, and the follow-up in the survival period is entered. In either case, a bone marrow examination to demonstrate CRc must be performed on or before day 42 after the second induction therapy. If CRc is achieved after 42 days, the investigator will decide whether to accept the consolidation phase treatment according to the benefit ratio of the subjects.
  • Days 1, 3, and 5 continuous intravenous infusion of high-dose cytarabine (HiDAC) 3g/m2, q12h.
  • HiDAC high-dose cytarabine
  • Day 8-21 Oral compound I trihydrochloride, in principle, the dose is the same as the dose of the previous cycle, twice a day (BID), for 14 consecutive days.
  • the investigator determines the number of cycles for the subjects to receive induction therapy and consolidation therapy.
  • HSCT Allogeneic hematopoietic stem cell transplantation
  • Subjects who obtain CRc after induction therapy can undergo allogeneic hematopoietic stem cell transplantation (HSCT) without the need for group out. While the subjects are waiting for HSCT, they can receive consolidation therapy first, up to a maximum of 4 cycles. However, the trial drug should be discontinued prior to initiation of a conditioning regimen for HSCT, followed by a pre-HSCT treatment/end of treatment visit within 7 days of discontinuation.
  • HSCT allogeneic hematopoietic stem cell transplantation
  • Oral compound I trihydrochloride in principle, the dose is the same as the dose of the previous cycle, twice a day (BID), taken daily, unless the subject meets the criteria for discontinuing the drug or withdrawing from the study, the subject can receive up to the maintenance period treatment 12 cycles.
  • Daunorubicin If the total bilirubin (TBIL) is >2 times ULN, the DNR can be down-regulated from 60 mg/m 2 to 45 mg/m 2 in the second induction period.
  • HiDAC High-dose cytarabine
  • Compound I trihydrochloride 1 Induction period and consolidation period: Compound I trihydrochloride will not undergo dose adjustment due to adverse reactions, but the medication can be suspended. 2Maintenance period: the dose can be reduced due to ADR; after the dose reduction due to ADR, the dose can be gradually increased when ADR recovers.
  • Compound I trihydrochloride dose adjustment gradient is as follows:
  • CYP2C8 and CYP3A4 enzymes and strong inducers or inhibitors or substrates of P-gp should be avoided as much as possible in the trial, and the use of concomitant drugs known to prolong the QT or QTc interval should be avoided.
  • Blood collection time (1) Induction period: C1D8 (before the first dose and 0.5h, 1h, 1.5h, 2h, 4h, 8h, 12h after the first dose), C1D15 (before the first dose), C1D18 (before the first dose), C1D21 ( Only administered once in the morning, before and 0.5h, 1h, 1.5h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, 96h); (2) Consolidation period: C1D8, C1D21 and C4D8, C4D21 Before the first dose; (3) Maintenance period: before the first dose of C8D1 and C12D1. The venous blood was collected, the blood concentration was detected, and the pharmacokinetic study was carried out.
  • Efficacy evaluation criteria refer to the revised [Cheson et al, "Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia", J Clin Oncol 21:4642-4649.2003 by American Society of Clinical Oncology.] and Criteria for the Diagnosis and Efficacy of Blood Disorders, 4th Edition.
  • CRc rate at the end of the induction period the number of subjects with the best response at the end of the first or second induction period was CRc (CR+CRh+CRp+CRi) divided by the total number of cases in the protocol analysis set.
  • CR rate at the end of the induction period the number of subjects with the best response at the end of the first or second induction period was divided by the total number of cases in the protocol analysis set.
  • Duration of remission includes CRc duration (CR+CRh+CRp+CRi), CR duration, CR/CRh duration, and CR/CRi duration. See revised [Cheson et al, 2003].
  • OS Overall survival
  • Event-Free Survival defined as the time from the first administration to the occurrence of treatment failure (the CRc was not reached at the end of the second induction treatment) or relapse or death due to any cause (the previous whichever occurs).
  • LFS Leukemia-free survival
  • Hematopoietic stem cell transplantation rate defined as the number of subjects undergoing hematopoietic stem cell transplantation divided by the total number of cases in the corresponding analysis set.
  • the hypothesis test will use a two-sided test, with a test level of 0.05, and a 95% confidence interval for parameter estimation.
  • Compound I or its pharmaceutically acceptable salts (such as trihydrochloride) combined with the "7+3" standard chemotherapy regimen in the treatment of newly diagnosed AML with FLT3 mutation has a better response rate than the "7+3" standard chemotherapy regimen alone. Longer survival time for patients. This combination regimen is safe and tolerable, and the potential to improve outcomes far outweighs the risk of potential toxicity.
  • Example 3 A single-arm, multi-center, open-label, dose-escalation/expansion phase I/II study of compound I or its pharmaceutically acceptable salt combined with "7+3" standard chemotherapy in the treatment of newly diagnosed AML patients
  • the inclusion criteria for the trial population were as follows:
  • Serum AST and ALT ⁇ 3 ⁇ ULN a. Serum AST and ALT ⁇ 3 ⁇ ULN; b. Total serum bilirubin ⁇ 2.5 ⁇ ULN; c. Serum creatinine ⁇ 3 ⁇ ULN or glomerular filtration rate>30mL/min.
  • the subject can take the test drug orally;
  • Female/male subjects of childbearing age should take adequate non-drug contraceptive measures from the signing of the informed consent form until 180 days after the last administration, and should not donate sperm or eggs.
  • Example 2 Except for the above-mentioned inclusion criteria of the experimental population, the experimental design, exclusion criteria of the experimental population, drugs, treatment methods, pharmacokinetic research methods, evaluation indicators, and statistical analysis methods are the same as those in Example 2.
  • the patient male, 38 years old, was diagnosed with recurrent cough and fever for more than 1 month.
  • the patients were treated according to the phase I dosing regimen of the clinical trial (100 mg, BID dose group), and the efficacy was evaluated as CR (complete remission) after the first induction therapy. After two cycles of consolidation therapy, the patient underwent bone marrow transplantation.
  • the patient a 49-year-old female, was admitted to the hospital mainly due to the discovery of thrombocytopenia for 1 week.
  • Blood routine examination at admission WBC: 6.88 ⁇ 10 9 /L, NE: 0.65 ⁇ 10 9 /L, Hgb: 135g/L, Plt: 64 ⁇ 10 9 /L; Bone marrow morphology: acute myeloid leukemia (not M3) ; Flow: Consistent with the AML phenotype.
  • the patients were treated according to the phase I dosing regimen of the clinical trial (100 mg, BID dose group), and the efficacy was evaluated as CR (complete remission) after the first induction therapy. Then enter the consolidation treatment.

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Abstract

L'invention concerne un médicament et un procédé de traitement de la leucémie myéloïde aiguë au moyen d'une administration combinée d'un composé inhibiteur de kinases multi-cible I ou d'un sel pharmaceutiquement acceptable de celui-ci avec de la daunorubicine et de la cytarabine. La combinaison du composé I ou du sel pharmaceutiquement acceptable de celui-ci avec de la daunorubicine et de la cytarabine peut inhiber significativement la prolifération de cellules leucémiques humaines MV-4-11 et MOLM-13, produit un effet synergique, et présente une efficacité combinée qui est meilleure que celle d'un schéma uniquement à l'aide de daunorubicine et de cytarabine, et les patients traités présenteront une période de survie plus longue. Le potentiel du schéma thérapeutique combiné dans l'amélioration pronostique est bien supérieur au risque de toxicité potentielle de celui-ci, et le schéma a de bonnes perspectives d'application clinique.
PCT/CN2022/077828 2021-02-25 2022-02-25 Médicament thérapeutique combiné pour leucémie myéloïde aiguë WO2022179592A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101142215A (zh) * 2005-01-13 2008-03-12 西格诺药品有限公司 卤代芳基取代的氨基嘌呤、其组合物及其治疗方法
WO2011147066A1 (fr) * 2010-05-26 2011-12-01 四川大学 Dérivés arylaminés de purine, leur procédé de préparation et leur utilisation pharmaceutique
US20200113902A1 (en) * 2017-06-12 2020-04-16 Syros Pharmaceuticals, Inc. Compositions and methods for treating cancers with covalent inhibitors of cyclin-dependent kinase 7 (cdk7)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101142215A (zh) * 2005-01-13 2008-03-12 西格诺药品有限公司 卤代芳基取代的氨基嘌呤、其组合物及其治疗方法
WO2011147066A1 (fr) * 2010-05-26 2011-12-01 四川大学 Dérivés arylaminés de purine, leur procédé de préparation et leur utilisation pharmaceutique
US20200113902A1 (en) * 2017-06-12 2020-04-16 Syros Pharmaceuticals, Inc. Compositions and methods for treating cancers with covalent inhibitors of cyclin-dependent kinase 7 (cdk7)

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "CTR20211272, Phase I/II Study of SKLB1028 Capsule Combined with "7+3" Standard Chemotherapy in the Treatment of Single-arm, Multicenter, Open-label, and Dose-escalation/expansion in Patients Suffering fr"", CSPC ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD., 7 June 2021 (2021-06-07), XP055961811, Retrieved from the Internet <URL:http://zy.yaozh.com/linchuangshiyan/pdf/CTR20211272.pdf> *
CAO Z-X; LIU J-J; ZHENG R-L; YANG J; ZHONG L; XU Y; WANG L-J; ZHANG C-H; WANG B-L; MA S; WANG Z-R; XIE H-Z; WEI Y-Q; YANG S-Y: "SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants", LEUKEMIA, NATURE PUBLISHING GROUP UK, LONDON, vol. 26, no. 8, 9 March 2012 (2012-03-09), London, pages 1892 - 1895, XP037784522, ISSN: 0887-6924, DOI: 10.1038/leu.2012.67 *
SCHITTENHELM MARCUS, KERSTIN M KAMPA, KEVIN W H YEE, MICHAEL C HEINRICH: "The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin", CELL CYCLE, vol. 8, no. 16, 15 August 2009 (2009-08-15), pages 2621 - 2630, XP055961809, DOI: 10.4161/cc.8.16.9355 *
SUTAMTEWAGUL GRERK, VIGIL CARLOS E: "Clinical use of FLT3 inhibitors in acute myeloid leukemia", ONCOTARGETS AND THERAPY, vol. Volume 11, 16 October 2018 (2018-10-16), pages 7041 - 7052, XP055961807, DOI: 10.2147/OTT.S171640 *

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