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WO2024216136A1 - Combination therapy for the treatment of hematological cancers - Google Patents

Combination therapy for the treatment of hematological cancers Download PDF

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Publication number
WO2024216136A1
WO2024216136A1 PCT/US2024/024407 US2024024407W WO2024216136A1 WO 2024216136 A1 WO2024216136 A1 WO 2024216136A1 US 2024024407 W US2024024407 W US 2024024407W WO 2024216136 A1 WO2024216136 A1 WO 2024216136A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
subject
dimethylmorpholino
oxopropan
Prior art date
Application number
PCT/US2024/024407
Other languages
French (fr)
Inventor
Ammar ADAM
Martin F. Hentemann
Jessica C. PIEL
Michael P. COLLINS
Original Assignee
Foghorn Therapeutics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2024216136A1 publication Critical patent/WO2024216136A1/en

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Classifications

    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure relates to combination therapies including N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, and less than standard dose of cytarabine for the treatment of AML and related hematological cancers.
  • the combination therapies of the invention can reduce side effects, improve outcomes, and/or reduce the dosing burden on the patient.
  • the invention features a method of treating hematologic cancer in a subject in need thereof, the method including administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol- 2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide (aka FHD 286), or a pharmaceutically acceptable salt thereof, and (II) continuous intravenous infusion of 100 mg/m 2 /day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer.
  • the invention features a method including administering to the subject (i) N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, and (iii) an anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • the method includes administering between about 5.0 mg and about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for six to eight days, followed by six to eight days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the method includes administering between about 5.0 mg and about 22.5 mg per day of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for thirteen to fifteen days, followed by six to eight days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the method includes administering between about 5.0 mg and about 22.5 mg per day of the N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for six to fifteen days, followed by six to eight days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the method includes administering between about 5.0 mg and about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the method includes administering between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for fourteen days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the method includes administering between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven to fourteen days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the method includes administering 10 mg per day of the N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the method includes administering 20 mg per day of the N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the method can include (1) administering to the subject between about 5.0 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about 5.0 mg and about 10 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 5.0 mg and about
  • the invention provides a method of treating hematological cancer in a subject, wherein continuous intravenous infusion of 100 mg/m 2 /day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered between about once a day for 10 days and about once every 4 days. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered once a day for 4 days.
  • the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered once every 4 days. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg/m 2 every 12 hours. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg/m 2 every 12 hours.
  • the invention provides a method of treating hematological cancer in a subject, wherein the method can include administering to the subject between about 5.0 mg/m 2 and about 100 mg/m 2 per day of cytarabine, or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating hematological cancer in a subject, wherein the method can include administering to the subject between about 10 mg/m 2 and about 75 mg/m 2 (or between about 10 mg/m 2 and about 50 mg/m 2 ) per day of cytarabine, or a pharmaceutically acceptable salt thereof.
  • the cytarabine is administered for 1 to 10 days, after which only FHD 286 is administered.
  • the invention provides a method of treating hematological cancer in a subject, wherein the method comprises administering to the subject a low dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (c) a dose of 2.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (d) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • the cycle is performed once, twice, or three times.
  • the invention provides a method of treating hematological cancer in a subject, wherein the method comprises administering to the subject a high dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (e) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (f) a dose of 7.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • the cycle is performed once, twice, or three times.
  • the method can include (1) administering to the subject between about 1 .0 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about
  • 7.5 mg and about 10 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof can include (3) administering to the subject between about 5.0 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (4) administering to the subject between about 2.5 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (5) administering to the subject between about 1 .0 mg and about 5.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (6) administering to the subject between about 1 .0 mg and about 2.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (7) administering to the subject between about 1 mg and about 7.5 mg per day at least four times a day of the anti-fungal agent, or can
  • step (c) includes administering to the subject 2.5 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • step (e) includes administering to the subject 5.0 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • step (c) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
  • step (e) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
  • step (d) includes administering to the subject 5.0 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • step (f) includes administering to the subject 7.5 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • step (d) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
  • step (f) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
  • the method includes, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of cytarabine, or a pharmaceutically acceptable salt thereof.
  • the subject is pretreated for 1 , 2, 3, 4, 5, 6, 7, or 8 days with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy- 1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or one complete treatment cycle of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide prior to the administration of cytarabine, or a pharmaceutically acceptable salt thereof.
  • the method includes, at the completion of combination therapy in the subject, continuing to administer to the subject the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, without further administering to the subject cytarabine, or a pharmaceutically acceptable salt thereof.
  • the cytarabine treatment can be stopped after 1 to10 days of cytarabine administrations, after which the subject receives additional cycles of the N-(1-((4- (6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-l H-pyrrole-3-carboxamide therapy.
  • the method includes, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and/or cytarabine, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • the subject is pretreated for 1 , 2, 3, 4, 5, 6, 7, or 8 days with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, and/or cytarabine, or one complete treatment cycle of N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide and/or cytarabine prior to the administration of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • the method includes, at the completion of combination therapy in the subject, continuing to administer to the subject the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and/or cytarabine, or a pharmaceutically acceptable salt thereof, without further administering to the subject anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • the anti-fungal agent treatment can be stopped after one, two, or three cycles of the low dose regimen of the anti-fungal agent or high dose regiment of the anti-fungal agent administrations, after which the subject receives additional cycles of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide therapy and/or cytarabine.
  • the method comprises, or consists of, administering cytarabine for a period of 1 to 7 days, or 1 to 5 days.
  • the method includes at least 21 days, 28 days, 2 months, 3 months, 4 months, or 6 months of treatment.
  • the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally.
  • cytarabine or a pharmaceutically acceptable salt thereof, is administered intravenously.
  • the anti-fungal agent or a pharmaceutically acceptable salt thereof, is administered orally.
  • the invention provides a method of treating hematological cancer in a subject, wherein the risk of developing differentiation syndrome is reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, alone and/or relative to treatment with cytarabine, or a pharmaceutically acceptable salt thereof, alone.
  • the invention provides a method of treating hematological cancer in a subject, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and cytarabine, or a pharmaceutically acceptable salt thereof, alone and/or relative to treatment with the N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof
  • the invention provides a method of depleting or promoting differentiation of blast cells of the leukemia in a subject in need thereof, the method comprising administering to the subject (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) continuous intravenous infusion of 100 mg/m 2 /day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective in treating hematological cancer.
  • the hematological cancer is characterized by differentiation arrest.
  • the subject has been treated or is being treated for a hematological cancer is characterized by differentiation arrest.
  • the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.
  • the invention provides a method of treating hematological cancer in a subject, wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome.
  • the hematological cancer has or has been determined to have an inv(3) mutation. In some embodiments, the hematological cancer has or has been determined to have a -7/del(7q) mutation. In some embodiments, the hematological cancer has or has been determined to have a SF3B1 mutation. In some embodiments, the hematological cancer has or has been determined to have a MLLr mutation. In some embodiments, the hematological cancer has or has been determined to have a RUNX1 mutation. In some embodiments, the hematological cancer has or has been determined to have an ASXL1 mutation. In some embodiments, the hematological cancer has or has been determined to have a JAK2 mutation.
  • the hematological cancer has or has been determined to have a NRAS mutation. In some embodiments, the hematological cancer has or has been determined to have a KRAS mutation. In some embodiments, the hematological cancer has or has been determined to have a TP53 mutation. In some embodiments, the hematological cancer has or has been determined to have a TET2 mutation. In some embodiments, the hematological cancer has or has been determined to have a DNMT3 mutation.
  • the anti-fungal agent is polyene, amphotericin B, nystatin, natamycin, flucytosine, imidazole, miconazole, clotrimazole, econazole, ketoconazole, triazole, itraconazole, fluconazole, griseofulvin, terconazole, butoconazole, ciclopirox, ciclopirox olamine, haloprogin, tolnaftate, naftifine, or terbinafine.
  • the anti-fungal agent is a CYP3A4 inhibitor (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole).
  • CYP3A4 inhibitor e.g., itraconazole, ketoconazole, posaconazole, and voriconazole.
  • the anti-fungal agents is itraconazole, ketoconazole, posaconazole, and voriconazole.
  • the fungal infection is aspergillosis or candidiasis.
  • hematologic cancer refers to cancers that begin in blood-forming tissue, such as the bone marrow, or in the cells of the immune system, e.g., leukemias, lymphomas, and myelomas.
  • Leukemias are cancers found in blood and bone marrow which are caused by rapid production of abnormal white blood cells.
  • Lymphomas are cancers which effect the lymphatic system.
  • Myelomas are cancers of the plasma cells.
  • normal blood cell development is interrupted by uncontrolled growth of an abnormal type of blood cell. The abnormal blood cells prevent the blood from performing many of its functions.
  • Hematologic cancers account for about 10% of all new cancer diagnoses. The 5-year relative survival rates for hematologic cancers range from about 50% to about 90%.
  • FHD 286 refers to N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide.
  • FHD 286 and the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide has the structure:
  • cytarabine refers to cytosine arabinoside. As used herein, cytarabine has the structure:
  • anti-fungal agent refers to an agent that when administered to a host selectively suppresses the growth of, or kills, fungi in the host, including but not limited to polyene antifungals (e.g., natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin, hamycin), imidazole antifungals (e.g., miconazole (MICATIN®, DAKTARIN®), ketoconazole (NIZORAL®, FUNGORAL®, SEBIZOLE®), clotrimazole (LOTRIMIN®, LOTRIMIN® AF, CANESTEN®), econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole (ERTACZO®), sulconazole, tioconazole), triazole anti
  • the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described.
  • the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.
  • administration refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.
  • Administration to an animal subject may be by any appropriate route.
  • administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.
  • bronchial including by bronchial instillation
  • a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition.
  • the treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated.
  • the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen.
  • administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic).
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human.
  • a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • any other pharmaceutically acceptable formulation e.g., for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as
  • a “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.
  • the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound described herein.
  • Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e g., by reacting a free base group with a suitable organic acid.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be, e.g., acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
  • progression-free survival refers to the length of time during and after medication or treatment during which the disease being treated (e.g., cancer) does not get worse.
  • the combination therapies of the invention can increase the likelihood of progression-free survival in a subject.
  • the term “proliferation” as used in this application involves reproduction or multiplication of similar forms (cells) due to constituting (cellular) elements.
  • the combination therapies of the invention can decrease proliferation of cancer cells.
  • the term “subject” refers to any organism to which a composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • animal e.g., mammals such as mice, rats, rabbits, non-human primates, and humans.
  • a subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • the terms “treat,” “treated,” or “treating” mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. In the context of treating cancer, treatment may include slowing the spread of metastasis and/or extending progression-free survival in a population of treated subjects as compared to a population of untreated subjects. Compounds of the disclosure may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder.
  • the terms “reduce the risk of a fungal infection” refers to reducing the likelihood that a patient acquires a fungal infection (e.g. aspergillosis or candidiasis) while undergoing a treatment of the invention.
  • a reduced risk of a fungal infection is assessed for a given patient population (e.g. patients who are undergoing treatment of hematological cancer according to the methods of the invention), where the likelihood of a fungal infection for a subject receiving FHD-286, cytarabine, and an anti-fungal agent is reduced relative to patients receiving an identical treatment regimen, but without any concurrent antifungal therapy.
  • the likelihood of fungal infection can be reduced , e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, using the methods described herein.
  • Fig. 1 depicts graphs showing the effects of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide on cells that are dosed for 7 days.
  • CD11 b expression was assessed by flow cytometry as described in Example 1. Note: in the DMSO condition, all cell lines had low levels of CD11 b positivity with the exception of the M6 line HEL92.1.7.
  • Fig. 2 depicts graphs showing the effect of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide on cells that are dosed for 14 days.
  • Cells were split on days 3, 7 and 10 with drug replenishment and cells were analyzed by flow cytometry on days 3, 7, 10 and 14 for the indicated markers as described in Example 2.
  • Values for BCL2 are mean fluorescence intensity (MFI) relative to DMSO control.
  • Fig. 3 depicts graphs showing HL60 cells exposed to the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide for 17 days and analyzed by flow cytometry on days 7, 14 and 16 (Ki67 days 14 and 17 only) as described in Example 3. Equal numbers of events were analyzed for all samples. Shown are 2-parameter pseudocolor plots with CD11 b MFI on the a-axis and BRG1 or Ki67 MFI on the y-axis. Values represent the percentage of cells within each quadrant. Fluorescent intensity distributions are shown as adjunct histograms.
  • Fig. 4 is a chart depicting the cell splitting and cell proliferation of CD11 B+ and CD11 b- cells as described in Example 3.
  • Fig. 5 is a graph depicting viable cell densities of HL60 cells exposed to the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide for 17 days, with CD11 b +A isolation on day 7 as described in Example 3.
  • Fig. 6 is a series of images depicting mice bearing cell line xenographs that were treated with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide daily for 7 days, and tumors were collected for histology 4 hours after the final dose as.
  • Studies are representative IHC images of tissues stained with an antibody specific for human CD1 1 b as described in Example 4.
  • Fig. 8 is a chart depicting the combination treatment design used in Example 6.
  • Fig. 9 is a table depicting the cell lines and drug concentrations that were tested in combination experiments in Example 6. Combination agent concentrations were chosen based on experimentally derived ICsovalues.
  • Fig. 10 is a heatmap depicting cell densities of cells exposed to the combination therapies as in Fig 12, relative to DMSO control on day 14, over a range of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide concentrations as described in Example 6.
  • Fig. 11 is a series of graphs depicting HL60 cells that were treated as in Fig. 1 , and analyzed by flow cytometry on days 7, 10 and 14 as described in Example 6. Equal volumes were analyzed for all samples, in order to observe effects on cell density as described in Example 6. Shown are 2-parameter pseudocolor plots with CD11 b MFI on the X-axis and Ki67 MFI on the y-axis. Values represent the percentage of cells within each quadrant. Similar results were obtained in other cell lines, and with decitabine combination.
  • Fig. 12 is a study design for mice inoculated with MV41 1 with the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, Cytarabine, and a combination therapy of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide and cytarabine.
  • Fig. 13 is a graph that depicts the tumor volume of the mice inoculated with MV411 as described in Example 7 that were treated with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide6, Cytarabine, or a combination therapy of FHD 286 and cytarabine as depicted in Figure 12.
  • Fig. 14 is a graph depicting the %survival of the mice inoculated with MV411 as described in Example 7 that were treated as in Figure 12 with FHD 286, Cytarabine, or a combination therapy of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide and cytarabine as in Figure 12.
  • the present disclosure features combination therapies including the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide and less than standard dose of cytarabine for the treatment of AML and related hematological cancers.
  • the combination therapies of the invention can reduce side effects, improve outcomes, and/or reduce the dosing burden on the patient.
  • the risk of developing differentiation syndrome can be reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, alone and/or relative to treatment with cytarabine, or a pharmaceutically acceptable salt thereof, alone.
  • the methods of the present disclosure result in one or more (e.g., two or more, three or more, four or more) of: (a) decrease blast count, (b) normal neutrophil counts, (c) normal platelet counts, (d) a bone marrow biopsy which reveals no clusters or collections of blast cells, (e) decreased tumor recurrence (f) increased survival of subject, (g) increased progression free survival of subject.
  • Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
  • T reating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
  • Exemplary hematological cancers that may be treated by the invention include, but are not limited to multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or nonHodgkin’s lymphoma.
  • the hematologic cancer can be characterized as having a inv(3) mutation, a -7/del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and/or a DNMT3A mutation.
  • the methods of the invention include treating hematologic cancer in a subject by administering to the subject (i) N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer.
  • the method can further include administering an antifungal agent
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 22.5 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 15 mg per day.
  • the N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy- 1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 10 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 7.5 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 22.5 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 15 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 10 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 10 mg and about 22.5 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 10 mg and about 15 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 15 mg and about 22.5 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 5.0 mg per day.
  • the N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 7.5 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 10 mg per day.
  • the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 15 mg per day.
  • the N- (1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 22.5 mg per day.
  • the methods of the invention include treating hematologic cancer in a subject by administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer.
  • the method can further include administering an anti-fungal agent to reduce the risk of fungal infection in the subject.
  • cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of less than 100 mg/m 2 intravenous daily for a period of 1 to 10 days. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg/m 2 by continuous intravenous transfusion every 12 hours. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg/m 2 by continuous intravenous transfusion every 12 hours. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered between about once a day for 4 days and about once every 4 days. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of between about 5.0 mg/m 2 and about 100 mg/m 2 per day (on days cytarabine is dosed). Anti-fungal Agent
  • the methods of the invention include treating hematologic cancer in a subject by administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer.
  • the method can further include administering an anti-fungal agent to reduce the risk of fungal infection in the subject.
  • the anti-fungal agent is a CYP3A4 inhibitor.
  • the anti-fungal agent can be posaconazole, which is approved for use by the FDA under the name NOXAFIL®.
  • the antifungal agent can be itraconazole, which is approved for use by the FDA under the name SPORANOX® or TOLSURA®.
  • the anti-fungal agent can be fluconazole, which is approved for use by the FDA under the name DIFLUCAN® or FUMYCIN®.
  • the anti-fungal agent can be isavuconazole, which is approved for use by the FDA under the name CRESEMBA®.
  • the anti-fungal agent can be amphotericin B, which is approved for use by the FDA under the name VFEND®.
  • the anti-fungal agent can be voriconazole, which is approved for use by the FDA under the name AMBISOME® or FUNGIZONE®.
  • the anti-fungal agent can be clotrimazole, which is approved for use by the FDA under the name LOTRIMIN®, LOTRIMIN® AF, or CANESTEN®.
  • the anti-fungal agent can be miconazole, which is approved for use by the FDA under the name MICATIN®, or DAKTARIN®.
  • the anti-fungal agent can be nystatin, which is approved for use by the FDA under the name BIO-STATIN®.
  • the anti-fungal agent can be anidulafungin (an echinocandin), which is approved for use by the FDA under the name ERAXIS® or ECALTA®.
  • the anti-fungal agent can be caspofungin (an echinocandin), which is approved for use by the FDA under the name CANCIDAS®.
  • the anti-fungal agent can be micafungin (an echinocandin), which is approved for use by the FDA under the name MYCAMINE®.
  • the anti-fungal agent can be ketoconazole, which is approved for use by the FDA under the name NIZORAL®, FUNGORAL®, SEBIZOLE®.
  • the anti-fungal agent can be sertaconazole, which is approved for use by the FDA under the name ERTACZO®.
  • the anti-fungal agent can be tolnaftate, which is approved for use by the FDA under the name TINACTIN®, DESENEX®, or AFTATE®.
  • Other anti-fungal agents can also be used.
  • the anti-fungal agent or a pharmaceutically acceptable salt thereof is administered as a low dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (c) a dose of 2.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (d) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • the anti-fungal agent or a pharmaceutically acceptable salt thereof is administered as a high dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (c) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (d) a dose of 7.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
  • step (c) of the the low dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof is administered for 14 days.
  • step (d) of the low dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof is administered for 14 days.
  • step (e) of the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof is administered for 14 days.
  • step (f) of the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof is administered for 14 days.
  • the combination therapy can include, one, two, three, or more cycles of the low dose regimen of the anti-fungal agent administered in combination with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide treatment and/or cytarabine treatment.
  • the combination therapy can include, one, two, three, or more cycles of the high dose regimen of the anti-fungal agent administered in combination with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide treatment and/or cytarabine treatment.
  • compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.
  • Pharmaceutical compositions typically include an active agent as described herein and a physiologically acceptable excipient (e.g., a pharmaceutically acceptable excipient).
  • a physiologically acceptable excipient e.g., a pharmaceutically acceptable excipient.
  • Formulation principles for the compounds disclosed herein may be those described, e g., in WO 2020/160180, the disclosure of which is incorporated by reference herein in its entirety.
  • the compounds of the disclosure may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration.
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • the compound is administered orally.
  • Suitable pharmaceutical carriers as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary).
  • N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide may be formulated into a unit dosage form for oral administration (e.g., a capsule) as described in Table 1.
  • the cell culture method, flow cytometry method and flow cytometry analysis methods are relevant to the examples below.
  • AML cell lines were maintained in vitro as suspension cells in the media listed (Table 2) and subcultured every 3 or 4 days by diluting to 0.5 x 10 s cells/mL or 0.3 x 10 6 cells/mL, respectively, in fresh growth medium. Cells were discarded upon reaching passage 15.
  • CD34+ cells were isolated from primary cell samples (Proteogenex; Inglewood, CA) using EasySep Human CD34 Positive Selection Kit II (STEMCELL Technologies [STEMCELL]; Vancouver, BC, Canada) per manufacturer protocol. The separation step was repeated a total of 4 times. The cells were resuspended in 1 mL of Stem Cell Medium and seeded at 0.5 x 1 o 6 cells/mL for immediate use in the 7- day differentiation assay.
  • AML acute myeloid leukemia
  • FBS fetal bovine serum
  • IMDM Iscove’s Modified
  • pen/strep penicillin/streptomycin
  • rG- CSF recombinant granulocyte colony-stimulating factor
  • rGM-CSF recombinant granulocyte macrophage stimulating factor
  • RPMI Roswell Park Memorial Institute.
  • the plate was blocked with 50 pL/well of Fc block diluted 1 :20 in FACS buffer for 15 minutes on ice in the dark. The Fc block was removed by centrifugation and then the plate was washed with FACS buffer as before. Cells were resuspended in 50 pL surface antibody cocktail diluted in FACS buffer and incubated for 30 minutes on ice in the dark. The antibody cocktail was removed by centrifugation and then the plate was washed with FACS buffer as before. Cells were resuspended in Fix/Perm at 200 pL/well and incubated for 30 minutes on ice in the dark. The Fix/Perm was removed by centrifugation, and the plate was washed as before with 200 pL/well Perm buffer.
  • AF Alexa Fluor
  • APC allophycocyanin
  • CF cyanine-based fluorescence
  • FBS fetal bovine serum
  • PBS phosphate-buffered saline
  • PE phycoerythrin
  • SB Super Bright 780.
  • FlowJo (v10.7; Becton Dickinson; Franklin Lakes, NJ) was used for data analysis. First, cell gates were determined by forward scatter (FSC) versus side scatter (SSC) and debris was excluded. Single cells were then identified using SSC-Area and SSC-Height, and dead cells staining for viability dye were gated out.
  • FSC forward scatter
  • SSC side scatter
  • thresholds for positive and negative marker expression were defined using an unstained control sample.
  • BRG1 and Ki67 expression levels were evaluated by 2-parameter plots against CD11 b.
  • Cell populations of interest were divided into subpopulations of high or low marker expression by setting a visual threshold.
  • mean fluorescence intensity was calculated using FlowJo software.
  • the AML cell lines and primary AML cells were prepared and cultured as described in cell culture methods. On Day 0, cells were seeded in 6-well plates in 3 mL at the indicated densities (Table 4). Cell cultures were not split during the assay; however, to prevent the HEL92.1 .7 and MV-4-11 cells from becoming overconfluent, the growth media were increased by 50% on Day 4, using fresh medium containing either DMSO or N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide at appropriate concentrations. After 7-day exposure to FHD-286, cells were collected and analyzed by flow cytometry as shown in Figure 1 .
  • DMSO dimethyl sulfoxide
  • the AML cell lines were cultured as described in cell culture methods. On Day 0, cells were seeded in 6-well plates at the indicated densities (Table 5). Addition of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide6 was staggered so that all time points for a given cell line were collected and analyzed on the same day to minimize potential variations in fluorescence intensity measurements. After exposure to FHD-286, cells were collected on the days indicated and analyzed by flow cytometry as shown in Figure 2.
  • DMSO dimethyl sulfoxide. Note: Medium containing DMSO or FHD-286 was replenished as necessary to maintain FHD-286 concentration.
  • the AML cell line HL60 was cultured as described in cell culture methods. On Day 0, cells were seeded in 6-well plates at the indicated density (Table 6). After exposure to N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, cells were collected on the days indicated and analyzed by flow cytometry as shown in Figure 4.
  • CD11 b+ and CD11 b- HL60 cells were separated using EasySep Human CD11 b Positive Selection and Depletion Kit (STEMCELL) per manufacturer protocol.
  • an EasySep Magnet (STEMCELL) was used to capture CD11 b+ cells while CD11 b- cells were poured off and collected as shown in Figure 7.
  • the cells were resuspended in medium and seeded at 0.5 x 10 6 cells/mL. Cells were collected on the days 14 and 17, and analyzed by flow cytometry as shown in Figure 3 and 5.
  • DMSO dimethyl sulfoxide.
  • Medium containing DMSO or FHD-286 was replenished as necessary to maintain FHD-286 concentration.
  • a Viability was assessed by propidium iodide staining on Day 17, 3 days after splitting.
  • mice (CB.17/SCID) were inoculated subcutaneously in the right flank with a single cell suspension of 2*10 6 EOL-1 human acute myeloid leukemia (AML) cells in 100 pL of sterile cold 1 x PBS. Dosing began when the range of the group mean tumor size reached 50-70 mm 3 and mice were randomized into groups.
  • AML human acute myeloid leukemia
  • N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide was administered once daily (QD) by oral gavage at a volume of 10 mL/kg, according to the study design in Table 7.
  • NBF neutral buffered formalin
  • H-scores were derived using the following formula:
  • %weak the percentage of cells weakly positive for CD11 b
  • % moderate the percentage of cells moderately positive for CD11 b
  • Results Treatment of AML cell line xenografts with FHD 286 can result in a dose-dependent upregulation of CD11 b in vivo.
  • the AML cell lines were cultured as described in cell culture methods._To determine the concentrations of the combination agents to be used, prior to the study, each cell line was exposed to combination agent of varying doses alone for 7 days. Cell viability was assessed on Day 7 using CellTiter-Glo (Promega #G7571) per manufacturer protocol, from which half-maximal inhibitory concentration (ICso) curves were generated.
  • ICso half-maximal inhibitory concentration
  • Combination agents (cytarabine, decitabine, or venetoclax) were then added at 3 predetermined concentrations as shown in Figure 9 (1 at the ICso value and 1 each above and below it); DMSO-only cells were exposed to each cytotoxic agent or DMSO alone for an additional 7 days, while N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide-only cells were exposed to N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide in combination with each cytotoxic
  • Flow cytometric analysis of cell density was performed in all cell lines on Days 7 (prior to combination agent addition) and 14 (7 days after combination agent addition) as shown in Figure 10.
  • Flow cytometric analysis of CD11 b and Ki67 co-expression in HL60 cells was performed on Days 7, 10 (3 days after combination agent addition), and 14 as shown in Figure 11 .
  • IC50 half-maximal inhibitory concentration
  • Example 7 In vivo comparison study of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, cytarabine, and combination therapy of FHD 286 and cytarabine.
  • mice (CB.17/SCID) were inoculated subcutaneously in the left flank with a single cell suspension of 10 x 10 6 MV-4-11 human AML cells in 100 pL with Matrigel (1 :1) in cold sterile 1 x phosphate-buffered saline for tumor development.
  • mice When the mean tumor size reached approximately 83 mm 3 (range 55 to 154 mm 3 ), mice were randomized into treatment groups (Day 0) and dosed according to the study design in Table 9.
  • mice On Day 1 , tumor-bearing mice were treated with either vehicle control (20% HP-p-CD in 5 mM citrate buffer, pH 5), FHD-286 PO at 1.5 mg/kg, or cytarabine IP at 30 mg/kg.
  • FHD 286 + cytarabine combination was started; mice that had initially received 5 days of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide had cytarabine IP at 30 mg/kg added. All test articles were dosed 5-days on, and then 2-days off for 21 days total (Table 9).
  • Tumor volume was calculated using the following formula:
  • Tumor volume (length x [width] A 2)/2 where length is the greater of the 2 measurements, and width is the smaller as shown in Figure 13.
  • Tumor growth inhibition was assessed by comparing the difference in tumor volume between control and treated groups using the following formula:
  • TGI (1-T/C) x 100% where T and C are the mean relative volumes (% tumor growth) of the tumors in the treated and control groups, respectively, on a given day after tumor inoculation.
  • HP-p-CD 2-hydroxypropyl-p-cyclodextrin
  • IP intraperitoneal
  • n/a not applicable
  • PO oral (gavage).
  • Example 8 A study of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide and less than standard dose of cytarabine for the treatment of acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • Subjects with acute myeloid leukemia are treated with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide administered orally in combination with low dose less than standard dose of cytarabine administered by infusion.
  • the subjects, who are not previously treated with either drug commence combination therapy with both drugs initially first administered to the subjects within 24 hours of each other.
  • N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally in a cyclical on/off dosing regimen with a total dose of between about 5.0 mg to 22.5 mg per day for about six to fifteen days, followed by about six to eight days without administration of N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  • the cycle is repeated multiple times, as needed.
  • Cytarabine or a pharmaceutically acceptable salt thereof, is administered in a continuous intravenous infusion of from 5 mg/m 2 /day to 100 mg/m 2 /day for a period of 10 days or less.
  • the cytarabine treatment is optionally repeated, as needed.
  • Subjects receiving the combination of FHD 286 and low dose less than standard dose of cytarabine can benefit from a reduction in the risk of developing differentiation syndrome and/or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide alone or less than standard dose of cytarabine alone.
  • Example 9 A study of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide and less than standard dose of cytarabine for the treatment of acute myeloid leukemia (AML) with pre-treatment of FHD 286.
  • AML acute myeloid leukemia
  • Subjects with acute myeloid leukemia are treated with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide administered orally in combination with low dose less than standard dose of cytarabine administered by infusion.
  • the subjects who are not previously treated with either drug, commence combination therapy by first receiving a treatment with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, followed by treatment with both drugs.
  • N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally in a cyclical on/off dosing regimen with a total dose of between about 5.0 mg to 22.5 mg per day for about six to fifteen days, followed by about six to eight days without administration of FHD 286, or a pharmaceutically acceptable salt thereof. The cycle is repeated multiple times, as needed.
  • Cytarabine or a pharmaceutically acceptable salt thereof, is administered in a continuous intravenous infusion of from 5 mg/m 2 /day to 100 mg/m 2 /day for a period of 10 days or less.
  • the cytarabine treatment is optionally repeated, as needed.
  • cytarabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286.
  • Subjects receiving the combination of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide and low dose less than standard dose of cytarabine can benefit from a reduction in the risk of developing differentiation syndrome and/or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide alone or less than standard dose of cytarabine alone.

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Abstract

The present disclosure features a combination therapy useful for the treatment of AML and related hematological cancers.

Description

COMBINATION THERAPY FOR THE TREATMENT OF HEMATOLOGICAL CANCERS
BACKGROUND OF THE INVENTION
The present disclosure relates to combination therapies including N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, and less than standard dose of cytarabine for the treatment of AML and related hematological cancers. The combination therapies of the invention can reduce side effects, improve outcomes, and/or reduce the dosing burden on the patient.
SUMMARY
The invention features a method of treating hematologic cancer in a subject in need thereof, the method including administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol- 2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide (aka FHD 286), or a pharmaceutically acceptable salt thereof, and (II) continuous intravenous infusion of 100 mg/m2/day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer.
In another aspect, the invention features a method including administering to the subject (i) N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, and (iii) an anti-fungal agent, or a pharmaceutically acceptable salt thereof.
In certain embodiments, (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other, or are administered within 24 hours of each other, or are administered simultaneously.
In certain embodiments, (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, and (iii) the antifungal agent, or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other, or are administered within 24 hours of each other, or are administered simultaneously.
In some embodiments, the method includes administering between about 5.0 mg and about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for six to eight days, followed by six to eight days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the method includes administering between about 5.0 mg and about 22.5 mg per day of FHD 286, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for thirteen to fifteen days, followed by six to eight days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
In particular embodiments, the method includes administering between about 5.0 mg and about 22.5 mg per day of the N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for six to fifteen days, followed by six to eight days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
In some embodiments, the method includes administering between about 5.0 mg and about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the method includes administering between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for fourteen days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
In particular embodiments, the method includes administering between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven to fourteen days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
In particular embodiments, the method includes administering 10 mg per day of the N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
In particular embodiments, the method includes administering 20 mg per day of the N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
For example, on dosing days the method can include (1) administering to the subject between about 5.0 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about 5.0 mg and about 10 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 5.0 mg and about 7.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (4) administering to the subject between about
7.5 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (5) administering to the subject between about
7.5 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (6) administering to the subject between about
7.5 mg and about 10 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (7) administering to the subject between about 10 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (8) administering to the subject between about 10 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (9) administering to the subject between about 15 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (10) administering to the subject about 5.0 mg per day, about 7.5 mg per day, about 10 mg per day, about 15 mg per day, or about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein continuous intravenous infusion of 100 mg/m2/day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered between about once a day for 10 days and about once every 4 days. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered once a day for 4 days. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered once every 4 days. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg/m2 every 12 hours. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg/m2 every 12 hours. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein the method can include administering to the subject between about 5.0 mg/m2 and about 100 mg/m2 per day of cytarabine, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein the method can include administering to the subject between about 10 mg/m2 and about 75 mg/m2 (or between about 10 mg/m2 and about 50 mg/m2) per day of cytarabine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the cytarabine is administered for 1 to 10 days, after which only FHD 286 is administered.
In certain embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein the method comprises administering to the subject a low dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (c) a dose of 2.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (d) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In certain embodiments, the cycle is performed once, twice, or three times.
In certain embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein the method comprises administering to the subject a high dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (e) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (f) a dose of 7.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In certain embodiments, the cycle is performed once, twice, or three times.
For example, on dosing days the method can include (1) administering to the subject between about 1 .0 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about
7.5 mg and about 10 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 5.0 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (4) administering to the subject between about 2.5 mg and about 10.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (5) administering to the subject between about 1 .0 mg and about 5.0 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (6) administering to the subject between about 1 .0 mg and about 2.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (7) administering to the subject between about 1 mg and about 7.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (8) administering to the subject between about 5 mg and about 7.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (9) administering to the subject between about
2.5 mg and about 7.5 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof, or can include (10) administering to the subject about 2.5 mg per day, 5.0 mg per day, about 7.5 mg per day, about 10 mg per day at least four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
In some embodiments, step (c) includes administering to the subject 2.5 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
In some embodiments, step (e) includes administering to the subject 5.0 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
In some embodiments, step (c) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
In some embodiments, step (e) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
In some embodiments, step (d) includes administering to the subject 5.0 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
In some embodiments, step (f) includes administering to the subject 7.5 mg per day four times a day of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
In some embodiments, step (d) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days. In some embodiments, step (f) includes administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
In some embodiments, the method includes, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of cytarabine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is pretreated for 1 , 2, 3, 4, 5, 6, 7, or 8 days with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy- 1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or one complete treatment cycle of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide prior to the administration of cytarabine, or a pharmaceutically acceptable salt thereof.
In some embodiments, the method includes, at the completion of combination therapy in the subject, continuing to administer to the subject the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, without further administering to the subject cytarabine, or a pharmaceutically acceptable salt thereof. For example, the cytarabine treatment can be stopped after 1 to10 days of cytarabine administrations, after which the subject receives additional cycles of the N-(1-((4- (6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-l H-pyrrole-3-carboxamide therapy.
In some embodiments, the method includes, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and/or cytarabine, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is pretreated for 1 , 2, 3, 4, 5, 6, 7, or 8 days with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, and/or cytarabine, or one complete treatment cycle of N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide and/or cytarabine prior to the administration of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
In some embodiments, the method includes, at the completion of combination therapy in the subject, continuing to administer to the subject the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and/or cytarabine, or a pharmaceutically acceptable salt thereof, without further administering to the subject anti-fungal agent, or a pharmaceutically acceptable salt thereof. For example, the anti-fungal agent treatment can be stopped after one, two, or three cycles of the low dose regimen of the anti-fungal agent or high dose regiment of the anti-fungal agent administrations, after which the subject receives additional cycles of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide therapy and/or cytarabine.
In some embodiments, the method comprises, or consists of, administering cytarabine for a period of 1 to 7 days, or 1 to 5 days.
In some embodiments, the method includes at least 21 days, 28 days, 2 months, 3 months, 4 months, or 6 months of treatment.
In some embodiments of any of the above methods, the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally.
In some embodiments of any of the above methods, cytarabine, or a pharmaceutically acceptable salt thereof, is administered intravenously.
In some embodiments of any of the above methods, the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered orally.
In some embodiments, the invention provides a method of treating hematological cancer in a subject, wherein the risk of developing differentiation syndrome is reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, alone and/or relative to treatment with cytarabine, or a pharmaceutically acceptable salt thereof, alone.
In some embodiments, the invention provides a method of treating hematological cancer in a subject, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and cytarabine, or a pharmaceutically acceptable salt thereof, alone and/or relative to treatment with the N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and cytarabine, or a pharmaceutically acceptable salt thereof, and the anti-fungal agent or a pharmaceutically acceptable salt thereof.
In some embodiments of any of the above methods, the invention provides a method of depleting or promoting differentiation of blast cells of the leukemia in a subject in need thereof, the method comprising administering to the subject (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) continuous intravenous infusion of 100 mg/m2/day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective in treating hematological cancer.
In some embodiments of any of the above methods, the hematological cancer is characterized by differentiation arrest.
In some embodiments of any of the above methods, the subject has been treated or is being treated for a hematological cancer is characterized by differentiation arrest.
In some embodiments of any of the above methods, the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.
In some embodiments, the invention provides a method of treating hematological cancer in a subject, wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome.
In some embodiments, the hematological cancer has or has been determined to have an inv(3) mutation. In some embodiments, the hematological cancer has or has been determined to have a -7/del(7q) mutation. In some embodiments, the hematological cancer has or has been determined to have a SF3B1 mutation. In some embodiments, the hematological cancer has or has been determined to have a MLLr mutation. In some embodiments, the hematological cancer has or has been determined to have a RUNX1 mutation. In some embodiments, the hematological cancer has or has been determined to have an ASXL1 mutation. In some embodiments, the hematological cancer has or has been determined to have a JAK2 mutation. In some embodiments, the hematological cancer has or has been determined to have a NRAS mutation. In some embodiments, the hematological cancer has or has been determined to have a KRAS mutation. In some embodiments, the hematological cancer has or has been determined to have a TP53 mutation. In some embodiments, the hematological cancer has or has been determined to have a TET2 mutation. In some embodiments, the hematological cancer has or has been determined to have a DNMT3 mutation.
In some embodiments, the anti-fungal agent is polyene, amphotericin B, nystatin, natamycin, flucytosine, imidazole, miconazole, clotrimazole, econazole, ketoconazole, triazole, itraconazole, fluconazole, griseofulvin, terconazole, butoconazole, ciclopirox, ciclopirox olamine, haloprogin, tolnaftate, naftifine, or terbinafine.
In some embodiments, the anti-fungal agent is a CYP3A4 inhibitor (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole).
In some embodiments, the anti-fungal agents is itraconazole, ketoconazole, posaconazole, and voriconazole.
In some embodiments, the fungal infection is aspergillosis or candidiasis.
Definitions
In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and/or”; and (iii) the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.
As used herein, the term “hematologic cancer”, refers to cancers that begin in blood-forming tissue, such as the bone marrow, or in the cells of the immune system, e.g., leukemias, lymphomas, and myelomas. Leukemias are cancers found in blood and bone marrow which are caused by rapid production of abnormal white blood cells. Lymphomas are cancers which effect the lymphatic system. Myelomas are cancers of the plasma cells. In most hematologic cancers, normal blood cell development is interrupted by uncontrolled growth of an abnormal type of blood cell. The abnormal blood cells prevent the blood from performing many of its functions. Hematologic cancers account for about 10% of all new cancer diagnoses. The 5-year relative survival rates for hematologic cancers range from about 50% to about 90%.
As used herein, the term “FHD 286” refers to N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide. As used herein, FHD 286 and the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide has the structure:
Figure imgf000009_0001
As used herein, cytarabine refers to cytosine arabinoside. As used herein, cytarabine has the structure:
Figure imgf000009_0002
As used herein, the term “anti-fungal agent” refers to an agent that when administered to a host selectively suppresses the growth of, or kills, fungi in the host, including but not limited to polyene antifungals (e.g., natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin, hamycin), imidazole antifungals (e.g., miconazole (MICATIN®, DAKTARIN®), ketoconazole (NIZORAL®, FUNGORAL®, SEBIZOLE®), clotrimazole (LOTRIMIN®, LOTRIMIN® AF, CANESTEN®), econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole (ERTACZO®), sulconazole, tioconazole), triazole antifungals (e.g., albaconazole fluconazole, itraconazole (SPORANOX® or TOLSURA®), isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole), thiazole antifungals (e.g., abafungin), allylamines (e.g., terbinafine (LAMISIL®), naftifine (NAFTIN®), butenafine (LOTRIMIN® Ultra)), echinocandins (e.g., anidulafungin, caspofungin, micafungin), and others (e.g., polygodial, benzoic acid, ciclopirox, tolnaftate (TINACTIN®, DESENEX®, AFTATE®), undecylenic acid, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, sodium bicarbonate, allicin).
As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.
As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.
As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.
The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
A “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.
As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound described herein. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e g., by reacting a free base group with a suitable organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be, e.g., acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
As used herein, the term “progression-free survival” as used herein, refers to the length of time during and after medication or treatment during which the disease being treated (e.g., cancer) does not get worse. The combination therapies of the invention can increase the likelihood of progression-free survival in a subject.
As used herein, the term “proliferation” as used in this application involves reproduction or multiplication of similar forms (cells) due to constituting (cellular) elements. The combination therapies of the invention can decrease proliferation of cancer cells.
As used herein, the term “subject” refers to any organism to which a composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
As used herein, the terms "treat," "treated," or "treating" mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. In the context of treating cancer, treatment may include slowing the spread of metastasis and/or extending progression-free survival in a population of treated subjects as compared to a population of untreated subjects. Compounds of the disclosure may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder.
As used herein, the terms “reduce the risk of a fungal infection” refers to reducing the likelihood that a patient acquires a fungal infection (e.g. aspergillosis or candidiasis) while undergoing a treatment of the invention. A reduced risk of a fungal infection is assessed for a given patient population (e.g. patients who are undergoing treatment of hematological cancer according to the methods of the invention), where the likelihood of a fungal infection for a subject receiving FHD-286, cytarabine, and an anti-fungal agent is reduced relative to patients receiving an identical treatment regimen, but without any concurrent antifungal therapy. The likelihood of fungal infection can be reduced , e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, using the methods described herein.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts graphs showing the effects of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide on cells that are dosed for 7 days. Following treatments, CD11 b expression was assessed by flow cytometry as described in Example 1. Note: in the DMSO condition, all cell lines had low levels of CD11 b positivity with the exception of the M6 line HEL92.1.7. Since CD11 b expression is lost during erythropoiesis, the observed decrease upon the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide exposure may be the result of erythrocytic differentiations in this cell line.
Fig. 2 depicts graphs showing the effect of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide on cells that are dosed for 14 days. Cells were split on days 3, 7 and 10 with drug replenishment and cells were analyzed by flow cytometry on days 3, 7, 10 and 14 for the indicated markers as described in Example 2. Values for BCL2 are mean fluorescence intensity (MFI) relative to DMSO control.
Fig. 3 depicts graphs showing HL60 cells exposed to the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide for 17 days and analyzed by flow cytometry on days 7, 14 and 16 (Ki67 days 14 and 17 only) as described in Example 3. Equal numbers of events were analyzed for all samples. Shown are 2-parameter pseudocolor plots with CD11 b MFI on the a-axis and BRG1 or Ki67 MFI on the y-axis. Values represent the percentage of cells within each quadrant. Fluorescent intensity distributions are shown as adjunct histograms.
Fig. 4 is a chart depicting the cell splitting and cell proliferation of CD11 B+ and CD11 b- cells as described in Example 3. Fig. 5 is a graph depicting viable cell densities of HL60 cells exposed to the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide for 17 days, with CD11 b+A isolation on day 7 as described in Example 3.
Fig. 6 is a series of images depicting mice bearing cell line xenographs that were treated with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide daily for 7 days, and tumors were collected for histology 4 hours after the final dose as. Studies are representative IHC images of tissues stained with an antibody specific for human CD1 1 b as described in Example 4.
Fig. 7 is a graph depicting the CD11 b IHC that was quantified on a per-cell basis by image analysis using HALO v3.3 (Indica Labs) as described in Example 5. Bars represent group mean and error bars are SEM. n = 3 mice per group.
Fig. 8 is a chart depicting the combination treatment design used in Example 6.
Fig. 9 is a table depicting the cell lines and drug concentrations that were tested in combination experiments in Example 6. Combination agent concentrations were chosen based on experimentally derived ICsovalues.
Fig. 10 is a heatmap depicting cell densities of cells exposed to the combination therapies as in Fig 12, relative to DMSO control on day 14, over a range of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide concentrations as described in Example 6.
Fig. 11 is a series of graphs depicting HL60 cells that were treated as in Fig. 1 , and analyzed by flow cytometry on days 7, 10 and 14 as described in Example 6. Equal volumes were analyzed for all samples, in order to observe effects on cell density as described in Example 6. Shown are 2-parameter pseudocolor plots with CD11 b MFI on the X-axis and Ki67 MFI on the y-axis. Values represent the percentage of cells within each quadrant. Similar results were obtained in other cell lines, and with decitabine combination.
Fig. 12 is a study design for mice inoculated with MV41 1 with the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, Cytarabine, and a combination therapy of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide and cytarabine.
Fig. 13 is a graph that depicts the tumor volume of the mice inoculated with MV411 as described in Example 7 that were treated with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide6, Cytarabine, or a combination therapy of FHD 286 and cytarabine as depicted in Figure 12.
Fig. 14 is a graph depicting the %survival of the mice inoculated with MV411 as described in Example 7 that were treated as in Figure 12 with FHD 286, Cytarabine, or a combination therapy of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide and cytarabine as in Figure 12.
DETAILED DESCRIPTION OF THE INVENTION The present disclosure features combination therapies including the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide and less than standard dose of cytarabine for the treatment of AML and related hematological cancers. The combination therapies of the invention can reduce side effects, improve outcomes, and/or reduce the dosing burden on the patient. For example, using the methods described herein the risk of developing differentiation syndrome can be reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, alone and/or relative to treatment with cytarabine, or a pharmaceutically acceptable salt thereof, alone. In some embodiments, the methods of the present disclosure result in one or more (e.g., two or more, three or more, four or more) of: (a) decrease blast count, (b) normal neutrophil counts, (c) normal platelet counts, (d) a bone marrow biopsy which reveals no clusters or collections of blast cells, (e) decreased tumor recurrence (f) increased survival of subject, (g) increased progression free survival of subject.
Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
T reating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
Exemplary hematological cancers that may be treated by the invention include, but are not limited to multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or nonHodgkin’s lymphoma.
The hematologic cancer can be characterized as having a inv(3) mutation, a -7/del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and/or a DNMT3A mutation.
N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamideThe methods of the invention include treating hematologic cancer in a subject by administering to the subject (i) N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer. In particular embodiments, the method can further include administering an antifungal agent to reduce the risk of fungal infection in the subject.
Methods for synthesizing the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)- 3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide are described in International Application No. PCT/US2021/015876, the content of which is incorporated herein by reference in its entirety. Methods of treatment of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)- 3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide are described in International Application No. PCT/US2021/015876, the content of which is incorporated herein by reference in its entirety. Methods of treating cancer by the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide are described in International Application No. PCT/US23/17829, the content of which is incorporated herein by reference in its entirety.
In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 22.5 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 15 mg per day. In some embodiments, the N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy- 1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 10 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 7.5 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 22.5 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 15 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 10 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 10 mg and about 22.5 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 10 mg and about 15 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 15 mg and about 22.5 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 5.0 mg per day. In some embodiments, the N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 7.5 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 10 mg per day. In some embodiments, the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 15 mg per day. In some embodiments, the N- (1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 22.5 mg per day.
Additional details are provided in the Examples.
Cytarabine
The methods of the invention include treating hematologic cancer in a subject by administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer. In particular embodiments, the method can further include administering an anti-fungal agent to reduce the risk of fungal infection in the subject.
Methods of treatment of cytarabine are described in "Nicholas D. Reese, Gary J. Schiller; Curr Hematol Malig Rep. 2013, 141-148," and Methods of treatment of low dose cytarabine are described in “Jehn U, Gbldel N, Vehling-Kaiser U. Low-dose cytosine arabinoside (LD-Ara C) treatment in dysmyelopoietic syndromes (DMPS) and acute myelogenous leukemia (AML). Anticancer Res. 1987. :505-8.” Cytarabine is approved for use by the FDA under the name Cytosar-U®.
In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of less than 100 mg/m2 intravenous daily for a period of 1 to 10 days. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg/m2 by continuous intravenous transfusion every 12 hours. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg/m2 by continuous intravenous transfusion every 12 hours. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered between about once a day for 4 days and about once every 4 days. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of between about 5.0 mg/m2 and about 100 mg/m2 per day (on days cytarabine is dosed). Anti-fungal Agent
The methods of the invention include treating hematologic cancer in a subject by administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer. In particular embodiments, the method can further include administering an anti-fungal agent to reduce the risk of fungal infection in the subject. In particular embodiments, the anti-fungal agent is a CYP3A4 inhibitor. For example, the anti-fungal agent can be posaconazole, which is approved for use by the FDA under the name NOXAFIL®. For example, the antifungal agent can be itraconazole, which is approved for use by the FDA under the name SPORANOX® or TOLSURA®. For example, the anti-fungal agent can be fluconazole, which is approved for use by the FDA under the name DIFLUCAN® or FUMYCIN®. For example, the anti-fungal agent can be isavuconazole, which is approved for use by the FDA under the name CRESEMBA®. For example, the anti-fungal agent can be amphotericin B, which is approved for use by the FDA under the name VFEND®. For example, the anti-fungal agent can be voriconazole, which is approved for use by the FDA under the name AMBISOME® or FUNGIZONE®. For example, the anti-fungal agent can be clotrimazole, which is approved for use by the FDA under the name LOTRIMIN®, LOTRIMIN® AF, or CANESTEN®. For example, the anti-fungal agent can be miconazole, which is approved for use by the FDA under the name MICATIN®, or DAKTARIN®. For example, the anti-fungal agent can be nystatin, which is approved for use by the FDA under the name BIO-STATIN®. For example, the anti-fungal agent can be anidulafungin (an echinocandin), which is approved for use by the FDA under the name ERAXIS® or ECALTA®. For example, the anti-fungal agent can be caspofungin (an echinocandin), which is approved for use by the FDA under the name CANCIDAS®. For example, the anti-fungal agent can be micafungin (an echinocandin), which is approved for use by the FDA under the name MYCAMINE®. For example, the anti-fungal agent can be ketoconazole, which is approved for use by the FDA under the name NIZORAL®, FUNGORAL®, SEBIZOLE®. For example, the anti-fungal agent can be sertaconazole, which is approved for use by the FDA under the name ERTACZO®. For example, the anti-fungal agent can be tolnaftate, which is approved for use by the FDA under the name TINACTIN®, DESENEX®, or AFTATE®. Other anti-fungal agents can also be used.
In some embodiments, the anti-fungal agent or a pharmaceutically acceptable salt thereof is administered as a low dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (c) a dose of 2.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (d) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-fungal agent or a pharmaceutically acceptable salt thereof is administered as a high dose regimen of the anti-fungal agent, or a pharmaceutically acceptable salt thereof the regimen comprises (c) a dose of 5.0 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof followed by (d) a dose of 7.5 mg per day at least four times a day for ten to 20 days of the anti-fungal agent, or a pharmaceutically acceptable salt thereof. In some embodiments, step (c) of the the low dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof, is administered for 14 days. In some embodiments, step (d) of the the low dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof, is administered for 14 days. In some embodiments, step (e) of the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof, is administered for 14 days. In some embodiments, step (f) of the high dose regimen of the anti-fungal agent or a pharmaceutically acceptable agent thereof, is administered for 14 days. The combination therapy can include, one, two, three, or more cycles of the low dose regimen of the anti-fungal agent administered in combination with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide treatment and/or cytarabine treatment. The combination therapy can include, one, two, three, or more cycles of the high dose regimen of the anti-fungal agent administered in combination with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide treatment and/or cytarabine treatment.
Pharmaceutical Compositions
The compounds of the present disclosure may be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include an active agent as described herein and a physiologically acceptable excipient (e.g., a pharmaceutically acceptable excipient). Formulation principles for the compounds disclosed herein may be those described, e g., in WO 2020/160180, the disclosure of which is incorporated by reference herein in its entirety.
The compounds of the disclosure may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. Preferably, the compound is administered orally.
Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary).
In one embodiment, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide may be formulated into a unit dosage form for oral administration (e.g., a capsule) as described in Table 1.
Table 1
Figure imgf000018_0001
Figure imgf000019_0001
Examples
The cell culture method, flow cytometry method and flow cytometry analysis methods are relevant to the examples below.
Cell culture method
AML cell lines were maintained in vitro as suspension cells in the media listed (Table 2) and subcultured every 3 or 4 days by diluting to 0.5 x 10s cells/mL or 0.3 x 106 cells/mL, respectively, in fresh growth medium. Cells were discarded upon reaching passage 15.
CD34+ cells were isolated from primary cell samples (Proteogenex; Inglewood, CA) using EasySep Human CD34 Positive Selection Kit II (STEMCELL Technologies [STEMCELL]; Vancouver, BC, Canada) per manufacturer protocol. The separation step was repeated a total of 4 times. The cells were resuspended in 1 mL of Stem Cell Medium and seeded at 0.5 x 1 o6 cells/mL for immediate use in the 7- day differentiation assay.
All cells were maintained at 37°C in an atmosphere of 5% CO2.
Table 2: AML Cells and Culture Conditions
Figure imgf000019_0002
Abbreviations: AML = acute myeloid leukemia; FBS = fetal bovine serum; IMDM = Iscove’s Modified
Dulbecco’s medium; MEM = minimum essential medium; pen/strep = penicillin/streptomycin; rG- CSF = recombinant granulocyte colony-stimulating factor; rGM-CSF = recombinant granulocyte macrophage stimulating factor; RPMI = Roswell Park Memorial Institute.
Flow Cytometry Method
On the day of analysis treated cells were transferred to v-bottomed plates. Medium and test article were removed by centrifuging the plate at 300 RCF for 5 minutes and discarding the supernatant. The plate was washed by adding 200 pL/well of cold FACS buffer, centrifuged at 400 RCF for 5 minutes, and then the supernatant was discarded. Cells were resuspended in viability stain diluted 1 :1000 in phosphate-buffered saline (PBS) and incubated for 15 minutes on ice in the dark. The stain was removed by centrifugation and then the plate was washed with FACS buffer as before. The plate was blocked with 50 pL/well of Fc block diluted 1 :20 in FACS buffer for 15 minutes on ice in the dark. The Fc block was removed by centrifugation and then the plate was washed with FACS buffer as before. Cells were resuspended in 50 pL surface antibody cocktail diluted in FACS buffer and incubated for 30 minutes on ice in the dark. The antibody cocktail was removed by centrifugation and then the plate was washed with FACS buffer as before. Cells were resuspended in Fix/Perm at 200 pL/well and incubated for 30 minutes on ice in the dark. The Fix/Perm was removed by centrifugation, and the plate was washed as before with 200 pL/well Perm buffer. Cells were resuspended in 50 pL/well of intracellular antibody cocktail diluted in Perm buffer and incubated for 30 minutes on ice in the dark. The Perm buffer was removed by centrifugation, and then the plate was washed as before with 200 pL/well Perm buffer. Cells were resuspended in 100 pL/well FACS buffer and analyzed on the flow cytometer. Compensation was performed per manufacturer protocols. Number of events collected were > 50,000 for the 7-day assay; 200,000 for the 14-day assays; and 150,000 for the 17-day assay. For the combination experiments, constant sample volume was analyzed to enable comparison of number of events between samples. Antibodies and key flow cytometry reagents used in the study are summarized in Table 3.
Table 3: Antibodies and Key Reagents Used for Flow Cytometric Analysis
Figure imgf000020_0001
Abbreviations: AF = Alexa Fluor; APC = allophycocyanin; CF = cyanine-based fluorescence; FBS = fetal bovine serum; PBS = phosphate-buffered saline; PE = phycoerythrin; SB = Super Bright 780.
Flow Cytometry Analysis Method
Flow cytometry data were acquired using CytExpert (v2.5; Beckman Coulter; Brea, CA), and
FlowJo (v10.7; Becton Dickinson; Franklin Lakes, NJ) was used for data analysis. First, cell gates were determined by forward scatter (FSC) versus side scatter (SSC) and debris was excluded. Single cells were then identified using SSC-Area and SSC-Height, and dead cells staining for viability dye were gated out.
For CD11 b, thresholds for positive and negative marker expression were defined using an unstained control sample. BRG1 and Ki67 expression levels were evaluated by 2-parameter plots against CD11 b. Cell populations of interest were divided into subpopulations of high or low marker expression by setting a visual threshold. For BCL-2, mean fluorescence intensity was calculated using FlowJo software.
Example 1. Seven-Day Differentiation Assay.
The AML cell lines and primary AML cells were prepared and cultured as described in cell culture methods. On Day 0, cells were seeded in 6-well plates in 3 mL at the indicated densities (Table 4). Cell cultures were not split during the assay; however, to prevent the HEL92.1 .7 and MV-4-11 cells from becoming overconfluent, the growth media were increased by 50% on Day 4, using fresh medium containing either DMSO or N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide at appropriate concentrations. After 7-day exposure to FHD-286, cells were collected and analyzed by flow cytometry as shown in Figure 1 .
Results: Treatment of AML cells with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide can result in dose-dependent upregulation of myeloid maturation marker CD11 b.
Table 4: Study Design for 7-Day Differentiation Assay
Figure imgf000021_0001
Abbreviation: DMSO = dimethyl sulfoxide.
Example 2 Fourteen-Day Differentiation Time Course Assay.
The AML cell lines were cultured as described in cell culture methods. On Day 0, cells were seeded in 6-well plates at the indicated densities (Table 5). Addition of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide6 was staggered so that all time points for a given cell line were collected and analyzed on the same day to minimize potential variations in fluorescence intensity measurements. After exposure to FHD-286, cells were collected on the days indicated and analyzed by flow cytometry as shown in Figure 2.
Results: Treatment of cells with FHD 286 can result in CD11 b upregulation and downregulation of blast proliferation and survival markers. Table 5: Study Design for 14-Day Differentiation Time Courses
Figure imgf000022_0001
Abbreviation: DMSO = dimethyl sulfoxide. Note: Medium containing DMSO or FHD-286 was replenished as necessary to maintain FHD-286 concentration.
Example 3 Seventeen-Day Differentiation Time Course and CD11b Selection.
The AML cell line HL60 was cultured as described in cell culture methods. On Day 0, cells were seeded in 6-well plates at the indicated density (Table 6). After exposure to N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, cells were collected on the days indicated and analyzed by flow cytometry as shown in Figure 4.
On Day 7, CD11 b+ and CD11 b- HL60 cells were separated using EasySep Human CD11 b Positive Selection and Depletion Kit (STEMCELL) per manufacturer protocol. In the separation step, an EasySep Magnet (STEMCELL) was used to capture CD11 b+ cells while CD11 b- cells were poured off and collected as shown in Figure 7. The cells were resuspended in medium and seeded at 0.5 x 106 cells/mL. Cells were collected on the days 14 and 17, and analyzed by flow cytometry as shown in Figure 3 and 5.
Results: Treatment of HL60 cells with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide can result in less cell proliferation, reduced cell density, and reduction of BRG1 and Ki67 protein levels in CD1 1 b+ cells compared to CD11 b- cells.
Table 6: Study Design for 17-Day Differentiation Time Course and Washout
Figure imgf000022_0002
Abbreviation: DMSO = dimethyl sulfoxide. Note: Medium containing DMSO or FHD-286 was replenished as necessary to maintain FHD-286 concentration. a Viability was assessed by propidium iodide staining on Day 17, 3 days after splitting.
Example 4 IHC on Tumor Tissue.
Mice (CB.17/SCID) were inoculated subcutaneously in the right flank with a single cell suspension of 2*106 EOL-1 human acute myeloid leukemia (AML) cells in 100 pL of sterile cold 1 x PBS. Dosing began when the range of the group mean tumor size reached 50-70 mm3 and mice were randomized into groups. N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide was administered once daily (QD) by oral gavage at a volume of 10 mL/kg, according to the study design in Table 7.
Portions of tumor tissue were collected at the 4-hour time point were fixed in 10% neutral buffered formalin (NBF) at room temperature for 24 hours, transferred to 70% ethanol. Formalin-fixed tumor samples were processed per standard procedures, embedded in paraffin, sectioned at a thickness of
4 pm, and stained with hematoxylin and eosin. Stained sections were reviewed by a board-certified pathologist for viable tumor content and tissue quality. After this quality control review, IHC was performed to detect CD11 b as shown in Figure 6.
Results: Treatment of AML cell line xenografts with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide can result in upregulation of CD11 b in vivo.
Table 7: Study Design
Figure imgf000023_0001
Example 5 IHC Image Processing and Analysis.
Whole-slide image acquisition of tumor samples from Example 4 was performed with an Aperio AT2 scanner (Leica Biosystems, Wetzlar, Hesse, Germany) at 40X magnification. HALO image analysis software (v3.3; Indica Labs, Albuquerque, New Mexico, USA) was used to select regions of viable tumor for analysis, and the Multiplex IHC module (v3.1.4) was used to quantify biomarker staining intensity on a per-cell basis as shown in Figure 7.
H-scores were derived using the following formula:
H-SCOre = (1 x %weak) + (2 x %moderate) + (3 x %strong)
Where:
%weak = the percentage of cells weakly positive for CD11 b
% moderate = the percentage of cells moderately positive for CD11 b
“/□strong = the percentage of cells strongly positive for CD11 b
Results: Treatment of AML cell line xenografts with FHD 286 can result in a dose-dependent upregulation of CD11 b in vivo.
Example 6 In Vitro Combo Study.
The AML cell lines were cultured as described in cell culture methods._To determine the concentrations of the combination agents to be used, prior to the study, each cell line was exposed to combination agent of varying doses alone for 7 days. Cell viability was assessed on Day 7 using CellTiter-Glo (Promega #G7571) per manufacturer protocol, from which half-maximal inhibitory concentration (ICso) curves were generated.
On Day 0, cells were seeded in 6-well plates at the indicated densities (Table 8) and then exposed to DMSO (control) or N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide alone for 7 days, at which time flow cytometric assessment of cell density, CD11 b, and Ki67 was performed. Combination agents (cytarabine, decitabine, or venetoclax) were then added at 3 predetermined concentrations as shown in Figure 9 (1 at the ICso value and 1 each above and below it); DMSO-only cells were exposed to each cytotoxic agent or DMSO alone for an additional 7 days, while N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide-only cells were exposed to N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide in combination with each cytotoxic agent or DMSO for an additional 7 days as shown in Figure 8. Flow cytometric analysis of cell density was performed in all cell lines on Days 7 (prior to combination agent addition) and 14 (7 days after combination agent addition) as shown in Figure 10. Flow cytometric analysis of CD11 b and Ki67 co-expression in HL60 cells was performed on Days 7, 10 (3 days after combination agent addition), and 14 as shown in Figure 11 .
Results: Treatment of AML cells with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide and standard of care cytotoxic agents can result in more reduction of the cell densities and less cell proliferation over treatment with FHD 286 alone. FHD 286 can also sensitize the AML cells to the standard cytotoxic agents. The cytarabine combination can be more effective than the venetoclax combination.
Table 8: Test Article Concentrations
Figure imgf000024_0001
Abbreviation: IC50 = half-maximal inhibitory concentration.
Note: Concentrations of combination agent were predetermined by exposing cell lines to combination agent of varying doses alone for 7 days, at which time cell viability was assessed using CellTiter-Glo reagent and IC50 curves were generated. The IC50 graphs for each combination agent alone are providedjn Appendix A.
Example 7. In vivo comparison study of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, cytarabine, and combination therapy of FHD 286 and cytarabine.
Mice (CB.17/SCID) were inoculated subcutaneously in the left flank with a single cell suspension of 10 x 106 MV-4-11 human AML cells in 100 pL with Matrigel (1 :1) in cold sterile 1 x phosphate-buffered saline for tumor development. When the mean tumor size reached approximately 83 mm3 (range 55 to 154 mm3), mice were randomized into treatment groups (Day 0) and dosed according to the study design in Table 9.
On Day 1 , tumor-bearing mice were treated with either vehicle control (20% HP-p-CD in 5 mM citrate buffer, pH 5), FHD-286 PO at 1.5 mg/kg, or cytarabine IP at 30 mg/kg. On Day 6, FHD 286 + cytarabine combination was started; mice that had initially received 5 days of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide had cytarabine IP at 30 mg/kg added. All test articles were dosed 5-days on, and then 2-days off for 21 days total (Table 9).
Tumor volume was calculated using the following formula:
Tumor volume = (length x [width] A2)/2 where length is the greater of the 2 measurements, and width is the smaller as shown in Figure 13.
Tumor growth inhibition was assessed by comparing the difference in tumor volume between control and treated groups using the following formula:
TGI = (1-T/C) x 100% where T and C are the mean relative volumes (% tumor growth) of the tumors in the treated and control groups, respectively, on a given day after tumor inoculation.
Statistical tests were performed using GraphPad Prism software (v.9.5.1 ; Boston, MA) with the level of significance set at 5%, or p < 0.05. Terminal group means were determined and assessed for statistical significance by 2-tailed unpaired t-test as shown in Figure 13.
Kaplan-Meier (log-rank test) analysis in Prism was used to compare differences between groups in the survival of mice as shown in Figure 14.
Table 9: Study Design
Figure imgf000025_0001
Abbreviations: HP-p-CD = 2-hydroxypropyl-p-cyclodextrin; IP = intraperitoneal; n/a = not applicable; PO = oral (gavage).
Example 8. A study of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide and less than standard dose of cytarabine for the treatment of acute myeloid leukemia (AML). Subjects with acute myeloid leukemia (AML) are treated with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide administered orally in combination with low dose less than standard dose of cytarabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy with both drugs initially first administered to the subjects within 24 hours of each other.
N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally in a cyclical on/off dosing regimen with a total dose of between about 5.0 mg to 22.5 mg per day for about six to fifteen days, followed by about six to eight days without administration of N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. The cycle is repeated multiple times, as needed.
Cytarabine, or a pharmaceutically acceptable salt thereof, is administered in a continuous intravenous infusion of from 5 mg/m2/day to 100 mg/m2/day for a period of 10 days or less. The cytarabine treatment is optionally repeated, as needed.
For some responsive patients less than standard dose of cytarabine treatment is discontinued after 10 days of cytarabine administrations, after which the patients continue to receive treatment with N- (1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide alone for a period of at least one month, two months, three months, or four months.
Subjects receiving the combination of FHD 286 and low dose less than standard dose of cytarabine can benefit from a reduction in the risk of developing differentiation syndrome and/or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide alone or less than standard dose of cytarabine alone.
Example 9. A study of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide and less than standard dose of cytarabine for the treatment of acute myeloid leukemia (AML) with pre-treatment of FHD 286.
Subjects with acute myeloid leukemia (AML) are treated with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide administered orally in combination with low dose less than standard dose of cytarabine administered by infusion. The subjects, who are not previously treated with either drug, commence combination therapy by first receiving a treatment with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, followed by treatment with both drugs.
N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally in a cyclical on/off dosing regimen with a total dose of between about 5.0 mg to 22.5 mg per day for about six to fifteen days, followed by about six to eight days without administration of FHD 286, or a pharmaceutically acceptable salt thereof. The cycle is repeated multiple times, as needed.
Cytarabine, or a pharmaceutically acceptable salt thereof, is administered in a continuous intravenous infusion of from 5 mg/m2/day to 100 mg/m2/day for a period of 10 days or less. The cytarabine treatment is optionally repeated, as needed.
Less than standard dose of cytarabine treatment commences following at least 1 , 2, 3, 4, 5, 6, 7, or days, or one full cycle of treatment with FHD 286.
For some responsive patients less than standard dose of cytarabine treatment is discontinued after 10 days of cytarabine administrations, after which the patients continue to receive treatment with N- (1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide alone for a period of at least one month, two months, three months, or four months.
Subjects receiving the combination of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide and low dose less than standard dose of cytarabine can benefit from a reduction in the risk of developing differentiation syndrome and/or benefit from a reduction in the number of peripheral blasts over time, relative to either treatment with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide alone or less than standard dose of cytarabine alone.
Other Embodiments
While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.
Other embodiments are in the claims.

Claims

1 . A method of treating hematologic cancer in a subject in need thereof, the method comprising administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) continuous intravenous infusion of 100 mg/m2/day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective to treat the hematologic cancer.
2. The method of claim 1 , wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (II) the cytarabine, or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.
3. The method of claim 2, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, are administered within 24 hours of each other.
4. The method of claim 3, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, are administered substantially simultaneously.
5. The method of any one of claims 1-4, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for six to eight days, followed by six to eight days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
6. The method of any one of claims 1-4, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for thirteen to fifteen days, followed by six to eight days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy- 1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
7. The method of any one of claims 1-4, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for six to fifteen days, followed by six to eight days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
8. The method of any one of claims 1-4, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
9. The method of any one of claims 1-4, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for fourteen days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
10. The method of any one of claims 1 -4, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for seven to fourteen days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
11 . The method of any one of claims 1 -4, wherein (a) 10 mg per day of the N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
12. The method of any one of claims 1-4, wherein (a) 20 mg per day of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
13. The method of any one of claims 5-10, wherein step (a) comprises administering to the subject between about 5.0 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
14. The method of claim 13, wherein step (a) comprises administering to the subject between about 5.0 mg and about 10 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
15. The method of claim 14, wherein step (a) comprises administering to the subject between about 5.0 mg and about 7.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
16. The method of any one of claims 5-10, wherein step (a) comprises administering to the subject between about 7.5 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein step (a) comprises administering to the subject between about 7.5 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
18. The method of claim 17, wherein step (a) comprises administering to the subject between about 7.5 mg and about 10 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
19. The method of any one of claims 5-10, wherein step (a) comprises administering to the subject between about 10 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
20. The method of claim 19, wherein step (a) comprises administering to the subject between about 10 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
21 . The method of claim 19, wherein step (a) comprises administering to the subject between about 15 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
22. The method of any one of claims 5-10, wherein step (a) comprises administering to the subject about 5.0 mg per day, about 7.5 mg per day, about 10 mg per day, about 15 mg per day, or about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
23. The method of any one of claims 1-22, wherein the frequency of administration of cytarabine, or a pharmaceutically acceptable salt thereof is between about once a day for 10 days and about once every
4 days.
24. The method of any one of claims 1-23, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered once a day for 10 days.
25. The method of any one of claims 1-23, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered once a day for 4 days.
26. The method of any one of claims 1-23, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered once every 4 days.
27. The method of any one of claims 1-22, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 20mg/m2 every 12 hours.
28. The method of any one of claims 1-26, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered in a continuous intravenous infusion at a dose of between 5 mg/m2 and 100 mg/m2.
29. The method of claim 28, wherein between about 10 mg/m2 and about 75 mg/m2 per day of cytarabine, or a pharmaceutically acceptable salt thereof is administered by continuous intravenous infusion.
30. The method of claim 29, wherein between about 10 mg/m2 and about 50 mg/m2 per day of cytarabine, or a pharmaceutically acceptable salt thereof is administered by continuous intravenous infusion.
31. The method of any one of claims 1-30, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of cytarabine, or a pharmaceutically acceptable salt thereof.
32. The method of claim 31 , wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, at least 7 days prior to administering to the subject a dose of the cytarabine, or a pharmaceutically acceptable salt thereof.
33. The method of claim 30, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, at least one cycle prior to administering to the subject a dose of the cytarabine, or a pharmaceutically acceptable salt thereof.
34. The method of any one of claims 1-30, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the subject the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, without further administering to the subject a dose of the cytarabine, or a pharmaceutically acceptable salt thereof.
35. The method of any one of claims 30-34, wherein the method comprises 1 to 10 days during which the cytarabine is administered to the subject.
36. The method of any one of claims 1-35, wherein the method comprises at least 21 days of treatment.
37. The method of any one of claims 1-35, wherein the method comprises at least 28 days of treatment.
38. The method of any one of claims 1-37, wherein the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally.
39. The method of any one of claims 1-37, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered intravenously.
40. The method of any one of claims 1-39, wherein the risk of developing differentiation syndrome is reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, alone and/or relative to treatment with cytarabine, or a pharmaceutically acceptable salt thereof, alone.
41 . The method of any one of claims 1-40, wherein the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.
42. The method of claim 41 , wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome.
43. The method of any one of claims 1-42, wherein the hematologic cancer has a inv(3) mutation, a -7/del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and/or a DNMT3A mutation.
44. The method of any one of claims 1-43, the method further comprising administering to the subject an anti-fungal agent or a pharmaceutically acceptable salt thereof, in an amount that is effective to reduce the risk of a fungal infection.
45. The method of claim 44, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, and (iii) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.
46. The method of claim 45, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol- 2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, and (iii) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 24 hours of each other.
47. The method of any one of claims 44-46, wherein (c) about 2.5 mg per day of the anti-fungal, or a pharmaceutically acceptable salt thereof, is administered to the subject at least four times a day for ten to 20 days, followed by (d) about 5.0 mg per day of the anti-fungal, or a pharmaceutically acceptable salt thereof, is administered to the subject at least four times a day for ten to 20 days.
48. The method of claim 47, wherein step (c) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
49. The method of claim 47 or 48, wherein step (d) comprises administering to the subject the antifungal agent or a pharmaceutically acceptable salt for fourteen days.
50. The method of any one of claims 44-46, wherein (e) about 5.0 mg per day of the anti-fungal, or a pharmaceutically acceptable salt thereof, is administered to the subject at least four times a day for ten to 20 days, followed by (f) about 7.5 mg per day of the anti-fungal, or a pharmaceutically acceptable salt thereof, is administered to the subject at least four times a day for ten to 20 days.
51 . The method of claim 50, wherein step (e) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
52. The method of claim 50 or 51 , wherein step (f) comprises administering to the subject the antifungal agent or a pharmaceutically acceptable salt for fourteen days.
53. The method of any one of claims 44-52, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
54. The method of any one of claims 44-52, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, at least 7 days prior to administering to the subject a dose of the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
55. The method of any one of claims 44-52, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, at least one cycle prior to administering to the subject a dose of anti-fungal, or a pharmaceutically acceptable salt thereof.
56. The method of any one of claims 44-52, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the subject the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, without further administering to the subject the anti-fungal agent, or a pharmaceutically acceptable salt thereof.
57. The method of any one of claims 44-56, wherein the method comprises administering 1 , 2, or 3 cycles of anti-fungal agent, or a pharmaceutically acceptable salt thereof.
58. The method of any one of claims 44-57, wherein the method comprises at least 21 days of treatment.
59. The method of any one of claims 44-58, wherein the method comprises at least 28 days of treatment.
60. The method of any one of claims 44-59, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and cytarabine, or a pharmaceutically acceptable salt thereof, alone and/or relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and cytarabine, or a pharmaceutically acceptable salt thereof, and the anti-fungal agent or a pharmaceutically acceptable salt thereof.
61 . The method of any one of claims 44-60, wherein the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, itraconazole, ketoconazole, or echinocandin.
62. The method of any one of claims 44-61 , wherein the anti-fungal agent is a CYP3A4 inhibitor.
63. The method of claim 62, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, and voriconazole.
64. The method of any one of claims 44-63, wherein the fungal infection is aspergillosis or candidiasis.
65. A method for treating hematologic cancer in a subject in need thereof, the method comprising administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, (ii) continuous intravenous infusion of 100 mg/m2/day, or less, of cytarabine,, or a pharmaceutically acceptable salt thereof, and (iii) an anti-fungal agent, or a pharmaceutically acceptable salt thereof.
66. The method of claim 65, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, and (iii) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other.
67. The method of claim 65, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, and (iii) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered within 24 hours of each other.
68. The method of claim 67, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, (ii) the cytarabine, or a pharmaceutically acceptable salt thereof, and (iii) the anti-fungal agent or a pharmaceutically acceptable salt thereof, are administered substantially simultaneously.
69. The method of any one of claims 65-68, wherein (c) about 2.5 mg per day of the anti-fungal, or a pharmaceutically acceptable salt thereof, is administered to the subject at least four times a day for ten to 20 days, followed by (d) about 5.0 mg per day of the anti-fungal, or a pharmaceutically acceptable salt thereof, is administered to the subject at least four times a day for ten to 20 days.
70. The method of claim 69, wherein step (c) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
71 . The method of claim 69 or 70, wherein step (d) comprises administering to the subject the antifungal agent or a pharmaceutically acceptable salt for fourteen days.
72. The method of any one of claims 65-71 , wherein (e) about 5.0 mg per day of the anti-fungal, or a pharmaceutically acceptable salt thereof, is administered to the subject at least four times a day for ten to 20 days, followed by (f) about 7.5 mg per day of the anti-fungal, or a pharmaceutically acceptable salt thereof, is administered to the subject at least four times a day for ten to 20 days.
73. The method of claim 72, wherein step (e) comprises administering to the subject the anti-fungal agent or a pharmaceutically acceptable salt for fourteen days.
74. The method of claim 72 or 73, wherein step (f) comprises administering to the subject the antifungal agent or a pharmaceutically acceptable salt for fourteen days.
75. The method of any one of claims 65-74, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for six to eight days, followed by six to eight days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
76. The method of any one of claims 65-74, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for thirteen to fifteen days, followed by six to eight days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
77. The method of any one of claims 65-74, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for six to fifteen days, followed by six to eight days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
78. The method of any one of claims 65-74, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
79. The method of any one of claims 65-74, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for fourteen days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
80. The method of any one of claims 65-74, wherein (a) between about 5.0 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for seven to fourteen days, followed by seven days without administration of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
81. The method of any one of claims 65-74, wherein (a) 10 mg per day of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
82. The method of any one of claims 65-74, wherein (a) 20 mg per day of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered to the subject at least once daily for seven days, followed by seven days without administration of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
83. The method of any one of claims 75-82, wherein step (a) comprises administering to the subject between about 5.0 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
84. The method of claim 83, wherein step (a) comprises administering to the subject between about 5.0 mg and about 10 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
85. The method of claim 84, wherein step (a) comprises administering to the subject between about 5.0 mg and about 7.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
86. The method of any one of claims 75-80, wherein step (a) comprises administering to the subject between about 7.5 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
87. The method of claim 86, wherein step (a) comprises administering to the subject between about 7.5 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
88. The method of claim 87, wherein step (a) comprises administering to the subject between about 7.5 mg and about 10 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
89. The method of any one of claims 75-80, wherein step (a) comprises administering to the subject between about 10 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
90. The method of claim 19, wherein step (a) comprises administering to the subject between about 10 mg and about 15 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
91 . The method of claim 90, wherein step (a) comprises administering to the subject between about 15 mg and about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
92. The method of any one of claims 75-80, wherein step (a) comprises administering to the subject about 5.0 mg per day, about 7.5 mg per day, about 10 mg per day, about 15 mg per day, or about 22.5 mg per day of the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
93. The method of any one of claims 65-92, wherein the frequency of administration of cytarabine, or a pharmaceutically acceptable salt thereof is between about once a day for 10 days and about once every 4 days.
94. The method of any one of claims 65-93, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered once a day for 10 days.
95. The method of any one of claims 65-93, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered once a day for 4 days.
96. The method of any one of claims 65-93, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered once every 4 days.
97. The method of any one of claims 65-92, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 20mg/m2 every 12 hours.
98. The method of any one of claims 65-97, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered in a continuous intravenous infusion at a dose of between 5 mg/m2 and 100 mg/m2.
99. The method of claim 98, wherein between about 10 mg/m2 and about 75 mg/m2 per day of cytarabine, or a pharmaceutically acceptable salt thereof is administered by continuous intravenous infusion.
100. The method of claim 99, wherein between about 10 mg/m2 and about 50 mg/m2 per day of cytarabine, or a pharmaceutically acceptable salt thereof is administered by continuous intravenous infusion.
101. The method of any one of claims 65-100, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of cytarabine, or a pharmaceutically acceptable salt thereof.
102. The method of claim 101 , wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, at least 7 days prior to administering to the subject a dose of the cytarabine, or a pharmaceutically acceptable salt thereof.
103. The method of claim 100, wherein the method comprises, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, at least one cycle prior to administering to the subject a dose of the cytarabine, or a pharmaceutically acceptable salt thereof.
104. The method of any one of claims 65-100, wherein the method comprises, at the completion of combination therapy in the subject, continuing to administer to the subject the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, without further administering to the subject a dose of the cytarabine, or a pharmaceutically acceptable salt thereof.
105. The method of any one of claims 100-104, wherein the method comprises 1 to 10 days during which the cytarabine is administered to the subject.
106. The method of any one of claims 65-105, wherein the N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally.
107. The method of any one of claims 65-106, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered intravenously.
108. The method of any one of claims 65-107, wherein the anti-fungal agent, or a pharmaceutically acceptable salt thereof, is administered intravenously or orally.
109. The method of any one of claims 65-108, wherein the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.
110. The method of claim 109, wherein the hematologic cancer is acute myeloid leukemia or myelodysplastic syndrome.
111. The method of any one of claims 65-1 10, wherein the hematologic cancer has a inv(3) mutation, a -7/del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and/or a DNMT3A mutation.
112. The method of any one of claims 65-1 11 , wherein the method comprises administering 1 , 2, or 3 cycles of anti-fungal agent, or a pharmaceutically acceptable salt thereof.
113. The method of any one of claims 65-1 12, wherein the method comprises administering 1 , 2, or 3 cycles of cytarabine.
114. The method of any one of claims 65-1 13, wherein the method comprises at least 21 days of treatment.
115. The method of any one of claims 65-1 14, wherein the method comprises at least 28 days of treatment.
116. The method of any one of claims 65-1 15, wherein the risk of developing a fungal infection is reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and cytarabine, or a pharmaceutically acceptable salt thererf, alone and/or relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and cytarabine, or a pharmaceutically acceptable salt thereof, and the anti-fungal agent or a pharmaceutically acceptable salt thereof.
117. The method of any one of claims 65-1 16, wherein the anti-fungal agent is posaconazole, fluconazole, isavuconazole, voriconazole, amphotericin B, clotrimazole, miconazole, nystatin, or echinocandin.
118. The method of any one of claims 65-1 16, wherein the anti-fungal agent is a CYP3A4 inhibitor.
119. The method of claim 118, wherein the CYP3A4 inhibitor is itraconazole, ketoconazole, posaconazole, and voriconazole.
120. The method of any one of claims 65-1 19, wherein the fungal infection is aspergillosis or candidiasis.
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Citations (4)

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US20100197621A1 (en) * 2009-02-05 2010-08-05 William Henry Methods of reducing the proliferation and viability of microbial agents
US20180303808A1 (en) * 2015-10-15 2018-10-25 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
WO2021236080A1 (en) * 2020-05-20 2021-11-25 Foghorn Therapeutics Inc. Methods of treating cancers
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US20100197621A1 (en) * 2009-02-05 2010-08-05 William Henry Methods of reducing the proliferation and viability of microbial agents
US20180303808A1 (en) * 2015-10-15 2018-10-25 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US20220125776A1 (en) * 2019-03-20 2022-04-28 Sumitomo Dainippon Pharma Oncology, Inc. Treatment of Acute Myeloid Leukemia (AML) with Venetoclax Failure
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