WO2019222130A1 - Traitement combiné avec des conjugués anticorps-médicament et des inhibiteurs flt3 - Google Patents

Traitement combiné avec des conjugués anticorps-médicament et des inhibiteurs flt3 Download PDF

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Publication number
WO2019222130A1
WO2019222130A1 PCT/US2019/032090 US2019032090W WO2019222130A1 WO 2019222130 A1 WO2019222130 A1 WO 2019222130A1 US 2019032090 W US2019032090 W US 2019032090W WO 2019222130 A1 WO2019222130 A1 WO 2019222130A1
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subject
quizartinib
antibody
day
pharmaceutically acceptable
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PCT/US2019/032090
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WO2019222130A8 (fr
Inventor
Russell Walker
Krystal WATKINS
Patrick Zweidler-Mckay
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Immunogen, Inc.
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Publication of WO2019222130A1 publication Critical patent/WO2019222130A1/fr
Publication of WO2019222130A8 publication Critical patent/WO2019222130A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Definitions

  • Acute myeloid leukemia is associated with the accumulation of abnormal blast cells in bone marrow.
  • Acute myeloid leukemia is one of the most common types of leukemia among adults. In the United States alone, over 18,000 new cases of AML are identified each year, and more than 10,000 deaths are associated with AML.
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • AML patients fail to achieve complete remission.
  • the majority of patients with AML relapse within 3-5 years from diagnosis.
  • AML patients harboring a FLT3 Internal Tandem Duplication (FLT3-ITD) have a poor diagnosis and high rates of relapse following treatment with standard agents.
  • the leukocyte differentiation antigen CD33 is a 364 amino acid transmembrane glycoprotein with sequence homology to members of the sialoadhesin family, including myelin- associated glycoprotein and CD22, as well as sialoadhesin itself (S. Peiper, 2002, Leucocyte Typing VII, White Cell Differentiation, Antigens, Proceedings of the Seventh International Workshop and Conference, Oxford University Press, p. 777).
  • CD33 appears to be highly specific to the hematopoietic compartment, with strong expression by myeloid precursor cells (S. Peiper, 2002). It is expressed by myeloid progenitor cells such as CFU-GEMM, CFU-GM, CFU-G and BFU-E,
  • CD33 is expressed by clonogenic, acute
  • AML myelogenous leukemia
  • pluripotent hematopoietic stem cells that give rise to "blast colonies" in vitro (Leary, A. G. et al, 1987, Blood 69:953) and that induce hematopoietic long-term marrow cultures (Andrews R. G. et al, 1989, J. Exp. Med.
  • ADCs antibody drug conjugates
  • DGN462 novel DNA alkylator
  • Quizartinib also known as AC220, is a small molecule FLT3 receptor tyrosine kinase inhibitor that is currently being evaluated in clinical trials for the treatment of
  • Quizartinib can be in its neutral form or free base form (structure shown below) or a salt form, such as a pharmaceutically acceptable salt form.
  • a dihydrochloride salt of quizartinib can be used in the methods of the present invention.
  • the present invention provides a method for treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and a therapeutically effective amount of an ADC of Formula (I):
  • the double line ⁇ between N and C represents either a single bond or a double bond, provided that when it is a double bond, X is absent and Y is hydrogen; and when it is a single bond, X is hydrogen and Y is -SO 3 H.
  • the term“Ab” is an anti-CD33 antibody or antigen-binding fragment thereof.
  • “Ab” is an anti-CD33 antibody or antigen-binding fragment comprising a heavy chain variable region (V H )
  • CDR complementary determining region
  • V H V H CDR2 sequence of SEQ ID NO:2
  • V H CDR3 V H CDR3 sequence of SEQ ID NO:3
  • V L light chain variable region
  • r is an integer from 1 to 10.
  • ADC of Formula (I) is also provided in the present invention.
  • the present invention also provides the use of an ADC of Formula (I) or a
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) is administered to the subject prior to the administration of the ADC.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC are administered to the subject concurrently.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) is administered to the subject after the administration of the ADC.
  • the ADC of the present invention (e.g., IMGN779) is
  • the doses“mg/kg” for the ADC of the present invention are based on antibody.
  • about 0.39-0.7 mg/kg of the ADC of the present invention is administered to the subject about weekly. In another embodiment, about 0.39 mg/kg. 0.54 mg/kg or 0.7 mg/kg of the ADC of the present invention (e.g., IMGN779) is administered to the subject about weekly.
  • about 0.3 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.35 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.39 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.4 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.45 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8,15, and 22 ofa 28- day cycle. In one embodiment, about 0.50 mg/kg of the ADC of the present invention (e.g ., IMGN779) is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.54 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.55 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.60 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.65 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.70 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.75 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • administration of the ADC of the present invention results in a decrease in peripheral blood blasts.
  • administration of the ADC of the present invention results in a decrease in peripheral blood blasts within 3-8 days of the first dose.
  • administration of the ADC of the present invention results in a decrease in peripheral blood blasts after a second dose.
  • administration of the ADC of the present invention results in at least a 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% decrease in peripheral blood blasts after a second dose.
  • administration of the ADC of the present invention achieves a peripheral blood blasts percentage of
  • administration of the ADC of the present invention results in a decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 40% decrease in bone marrmv blasts.
  • administration of the ADC of the present invention results in at least a 45% decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 48% decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 59% decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 96% decrease in bone marrow blasts.
  • administration of the ADC of the present invention e.g., IMGN779) achieves a bone marrow blasts percentage of about 5%, 4%, 3%, 2%, 1%, or less than 1%.
  • quizartinib dihydrochloride salt is used in the methods of present invention.
  • a total daily dose of 20-60 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the subject.
  • a total daily dose of 30-60 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the subject.
  • a total daily dose of 60 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the subject.
  • a total daily dose of 40 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the subject.
  • a total daily dose of 20 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the patient.
  • a total daily dose of 30 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the patient.
  • quizartinib or dihydrochloride salt thereof is administered to the subject daily.
  • the subject is treated with quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the antibody-drug conjugate for 5 days, a week, 10 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 8 months, 10 months or 1 year.
  • quizartinib or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt
  • the antibody-drug conjugate for 5 days, a week, 10 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 8 months, 10 months or 1 year.
  • the subject is treated with quizartinib or a pharmaceutically acceptable salt thereof every day (e.g. once a day) for 14 days. In another embodiment, the subject is treated with quizartinib or a pharmaceutically acceptable salt thereof every day (e.g. once a day) for 28 days.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC is used as a front line therapy for treating AML in a fit AML patient.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC is used as a front line therapy for treating AML in an unfit AML patient.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC is used as a second line therapy for treating AML in a fit AML patient.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC is used as a second line therapy for treating AML in an unfit AML patient.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC is used as a second line therapy for treating refractory or relapse AML in a fit AML patient.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC is used as a second line therapy for treating refractory or relapse AML in a fit AML patient.
  • ADC dihydrochloride salt
  • the ADC is used as a second line therapy for treating refractory or relapse AML in an unfit AML patient.
  • the method further comprises administering to the subject a therapeutically effective amount of an additional chemotherapeutic agent or therapy.
  • the additional chemotherapeutic agent is cytarabine, idarubicin, daunorubicin, or a combination thereof.
  • the methods of the present invention further comprises administering to the subject 100-200 mg/m / day of cytarabine for 7 days and 12 mg/m / day of idarubicin or 60-90 mg/m / day of daunorubicin for 3 days.
  • cytarabine is administered on day 1 to day 7 and idarubicin or daunorubicin is administered on day 1 to day 3 (7+3 dosing regimen).
  • quizartinib or a pharmaceutically acceptable salt thereof e.g., quizartinib dihydrochloride salt
  • the methods of the present invention further comprises administering to the subject 3000 mg/m / day of cytarabine every other day (high dose regimen).
  • cytarabine is administered to the subject on days 1, 3 and 5.
  • quizartinib or a pharmaceutically acceptable salt thereof is administered to the subject once a day on day 6 to day 19.
  • the method of present invention described herein is for treating a fit FLT3-ITD AML patient and the method further comprises admistrating to the patient 100- 200 mg/m / day of cytarabine for 7 days and 12 mg/m / day of idarubicin or 60-90 mg/m / day of daunorubicin for 3 days.
  • cytarabine is administered on day 1 to day 7 and idarubicin or daunorubicin is administered on day 1 to day 3 (7+3 dosing regimen).
  • the method of present invention described herein is for treating a fit FLT3-ITD patient and the method further comprises admistrating to the patient 3000 mg/m / day of cytarabine every other day (high dose regimen).
  • cytarabine is administered to the subject on days 1, 3 and 5.
  • the method of the present invention further comprises administering to the subject a therapeutically effective amount of azacitidine. In certain embodiments, the method of the present invention further comprises administering to the subject azacitidine to treat the unfit FLT3-ITD AML patient population. In certain embodiments, azacitidine is administered to the subject daily with a total daily dose of 75 mg/m 2 . In certain embodiments, azacitidine is administered to the subject through
  • azacitidine is administered to the patient daily for 7 days.
  • the method of the present invention described herein is for treating an unfit FLT3-ITD AML patient and the method further comprises administering to the patient a therapeutically effective amount of azacitidine.
  • a daily totoal of 75 mg/m 2 azacitidine is administered to the patient.
  • azacitidine is administered to the patient daily for 7 days.
  • the method further comprises administering stem cell transplantation to the subject.
  • the cancer is selected from the group consisting of leukemia, lymphoma and myeloma.
  • the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell lineage acute lymphoblastic leukemia (B ALL), T-cell lineage acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), myelodysplastic syndrome (MDS), basic plasmacytoid DC neoplasm (BPDCN) leukemia, non-Hodgkin lymphomas (NHL), mantle cell lymphoma, eosinophilic leukemia, B myelomonocytic leukemia and Hodgkin’s leukemia (HL).
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • B ALL B-cell lineage acute lymphoblastic leukemia
  • T-ALL T-cell lineage acute lympho
  • the cancer is chemotherapy sensitive. In another embodiment, the cancer is chemotherapy resistant. In yet another embodiment, the cancer is acute myeloid leukemia (AML). In yet another embodiment, the AML is refractory or relapse acute myeloid leukemia. In yet another embodiment, the AML is newly diagnosed. In one embodiment, the AML is characterized by overexpression of P-glycoprotein, overexpression of EVI1 , a p53 alteration, DNwIT3A mutation, FLT3 internal tandem duplication (ITD), a complex karyotype, decreased expression in BRCA1, BRCA2, or PALB2, or mutations in BRCA1, BRCA2, or PALB2. In one embodiment, the subject being treated with the methods described herein is a fit AML subject.
  • the subject being treated with the methods described herein is an unfit AML subject.
  • the AML is characterized by FLT3-ITD.
  • the AML is characterized by overexpression of P-glycoprotein, overexpression of EVI1 , a p53 alteration, DNwIT3A mutation, FLT3 internal tandem duplication, a complex karyotype, decreased expression in BRCA1, BRCA2, or PALB2, or mutations in BRCA1, BRCA2, or PALB2.
  • the MDS is a high risk MDS.
  • the method of the present invention further comprises detecting the
  • the method of the present invention further comprises detecting the
  • the method of the present invention further comprises detecting the
  • the method of the present invention further comprises detecting the
  • the sample obtained from the subject/patient is a blood sample or a buccal swab.
  • At least 20% of blasts from the cancer are CD33 -positive as measured by flow cytometry.
  • the administration results in saturation of free-CD33.
  • the administration results in a decrease in peripheral blood blasts.
  • administration results in a decrease in bone marrow blasts.
  • the subject is a human.
  • the cancer is chacterized by RAS mutation.
  • the cancer is chacterized by a TP53 mutation.
  • the cancer is chacterized by an IDH mutation.
  • the cancer is chacterized by an FLT3 mutation.
  • the anti-CD33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:7 or 9.
  • the anti-CD33 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:8 or 10.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the sequence of SEQ ID NO:9 and a light chain variable region comprising the sequence of SEQ ID NO: 10.
  • the anti-CD33 antibody comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 11 and a light chain having the amino acid sequence set forth in SEQ ID NO: 12.
  • the antibody is huMy9-6.
  • the antibody is a CDR-grafted or resurfaced antibody.
  • ADC1, ADC2, IMGN779 (defined below) and pharmaceutically acceptable salts thereof, are specific examples of ADCs that can be used in the disclosed methods of treatment.
  • Pharmaceutically acceptable salts are those which are suitable for use in humans and animals without undue toxicity, irritation, and allergic response.
  • suitable salts for the ADC of Formula (I), ADC1, ADC2, and IMGN779 are disclosed in U.S. Patent No. 8,765,740, the entire teachings of which are incorporated herein by reference.
  • the pharmaceutically acceptable salt for the ADCs of Formula (I), ADC1, ADC2, and IMGN779 is the sodium or potassium salt.
  • the ADC of Formula (I) is represented by the following formula:
  • a fourth embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising: i) a therapeutically effective amount of quizartinib; ii) a therapeutically effective amount of an ADC of Formula (I), ADC1, ADC2, or IMGN779 or a pharmaceutically acceptable salt thereof; and iii) a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable salt for the ADCs of Formula (I), ADC1, ADC2, and IMGN779 is the sodium or potassium salt.
  • the ADC of Formula (I) is ADC2’.
  • FIG. 1 shows in vivo efficacy of the combination of IMGN779 (single dose) and quizartinib (QDx5) in MV4-11 subcutaneous model.
  • FIG. 2 shows in vivo efficacy of the combination of IMGN779 (QWx3) and quizartinib (QDxl4) in MV4-11 disseminated model.
  • FIG. 3 shows in vivo efficacy of the combination of IMGN779 (QWx3) and quizartinib (QDxl4) in Molm-l3 disseminated model.
  • FIG. 4 shows in vitro dose dependent response in MV4-11 cells treated with increasing doses of quizartinib.
  • FIGs. 5A-5B show anti- apopto tic, pro-survival/proliferative, and DNA repair signaling in Molm-l3 cells (FIG. 5A) and MV4-11 (FIG. 5B) treated with the combination of IMGN779 and quizartinib.
  • FIGs. 6A-6C show increased apoptosis in Molm-l3 cells (FIGs. 6A and 6C) and MV4-11 (FIGs. 6B and 6C) treated with the combination of IMGN779 and quizartinib.
  • FIGs. 7A-7C show increased in dead cells in Molm-l3 cells (FIGs. 7A and 7C) and MV4-11 (FIGs. 7B and 7C) treated with the combination of IMGN779 and quizartinib.
  • the present invention features methods of treating patients with cancers, e.g., a hematologic cancer, such as AML, by administering a combination of a CD33 -targeted ADC containing an indo lino-benzodiazepine dimer cytotoxic payload, in particular, the ADC of Formula (I), and quizartinib (or a pharmaceutically acceptable salt thereof, e.g.,
  • the invention is based, at least in part, on the discovery that the combination of quizartinib and IMGN779 is significantly more active in vivo against AML xenografts in mice than the individual agents alone. Definitions
  • IMGN779 is a CD33-targeted ADC comprising the huMy9-6 antibody, also termed as Z4681A antibody (i.e., an antibody comprising the heavy chain CDR1-3 having the sequence of SEQ ID NOs:l-3, respectively and the light chain CDR1-3 having the sequence of SEQ ID NOs:4-6; an antibody comprising the heavy chain variable region having the sequence of SEQ ID NO:9 and a light chain variable region having the sequence of SEQ ID NO: 10; or an antibody comprising the heavy chain sequence having the sequence of SEQ ID NO: 11 and the light chain sequence having the sequence of SEQ ID NO: 12), conjugated to DGN462, via a cleavable disulfide linker.
  • IMGN779 may be represented as ADC3 as depicted below:
  • composition comprising ADC3 is between 2.4 and 3.0; or IMGN779 may also be represented as ADC4 as depicted below:
  • composition comprising ADC4 is between 2.4 and 3.0; or IMGN779 can be a combination of ADC3 and ADC4 or pharmaceutically acceptable salts thereof.
  • IMGN779 is a sodium salt of ADC3 and is represented by the following formula, wherein the average value for r in a composition comprising sodium salt of ADC3 is between 2.4 and 3.0:
  • P-glycoprotein is meant a polypeptide or fragment thereof having at least about 85% amino acid sequence identity to the human sequence provided at NCBI Accession No. NP_00l035830 and conferring multi-drug resistance on a cell in which it is expressed.
  • sequence of an exemplary human P-glycoprotein is provided below:
  • CD33 protein is meant a polypeptide or fragment thereof having at least about 85% amino acid sequence identity to the human sequence provided at NCBI Accession No. CAD36509 and having anti-CD33 antibody binding activity.
  • An exemplary human CD33 amino acid sequence is provided below:
  • FLT3 protein By“FLT3 protein,”“FLT3 polypeptide,”“FLT3,”“FLT-3 Receptor,” or“FLT-3R” is meant a polypeptide or fragment thereof having at least about 85%, 90%, 95%, 99% or 100% amino acid sequence identity to the human sequence of FLT3 tyrosine kinase receptor, also referred to as FLK-2 and STK-l, provided at NCBI Accession No. NP_004l l0 and having tyrosine kinase activity, including receptor tyrosine kinase activity.
  • the FLT3 amino acid sequence is the human FLT3 amino acid sequence provided below:
  • FLT3-ITD is meant a FLT3 polypeptide having internal tandem duplication(s) including but not limited to simple tandem duplication(s) and/or tandem duplication(s) with insertion.
  • FLT3 polypeptides having internal tandem duplications are activated FLT3 variants (e.g., constitutively autophosphorylated).
  • the FLT3-ITD includes tandem duplications and/or tandem duplication(s) with insertion in any exon or intron including, for example, exon 11, exon 11 to intron 11, and exon 12, exon 14, exon 14 to intron 14, and exon 15.
  • FLT3-ITD The internal tandem duplication mutation
  • WT wild-type FLT3
  • analog is meant a molecule that is not identical, but has analogous functional or structural features.
  • a polypeptide analog retains the biological activity of a corresponding naturally-occurring polypeptide, while having certain biochemical
  • An analog may include an unnatural amino acid.
  • substantially identical is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein).
  • a reference amino acid sequence for example, any one of the amino acid sequences described herein
  • nucleic acid sequence for example, any one of the nucleic acid sequences described herein.
  • such a sequence is at least 60%, more preferably 80% or 85%, and more preferably 90%, 95% or even 99% identical at the amino acid level or nucleic acid to the sequence used for comparison.
  • Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705,
  • BLAST, BESTFIT, GAP, or PILEUP/PRETTYBOX programs Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and/or other modifications.
  • Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine;
  • a BLAST program may be used, with a probability score between e 3 and e 100 indicating a closely related sequence.
  • An“anti-CD33 antibody or antigen-binding fragment thereof’ refers to an antibody or antigen-binding fragment thereof that specifically binds to CD33.
  • telomere binding an antibody or fragment thereof that recognizes and binds a polypeptide of interest, but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample, which naturally includes a polypeptide of the invention.
  • A“subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, sheep, pigs, horses, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • the term "therapeutically effective amount” refers to an amount of ADC, or quizartinib or other drug effective to "treat” a disease or disorder in a subject or mammal.
  • the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the tumor size or burden; inhibit (i.e., slow to some extent and in a certain embodiment, stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and in a certain embodiment, stop) tumor metastasis; inhibit, to some extent, tumor growth; relieve to some extent one or more of the symptoms associated with the cancer; and/or result in a favorable response such as increased progression- free survival (PFS), disease-free survival (DFS), or overall survival (OS), complete response (CR), partial response (PR), or, in some cases, stable disease (SD), a decrease in progressive disease (PD), a reduced time to progression (TTP), or any combination thereof. See the definition herein of "treating”. To the extent the drug can prevent growth and/or kill
  • a subject is successfully "treated” for cancer according to the methods of the present invention if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells; a reduction in the tumor size; inhibition of or an absence of cancer cell infiltration into peripheral organs including, for example, the spread of cancer into soft tissue and bone; inhibition of or an absence of tumor metastasis; inhibition or an absence of tumor growth; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; reduction in tumorigenicity, tumorigenic frequency, or tumorigenic capacity, of a tumor; reduction in the number or frequency of cancer stem cells in a tumor; differentiation of tumorigenic cells to a non-tumorigenic state; increased progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), a reduced time to progression (TTP), or any combination thereof.
  • PFS progression-free survival
  • PFS, DFS, and OS can be measured by standards set by the National Cancer Institute and the U.S. Food and Drug Administration for the approval of new drugs. See Johnson et al, (2003) J. Clin. Oncol. 21(7): 1404-1411
  • PFS progression-free survival
  • progression free survival refers to the situation wherein a patient remains alive, without the cancer getting worse.
  • TTP Time to Tumor Progression
  • a “complete response” or “complete remission” or “CR” indicates the disappearance of all signs of tumor or cancer in response to treatment. This does not always mean the cancer has been cured.
  • A“complete remission with incomplete hematologic recovery” or“CRi” refers to a patient response characterized by ⁇ 5% of blasts in the bone marrow but with blood counts (e.g., neutrophils and platelets) that are not within normal range.
  • a “partial response” or “PR” refers to a decrease in the size or volume of one or more tumors or lesions, or in the extent of cancer in the body, in response to treatment.
  • Stable disease refers to disease without progression or relapse. In stable disease there is neither sufficient tumor shrinkage to qualify for partial response nor sufficient tumor increase to qualify as progressive disease.
  • Progressive disease refers to the appearance of one more new lesions or tumors and/or the unequivocal progression of existing non-target lesions. Progressive disease can also refer to a tumor growth of more than 20 percent since treatment began, either due to an increases in mass or in spread of the tumor.
  • Disease-free survival refers to the length of time during and after treatment that the patient remains free of disease.
  • OS “Overall Survival” refers to the time from patient enrollment to death or censored at the date last known alive. OS includes a prolongation in life expectancy as compared to naive or untreated individuals or patients. Overall survival refers to the situation wherein a patient remains alive for a defined period of time, such as one year, five years, etc., e.g., from the time of diagnosis or treatment. In a population of patients, overall survival is measured as mean overall survival (mOS).
  • mOS mean overall survival
  • A“refractory” cancer is one that progresses even though an anti-tumor treatment, such as a chemotherapy, is administered to the cancer patient.
  • A“relapsed” patient is one who has signs or symptoms of cancer after remission.
  • the patient has relapsed after adjuvant or neoadjuvant therapy.
  • line of treatment or “line of therapy” refer to a therapeutic regimen that can include but is not limited to surgery, radiation therapy, chemotherapy, differentiating therapy, biotherapy, immune therapy, or the administration of one or more anti-cancer agents (e.g., a cytotoxic agent, an anti-proliferative compound, and/or an angiogenesis inhibitor).
  • anti-cancer agents e.g., a cytotoxic agent, an anti-proliferative compound, and/or an angiogenesis inhibitor.
  • first-line treatment refers to the preferred and standard initial treatment for a particular condition, e.g., a given type and stage of cancer. These treatments differ from “second-line” therapies, which are tried when a first-line therapy does not work adequately. “Third-line” therapies are tried when a first-line therapy and a second-line therapy do not work adequately.
  • the term“maintenance therapy” refers to therapy that is given to help keep cancer from coming back after it has disappeared following the initial therapy.
  • administer refers to methods that may be used to enable delivery of the ADCs or quizartinib to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like.
  • AD is administered intravenously.
  • fit AML is meant a subject having AML who is eligible for intensive therapy.
  • the measures for determining a subject with fit AML includes, e.g., physical performance (as determined by e.g., the Eastern Cooperative Oncology Group performance status (ECOG PS), the Karnofsky performance status (KPS), and the short physical performance battery (SPPB)), comorbid conditions (as determined by the Charlson comorbidity index (CCI) or the hematopoietic cell transplantation- specific comorbidity index (HCT-CI)), cognitive function, or prognostic models (including but not limited to, cytogenetic group, age, white blood cell count, LDH, type of AML).
  • a fit AML subject is a subject at the age of 60 or under the age of 60.
  • unfit AML is meant a subject having AML who is ineligible for intensive therapy.
  • the measures for determining a subject with unfit AML includes, e.g., physical performance (as determined by e.g., the Eastern Cooperative Oncology Group performance status (ECOG PS), the Karnofsky performance status (KPS), and the short physical performance battery (SPPB)), comorbid conditions (as determined by the Charlson comorbidity index (CCI) or the hematopoietic cell transplantation- specific comorbidity index (HCT-CI)), cognitive function, or prognostic models (including but not limited to, cytogenetic group, age, white blood cell count, LDH, type of AML).
  • an unfit AML subject is a subject over the age of 60.
  • the term“about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • the antibody in the ADC of formula (I), ADC1, ADC2 or ADC2’ is an anti-CD33 antibody, in particular, huMy9-6 antibody.
  • My9-6 is the murine anti-CD33 antibody from which huMy9-6 is derived.
  • My9-6 is fully characterized with respect to the germline amino acid sequence of both light and heavy chain variable regions, amino acid sequences of both light and heavy chain variable regions, the identification of the CDRs, the identification of surface amino acids and means for its expression in recombinant form. See, for example,
  • variable region is used herein to describe certain portions of antibody heavy chains and light chains that differ in sequence among antibodies and that cooperate in the binding and specificity of each particular antibody for its antigen. Variability is not usually evenly distributed throughout antibody variable regions. It is typically concentrated within three segments of a variable region called complementarity-determining regions (CDRs) or hypervariable regions, both in the light chain and the heavy chain variable regions. The more highly conserved portions of the variable regions are called the framework regions.
  • CDRs complementarity-determining regions
  • hypervariable regions hypervariable regions
  • the more highly conserved portions of the variable regions are called the framework regions.
  • the variable regions of heavy and light chains comprise four framework regions, largely adopting a beta- sheet configuration, with each framework region connected by the three CDRs, which form loops connecting the beta-sheet structure, and in some cases forming part of the beta- sheet structure.
  • the CDRs in each chain are held in close proximity by the framework regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of
  • the "constant" region is not involved directly in binding an antibody to an antigen, but exhibits various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.
  • Humanized antibodies may be produced using several technologies, such as resurfacing and CDR grafting.
  • the resurfacing technology uses a combination of molecular modeling, statistical analysis and mutagenesis to alter the non-CDR surfaces of antibody variable regions to resemble the surfaces of known antibodies of the target host.
  • the CDRs of My9-6 were identified by modeling and their molecular structures were predicted. Humanized My9-6 antibodies were then prepared and have been fully characterized as described, for example in U.S. Patent Nos. 7,342, 110 and 7,557, 189, which are incorporated herein by reference.
  • the amino acid sequences of the light and heavy chains of a number of huMy9-6 antibodies are described, for example, in U.S. Patent No. 8,337,855 and U.S. Patent Publication No.8, 765, 740, each of which is incorporated herein by reference.
  • the amino acid sequences shown in Table 2 describe the huMy9-6 antibody of the invention.
  • antibody or “antibodies” of the present invention may include both the full length muMy9-6 and huMy9-6 antibodies as well as epitope-binding fragments of these antibodies.
  • antibodies or epitope-binding fragments thereof comprising at least one complementarity-determining region having an amino acid sequence selected from the group consisting of SEQ ID NOs: l-6, and having the ability to bind CD33.
  • antibodies or epitope-binding fragments thereof comprising at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises three complementarity determining regions having amino acid sequences represented by SEQ ID NOs: l-3, respectively, and wherein said light chain variable region comprises three complementarity determining regions having amino acid sequences represented by SEQ ID NOs:4-6, respectively.
  • antibodies having a heavy chain variable region that has an amino acid sequence that shares at least 90% sequence identity with an amino acid sequence represented by SEQ ID NO:7, more preferably 95% sequence identity with SEQ ID NO:7, most preferably 100% sequence identity with SEQ ID NO:7.
  • antibodies having a light chain variable region that has an amino acid sequence that shares at least 90% sequence identity with an amino acid sequence represented by SEQ ID NO:8, more preferably 95% sequence identity with SEQ ID NO:8, most preferably 100% sequence identity with SEQ ID NO:8.
  • antibodies are provided having a humanized (e.g., resurfaced, CDR-grafted) heavy chain variable region that shares at least 90% sequence identity with an amino acid sequence represented by SEQ ID NO:9, more preferably 95% sequence identity with SEQ ID NO:9, most preferably 100% sequence identity with SEQ ID NO:9.
  • a humanized (e.g., resurfaced, CDR-grafted) heavy chain variable region that shares at least 90% sequence identity with an amino acid sequence represented by SEQ ID NO:9, more preferably 95% sequence identity with SEQ ID NO:9, most preferably 100% sequence identity with SEQ ID NO:9.
  • antibodies having a humanized (e.g., resurfaced, CDR- grafted) light chain variable region that shares at least 90% sequence identity with an amino acid sequence corresponding to SEQ ID NO: 10, more preferably 95% sequence identity with SEQ ID NO: 10, most preferably 100% sequence identity with SEQ ID NO: 10.
  • the antibody includes conservative mutations in the framework region outside of the CDRs.
  • antibody fragments include any portion of an antibody that retains the ability to bind to CD33, generally termed “epitope-binding fragments.”
  • antibody fragments preferably include, but are not limited to, Fab, Fab' and F(ab') 2 , Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a V L or V H domain.
  • Epitope-binding fragments, including single-chain antibodies may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CHI, CH2, and CH 3 domains.
  • Such fragments may contain one or both Fab fragments or the F(ab') 2 fragment.
  • the antibody fragments contain all six CDRs of the whole antibody, although fragments containing fewer than all of such regions, such as three, four or five CDRs, are also functional.
  • the functional equivalents may be or may combine members of any one of the following immunoglobulin classes: IgG, IgM, IgA, IgD, or IgE, and the subclasses thereof.
  • Fab and F(ab') 2 fragments may be produced by proteolytic cleavage, using enzymes such as papain (Fab fragments) or pepsin (F(ab') 2 fragments).
  • the single-chain FVs (scFvs) fragments are epitope-binding fragments that contain at least one fragment of an antibody heavy chain variable region (VH) linked to at least one fragment of an antibody light chain variable region (VL) ⁇
  • the linker may be a short, flexible peptide selected to assure that the proper three-dimensional folding of the (VL) and (VH) regions occurs once they are linked so as to maintain the target molecule binding- specificity of the whole antibody from which the single-chain antibody fragment is derived.
  • the carboxyl terminus of the (VL) or (VH) sequence may be covalently linked by a linker to the amino acid terminus of a complementary (VL) and (VH) sequence.
  • Single-chain antibody fragments may be generated by molecular cloning, antibody phage display library or similar techniques well known to the skilled artisan. These proteins may be produced, for example, in eukaryotic cells or prokaryotic cells, including bacteria.
  • the epitope-binding fragments of the present invention can also be generated using various phage display methods known in the art.
  • phage display methods functional antibody domains are displayed on the surface of phage particles which carry the
  • phage can be utilized to display epitope-binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine).
  • Phage expressing an epitope-binding domain that binds the antigen of interest can be selected or identified with antigen, e.g., using labeled CD33 or CD33 bound or captured to a solid surface or bead.
  • Phage used in these methods are typically filamentous phage including Fd and M13 binding domains expressed from phage with Fab, Fv or disulfide- stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein.
  • the regions of the phage encoding the fragments can be isolated and used to generate the epitope-binding fragments through expression in a chosen host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, using recombinant DNA technology, e.g., as described in detail below.
  • a chosen host including mammalian cells, insect cells, plant cells, yeast, and bacteria, using recombinant DNA technology, e.g., as described in detail below.
  • recombinantly produce Fab, Fab' and F(ab') 2 fragments can also be employed using methods known in the art such as those disclosed in PCT publication WO 92/22324; Mullinax et al, 1992, BioTechniques l2(6):864-869; Sawai et al, 1995, AJRI34:26-34; and Better et al, 1988, Science 240:1041-1043; said references incorporated by reference in their entireties.
  • Examples of techniques which can be used to produce single-chain Fvs and antibodies include those described in U.S. Pat. Nos.
  • Antibodies with homologous sequences are those antibodies with amino acid sequences that have sequence identity or homology with amino acid sequence of the murine My9-6 and humanized My9-6 antibodies of the present invention. Preferably identity is with the amino acid sequence of the variable regions of the murine My9-6 and humanized My9-6 antibodies of the present invention.
  • sequence identity and “sequence homology” as applied to an amino acid sequence herein is defined as a sequence with at least about 90%, 91%,
  • a chimeric antibody is one in which different portions of an antibody are derived from different animal species.
  • an antibody having a variable region derived from a murine monoclonal antibody paired with a human immunoglobulin constant region are known in the art. See, e.g., Morrison, 1985, Science 229:1202; Oi et al, 1986, BioTechniques 4:214; Gillies et al, 1989, J.
  • the CDRs are of primary importance for epitope recognition and antibody binding. However, changes may be made to the residues that comprise the CDRs without interfering with the ability of the antibody to recognize and bind its cognate epitope. For example, changes that do not affect epitope recognition, yet increase the binding affinity of the antibody for the epitope may be made. Thus, also included in the scope of the present invention are improved versions of both the murine and humanized antibodies, which also specifically recognize and bind CD33, preferably with increased affinity.
  • equivalents of the primary antibody have been generated by changing the sequences of the heavy and light chain genes in the CDR1, CDR2, CDR3, or framework regions, using methods such as oligonucleotide-mediated site-directed mutagenesis, cassette mutagenesis, error-prone PCR, DNA shuffling, or mutator- strains of E. coli (Vaughan, T. J. et al, 1998, Nature Biotechnology, 16, 535-539; Adey, N. B. et al, 1996, Chapter 16, pp. 277-291, in "Phage Display of Peptides and Proteins", Eds. Kay, B. K. et al, Academic Press).
  • the antibody sequences described herein can be used to develop anti-CD33 antibodies with improved functions, including improved affinity for CD33.
  • Improved antibodies also include those antibodies having improved characteristics that are prepared by the standard techniques of animal immunization, hybridoma formation and selection for antibodies with specific characteristics.
  • the present invention provides a method of treating a cancer, e.g., a hematologic cancer, in a subject comprising administering to the subject a cancer, e.g., a hematologic cancer, in a subject comprising administering to the subject a
  • the double line ⁇ between N and C represents either a single bond or a double bond, provided that when it is a double bond, X is absent and Y is hydrogen; and when it is a single bond, X is hydrogen and Y is -SO3H.
  • the term“Ab” is an anti- CD33 antibody or antigen-binding fragment thereof comprising a heavy chain variable region (V H ) complementary determining region (CDR)l sequence of SEQ ID NO:l, a V H CDR2 sequence of SEQ ID NO:2, and a V H CDR3 sequence of SEQ ID NO:3, and a light chain variable region (V L ) CDR1 sequence of SEQ ID NO:4, a V L CDR2 sequence of SEQ ID NO:5, and a V L CDR3 sequence of SEQ ID NO:6.
  • V H heavy chain variable region
  • CDR complementary determining region
  • V L light chain variable region
  • the term“r” is an integer from 1 to 10.
  • ADC1, ADC2, ADC2’, IMGN779, and pharmaceutically acceptable salts thereof are specific examples of ADCs that can be used in the disclosed methods of treatment.
  • ADC1, ADC2 or ADC2 for ADC of formula (I), ADC1, ADC2 or ADC2’ or a
  • the anti-CD33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:7 or 9.
  • the anti-CD33 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:8 or 10.
  • the antibody portion of the ADC of formula (I), ADC1, ADC2 or ADC2’ is an anti-CD33 antibody comprising a heavy chain variable region having at least about 90%, 91%, 92%, 93%, or 94% sequence identity, and more preferably at least about 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:9 and a light chain variable region having at least about 90%, 91%, 92%, 93%, or 94% sequence identity, and more preferably at least about 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 10.
  • the antibody portion of the ADC of formula (I), ADC1, ADC2 or ADC2’ comprises a heavy chain variable region comprising the sequence of SEQ ID NO:9 and a light chain variable region comprising the sequence of SEQ ID NO: 10.
  • the antibody portion of the ADC of formula (I), ADC1, ADC2 or ADC2’ is an anti-CD33 antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 11 and a light chain having the amino acid sequence set forth in SEQ ID NO: 12.
  • the antibody portion of the ADC of formula (I), ADC1, ADC2 or ADC2’ is the huMy9-6 antibody, also termed as“Z4681A.”
  • the antibody is a CDR-grafted or resurfaced antibody.
  • the CD33-targeted ADC is IMGN779.
  • IMGN779 comprises the huMy9-6 antibody, also termed as Z4681A antibody, conjugated to DGN462, via a cleavable disulfide linker.
  • IMGN779 may be represented as depicted below as ADC3:
  • IMGN779 may also be represented below as ADC4:
  • IMGN779 may also be a combination of
  • the ADC of the present invention (e.g., IMGN779) is
  • about 0.39-0.7 mg/kg of the ADC of the present invention is administered to the subject about weekly. In another embodiment, about 0.39 mg/kg. 0.54 mg/kg or 0.7 mg/kg of the ADC of the present invention (e.g., IMGN779) is administered to the subject about weekly.
  • about 0.3 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.35 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.39 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.4 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.45 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8,15, and 22 ofa 28- day cycle.
  • about 0.50 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.54 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.55 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.60 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.65 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.70 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • about 0.75 mg/kg of the ADC of the present invention is administered to the subject about weekly, e.g., on days 1, 8, 15, and 22 of a 28- day cycle.
  • administration of the ADC of the present invention results in a decrease in peripheral blood blasts. In some embodiments, administration of the ADC of the present invention (e.g., IMGN779) results in a decrease in peripheral blood blasts within 3-8 days of the first dose. In some embodiments, administration of the ADC of the present invention (e.g ., IMGN779) results in a decrease in peripheral blood blasts after a second dose.
  • administration of the ADC of the present invention results in at least a 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% decrease in peripheral blood blasts after a second dose.
  • administration of the ADC of the present invention achieves a peripheral blood blasts percentage of
  • administration of the ADC of the present invention results in a decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 40% decrease in bone marrmv blasts.
  • administration of the ADC of the present invention results in at least a 45% decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 48% decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 59% decrease in bone marrow blasts.
  • administration of the ADC of the present invention results in at least a 96% decrease in bone marrow blasts.
  • administration of the ADC of the present invention e.g., IMGN779) achieves a bone marrow blasts percentage of about 5%, 4%, 3%, 2%, 1%, or less than 1%.
  • the conjugate described herein may comprise 1-10 cytotoxic benzodiazepine dimer compounds, 2-9 cytototoxic benzodiazepine dimer compounds,
  • a composition comprising the conjugates described herein may comprise an average of 1-10 cytotoxic benzodiazepine dimer molecule per antibody molecule.
  • the average ratio of cytotoxic benzodiazepine dimer molecule per antibody molecule is referred to herein as the Drug Antibody Ratio (DAR).
  • the DAR is between 2-8, 3-7, 3-5, 2.5-3.5 or 2.4-3.0.
  • the DAR is 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4 or 3.5.
  • the DAR is 2.8.
  • the cytotoxic benzodiazepine dimer compound and the conjugates described herein can be prepared according to methods described in U.S. Patent Nos 8,765,740 and 9,353,127, for example, but not limited to, paragraphs [0395]-[0397] and [0598]-[0607], Figures 1, 15, 22, 23, 38-41, 43, 48, 55 and 60, and Examples 1, 6, 12, 13, 20, 21, 22, 23, 26-30 and 32 of U.S. Patent No. 8,765,740 and paragraphs [0007]-[0105], [0l97]-[029l], Figures 1-11, 16, 28 and Examples 1-7, 9-13, 15 and 16 of U.S. Patent No. 9,353,127.
  • cation refers to an ion with positive charge.
  • the cation can be
  • the cation is monovalent.
  • monovalent e.g ., Na + , K + , etc.
  • bi- valent e.g ., Ca 2+ , Mg 2+ , etc.
  • multi- valent e.g ., Al 3+ etc.
  • the cation is monovalent.
  • phrases“pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate“mesylate,” ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate ( i.e ., l,l’-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts,
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure.
  • a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • the pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • pharmaceutically acceptable salt is a sodium or a potassium salt.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid
  • an inorganic acid such as hydro
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • Quizartinib also known as AC220, is a chemotherapeutic agent in clinical development for treating acute myeloid leukemia (AML). It can be given orally.
  • it can be administered through intravenous infusion or other suitable administration routes.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) can be used as maintenance therapy for newly diagnosed FLT3- ITD positive AML
  • a pharmaceutically acceptable salt of quizartinib is used in the methods of the invention described herein.
  • quizartinib dihydrochloride salt is used in the methods of the invention described herein.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) can be administered to the subject in a total daily dose of 12-200 mg, 12-100 mg, 15-90 mg, or 15- 60 mg.
  • quizartinib dihydrochloride salt can be administered to the subject in a total daily dose of 12- 200 mg, 12-100 mg, 20-90 mg, 20-60 mg, 30-60 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg or 90 mg.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) can be administerd to the subject in a total daily dose of 30mg, 40mg or 60 mg.
  • a total daily dose of 30-60 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the subject.
  • a total daily dose of 60 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the subject.
  • a total daily dose of 40 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the subject.
  • a total daily dose of 30 mg of quizartinib dihydrochloride salt or an equivalent dose of quizartinib or a pharmaceutically acceptable thereof is administered to the patient.
  • quizartinib or dihydrochloride salt thereof is administered to the subject daily.
  • a“total daily dose” in the context of quizartinib or a
  • pharmaceutically acceptable salt thereof refers to the total amount of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) that can be administered to the subject within one day.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) can be administered to the subject every day (e.g., once a day) for 7 days in a 21 day cycle (i.e. treatment regimen), for 7 days in a 28 day cycle, for 14 days in a 28 day cycle, for 14 days in a 14 day cycle, for 28 days in a 28 day cycle.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) can be administered to the subject for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles with an optional rest period.
  • the rest period can be 1, 2, 3, 4, 5, 6, 7 days, a week, 2 weeks, 3 weeks, or 1 month.
  • the rest period is 14 days.
  • the rest period is 28 days
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) can be administered to the subject every day (e.g. once per day) for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 15 weeks, about 18 weeks, about 26 weeks, for 5 days to 1 month, for 14 days to 32 days, for 7 days, for 14 days or for 28 days,
  • 30 mg, 40 mg or 60 mg of quizartinib can be administered to the subject every day (e.g., once a day) for 7 days in a 28 day cycle ( i.e . treatment regimen), for 14 days in a 28 day cycle, or for 28 days in a 28 day cycle.
  • the methods of the present invention described above further comprises administering to the subject a therapeutically effective amount of one or more additional chemotherapeutic agents or therapies.
  • the one or more additional chemotherapeutic agents or therapies are cytarabine, idarubicin, daunorubicin, autologous stem cell transplantation, allogeneic stem cell transplantation or a combination thereof.
  • the methods of the present invention described above further comprises administering to the subject a therapeutically effective amount of cytarabine, idarubicin, daunorubicin, or a combination thereof.
  • the methods of the present invention described above further comprises administering to the subject cytarabine in a total daily dose of 20-3000 mg/m , 20-50 mg/m 2 , 50-200mg/m 2 , 200-500mg/m 2 , 500-l000mg/m 2 , or 1000-3000 mg/m 2 .
  • cytarabine can be administered to the subject daily or every other day. In certain embodiments, cytarabine can be administered for 5 days, 6 days, a week, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, etc.
  • cytarabine can be administered to the subject in a total daily dose of 110 mg/m every day for 7 days (e.g., on days 1-7 of the treatment regimen).
  • a high dose (e.g., 3,000 mg/m total daily dose) of cytarabine can be administered to the subject every other day (e.g., on days 1, 3 and 5 of the treatment regimen).
  • a low dose e.g., 20 mg/m or 30 mg/m total daily dose
  • cytarabine can be administered to the subject every day for 10 days, for example, on days 1-
  • the low dose is 20 mg/m total daily dose.
  • the low dose is 30 mg/m total daily dose.
  • an intermediate dose (e.g., 100-200 mg/m total daily dose, 100 mg/m total daily dose or 200 mg/m total daily dose) of cytarabine can be administered to the subject every day for 7 days, for example on days 1-7 of the treatment regimen.
  • the methods of the present invention described above further comprises administering to the subject 12 mg/m /day of idarubicin. In certain embodiments, the methods of the present invention described above further comprises administering to the subject 45-60 mg/m 2 / day or 60-90 mg/m 2 /day of daunorubicin. In certain embodiments, the idarubicin or daunorubicin can be administered to the subject every day for 3 days (e.g., on days 1-3 of the treatment regimen).
  • the combination of the CD33-targeted ADC and quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) of the present invention can be used in combination with standard induction therapy and/or consolidation therapy for treating AML.
  • the AML induction therapy comprises administering to the subject (a) 100-200 mg/m of cytarabine for 7 days, and (b) 12 mg/m / day of idarubicin for 3 days or 60-90 mg/m / day of daunorubicin for 3 days.
  • the cytarabine is administered on day 1 to day 7 and idarubicin or daunorubicin is administered on day 1 to day 3 (also known as 7+3 treatment regimen).
  • the method of present invention described herein is for treating a fit FLT3-ITD AML patient and the method further comprises admistrating to the patient 100- 200 mg/m / day of cytarabine for 7 days and 12 mg/m / day of idarubicin or 60-90 mg/m / day of daunorubicin for 3 days.
  • cytarabine is administered on day 1 to day 7 and idarubicin or daunorubicin is administered on day 1 to day 3 (7+3 dosing regimen).
  • the method of present invention described herein is for treating a fit FLT3-ITD patient and the method further comprises admistrating to the patient 3000 mg/m / day of cytarabine every other day (high dose regimen).
  • cytarabine is administered to the subject on days 1, 3 and 5.
  • the method of present invention comprises administering to the subject (a) 100 or 200 mg/m of cytarabine on day 1 to day 7, (b) 12 mg/m / day of idarubicin on day 1 to day 3 or 60-90 mg/m / day (e.g., 60 mg/m / day) of daunorubicin on day 1 to day 3, (c) quizartinib or quizartinib dihydrochloride salt in a total daily dose of 40 mg (or an equivalent dose of quizartinib or a pharmaceutically acceptable salt thereof, e.g., 35.4 mg of quizartinib free base) on day 8 to day 21; and (d) a therapeutically effective amount of IMGN779.
  • the AML consolidation therapy comprises administering to the subject 3000 mg/m cytarabine every other day, e.g., on days 1, 3 or 5.
  • the method of present invention comprises administered to the subject (a) 3000 mg/m cytarabine on days 1, 3 or 5, (b) quizartinib or quizartinib dihydrochloride salt in a total daily dose of 40 mg (or an equivalent dose of quizartinib or a pharmaceutically acceptable salt thereof, e.g., 35.4 mg of quizartinib free base) on day 6 to day 19.
  • the subject has received allogeneic stem cell transplantation.
  • the combination of the CD33-targeted ADC and quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) of the present invention can be used as maintenance therapy for treating AML.
  • the combination of the CD33 -targeted ADC and quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) of the present invention can be used as maintenance therapy for treating newly diagnosed FLT3-ITD positive AML.
  • a total daily dose of 30-60 mg of quizartinib or quizartinib dihydrochloride salt is administered to the subject for 28 days.
  • the method of the present invention further comprises administering to the subject a therapeutically effective amount of azacitidine. In certain embodiments, the method of the present invention further comprises administering to the subject azacitidine to treat the unfit FLT3-ITD AML patient population. In certain embodiments, azacitidine is administered to the subject daily with a total daily dose of 75 mg/m 2 . In certain embodiments, azacitidine is administered to the subject through
  • azacitidine is administered to the patient daily for 7 days.
  • the method of the present invention described herein is for treating an unfit FLT3-ITD AML patient and the method further comprises administering to the patient a therapeutically effective amount of azacitidine.
  • a daily total of 75 mg/m 2 azacitidine is administered to the patient.
  • azacitidine is administered to the patient daily for 7 days.
  • the present invention provides methods for treating patients with cancer, in particular a hematologic cancer, such as AML, by administering a combination of a CD33 -targeted ADC and quizartinib.
  • a“hematologic cancer” is a cancer that begins in blood-forming tissue, such as the bone marrow, or in the cells of the immune system.
  • hematologic cancer examples include leukemia, lymphoma and multiple myeloma.
  • cancers which can be treated using the disclosed methods include leukemia, lymphoma and myeloma.
  • the cancer can be chemotherapy sensitive; alternatively, the cancer can be chemotherapy resistant.
  • cancers which can be treated using the disclosed methods include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute pro-myelocytic leukemia (APL), myelodysplastic syndromes (MDS), acute monocytic leukemia (AMOL), hairy cell leukemia (HCL), T-cell pro lymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, small lymphocytic lymphoma (SLL), Hodgkin's lymphomas (Nodular sclerosis, Mixed cellularity, Lymphocyte-rich, Lymphocyte depleted or not depleted, and Nodular lymph
  • lymphoma/leukemia T cell prolymphocytic leukemia, T cell large granular lymphocytic leukemia, Aggressive NK cell leukemia, Adult T cell leukemia/lymphoma, extranodal NK/T cell lymphoma (nasal type), enteropathy-type T cell lymphoma, hepatosplenic T cell lymphoma, blastic NK cell lymphoma, mycosis fungoides / sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma (unspecified), anaplastic large cell lymphoma), and multiple myeloma (plasma cell myeloma Kahler's disease).
  • the cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell lineage acute lymphoblastic leukemia (B-ALL), T-cell lineage acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), myelodysplastic syndrome (MDS), basic plasmacytoid DC neoplasm (BPDCN) leukemia, non-Hodgkin lymphomas (NHL), mantle cell lymphoma, eosinophilic leukemia, B myelomonocytic leukemia and Hodgkin’s leukemia (HL).
  • the cancer is acute myeloid leukemia (AML).
  • the subject is a fit AML subject; while in other
  • the subject is an unfit AML subject.
  • the acute myeloid leukemia is refractory or relapsed acute myeloid leukemia.
  • the invention provides treatment of patients with multi-drug resistant AML.
  • P-glycoprotein (PGP) also known as MDR1
  • MDR multidrug resistance
  • AML cells expressing PGP are, at least to some degree, resistant to treatment with conventional chemotherapeutic s.
  • the invention also provides methods for treating PGP-expressing AML.
  • the invention also provides methods of treating a hematologic cancer having at least one negative prognostic factor, e.g., overexpression of P-glycoprotein, overexpression of EVI1, a p53 alteration, DNMT3A mutation, FLT3 internal tandem duplication (FLT3-ITD), and/or complex karyotype.
  • a hematologic cancer having at least one negative prognostic factor, e.g., overexpression of P-glycoprotein, overexpression of EVI1, a p53 alteration, DNMT3A mutation, FLT3 internal tandem duplication (FLT3-ITD), and/or complex karyotype.
  • the invention also provides methods of treating a hematologic cancer having decreased expression in BRCA1, BRCA2, or PALB2 or mutations in BRCA1, BRCA2, or PALB2.
  • Also within the scope of the invention is the selection of patients having at least one negative prognostic factor and/or decreased expression or mutations in BRCA1, BRCA2, or PALB2 prior to administration of the combination of a CD33 targeted ADC described herein and quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt).
  • the invention provides methods of treating AML in a patient with FLT3-ITD mutation.
  • the AML is refractory or relapsed AML.
  • the patient is a AML fit patient. In another embodiment, the patient is a AML unfit patient.
  • the CD33-targeted ADC is administered to a subject in a pharmaceutically acceptable dosage form.
  • ADCs may be administered intravenously as a bolus or by continuous infusion over a period of time, by intramuscular, subcutaneous, intra- articular, intrasynovial, intrathecal, oral, topical, or inhalation routes.
  • Pharmaceutical compositions containing ADCs are administered by intratumoral, peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects.
  • a pharmaceutically acceptable dosage form will generally include a pharmaceutically acceptable agent such as a carrier, diluent, and excipient.
  • a pharmaceutically acceptable agent such as a carrier, diluent, and excipient.
  • suitable carriers, diluents and/or excipients include: (1) Dulbecco's phosphate buffered saline, pH about 7.4, containing about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v NaCl), and (3) 5% (w/v) dextrose.
  • the ADC and quizartinib are administered in combination.
  • a combination therapy is meant to encompass administration of the two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, simultaneous administration in the same composition and administration at different times in separate compositions.
  • quizartinib or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt
  • the ADC can be administered to the subject concurrently.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) is administered to the subject before the administration of the ADC (e.g., IMGN779).
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) is administered to the subject after the administration of the ADC (e.g., IMGN779).
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC (e.g., IMGN779) are administered to the subject on the same day.
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) is administered to the subject 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days before the administration of the ADC (e.g., IMGN779).
  • quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) is administered to the subject after the administration of the ADC (e.g., IMGN779), e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after the administration of the ADC (e.g., IMGN779).
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC (e.g., IMGN779) can be used as a front line therapy for treating AML in a fit AML subject.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., IMGN779) can be used as a front line therapy for treating AML in a fit AML subject.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC (e.g., IMGN779) can be used for treating relapsed or refractory AML in a fit AML subjects.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC (e.g., IMGN779) can be used as a second line therapy for treating relapsed or refractory AML in a fit AML subjects.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC (e.g., IMGN779) can be used as a front line therapy for treating AML in an unfit AML subject.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., IMGN779) can be used as a front line therapy for treating AML in an unfit AML subject.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC (e.g., IMGN779) can be used for treating relapsed or refractory AML in an unfit AML subjects.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC (e.g., IMGN779) can be used as a second line therapy for treating relapsed or refractory AML in an unfit AML subjects.
  • the combination of quizartinib (or a pharmaceutically acceptable salt thereof, e.g., dihydrochloride salt) and the ADC (e.g., IMGN779) can be used for treating AML subjects who are FLT3-ITD positive.
  • the ADCs used in the disclosed methods and pharmaceutical compositions can be supplied as a solution or a lyophilized powder that are tested for sterility and for endotoxin levels.
  • Suitable pharmaceutically acceptable carriers, diluents, and excipients are well known and can be determined by those of ordinary skill in the art as the clinical situation warrants.
  • suitable carriers, diluents and/or excipients include: (1) Dulbecco’s phosphate buffered saline, pH about 7.4, containing or not containing about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v NaCl), and (3) 5% (w/v) dextrose; and may also contain an antioxidant such as tryptamine and a stabilizing agent such as Tween 20.
  • compositions that include an ADC, quizartinib, and typically at least one additional substance, such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings.
  • mice were weighed twice a week and were monitored for clinical signs throughout the duration of the study. The measured end-point was survival. Animals were euthanized when hind leg paralysis was present, body weight decreased by >20% of pre treatment weight, a visible tumor appeared, or any signs of distress were visible.
  • Tumor Growth Delay is calculated as T-C, where T is the median survival time (in days) of a treated group and C is the median survival time (in days) of the vehicle control group.
  • Anti-tumor activity was evaluated as per NCI standards for disseminated models: ILS ⁇ 25% is inactive, ILS > 25% is minimum active, ILS > 40% is active, and ILS > 50% is highly active.
  • mice were weighed twice a week and were monitored for clinical signs throughout the duration of the study. Animals were euthanized when hind leg paralysis was present, body weight decreased by >20% of pre-treatment weight, tumor ulceration occurred, or when any signs of distress were visible.
  • Tumor volumes were measured one to two times weekly in three dimensions using a caliper.
  • Activity was assessed as described in Bissery et al., Cancer Res. 51: 4845-52 (1991).
  • T/C Value (Median tumor volume of the treated / Median tumor volume of the control) x 100% .
  • Tumor volume was determined simultaneously for the treated (T) and the vehicle control (C) groups when tumor volume of the vehicle control reached a predetermined size (Bissery et al., Cancer Res. 51: 4845-52 (1991). The daily median tumor volume of each treated group was determined, including tumor- free mice (0 mm ). According to NCI standards, a T/C ⁇ 42% is the minimum level of anti-tumor activity. A T/C ⁇ 10% is considered a high anti-tumor activity level.
  • a disseminated tumor model was used as described in the protocol below.
  • mice Female C.B17 SCID mice were each inoculated with 1x10 MV4-11 cells, a human AML cell line, in 100 m ⁇ of 50% Matrigel: 50% serum free medium (v/v) subcutaneously in the right flank. On day 15, which is 24 h prior to conjugate administration for groups receiving conjugate treatment (either alone or in combination with quizartinib), all the mice in these treatment groups were injected intraperitoneally with 400 mg/kg of non-targeted chKTI antibody to block Fc receptors on the Mv4-l 1 AML cells, preventing non-specific up-take of conjugate.
  • conjugate treatment either alone or in combination with quizartinib
  • mice receiving conjugate received a second injection of 100 mg/kg of chKTI antibody again to block Fc receptors.
  • mice were randomized into the study groups based on tumor volume.
  • mice received a single intravenous injection, in the lateral tail vein, of either vehicle, or 5 pg/kg (by DGN462; 0.253 mg/kg by huCD33 Ab), or 10 pg/kg (by DGN462; 0.506 mg/kg by huCD33 Ab) IMGN779, or 5 pg/kg (by DGN462; 0.289 mg/kg by Ab) Ab-DGN462 non-targeted control conjugate, or 10 pg/kg (by DGN462; 0.577 mg/kg by Ab) Ab-DGN462 non-targeted control conjugate.
  • Quizartinib administration was also initiated on day 16; and the mice receiving quizartinib were given a single oral dose of 5 mg/kg quizartinib on each day of days 16, 17, 18, 19 and 20 post-cell implantation. In the combination group, the mice received administrations of both IMGN779 and quizartinib as outlined above.
  • a single dose of either 5 pg/kg or 10 pg/kg of IMGN779 was active and highly active, respectively, in this study, resulting in T/C values of 17% and 0%, respectively; and 0/6 and 4/6 long-term complete regressions (CRs), respectively, at the end of the study (day 120).
  • a single dose of either 5 pg/kg or 10 pg/kg of Ab-DGN462 was inactive, resulting in T/C values of 101% and 81%, respectively; and 0/6 long-term complete regressions (CRs) in each of these two treatment groups at the end of the study (day 120).
  • a disseminated tumor model was used as described in the protocol below.
  • mice Female NOD SCID mice were pre-treated with 150 mg/kg cyclophosphamide to partially ablate bone marrow in order to improve the engraftment of MV4- 11 cells.
  • the cyclophosphamide (Sigma, C0768, Lot # MKBX1822V) was dissolved in 0.9% NaCl and was administered intraperitoneally to the mice on day -3 and day -2 prior to MV4-11 cell inoculation.
  • mice were each injected intravenously in the lateral tail vein with 3xl0 6 MV4-11 cells, a human AML cell line, in 100 pl of serum- free medium on day 0 in the study.
  • mice On day 21 post-MV4-l 1 inoculation, mice were randomized into the study groups based on body weight.
  • the mice were injected intraperitoneally with 150 mg/kg of non-targeted chKTI antibody to block Fc receptors on the MV4-11 AML cells, preventing non-specific up-take of conjugate.
  • Quizartinib was given once a day (QD) at a dose of 1 mg/kg for 14 consecutive days (xl4) according to two different quizartinib dosing schedules, either alone or in combination with IMGN779. These two different quizartinib dosing schedules were: either i) days 21 to 34 (referred to as“Day 21” for quizartinib); or ii) days 25 to 38 (referred to as“Day 25” for quizartinib).
  • Single-agent groups were included that received a QW x 3 dosing regimen of 1 pg/kg by DGN462 (0.0556 mg/kg by antibody) of a non-targeted control conjugate, Ab-DGN462, according to two different dosing schedules which corresponded to the two different dosing schedules of IMGN779. These two different Ab-DGN462 dosing schedules were: either i) days 21, 28 and 35 (referred to as“Day 21” for Ab-DGN462, Group I); or ii) days 25, 32 and 39 (referred to as“Day 25” for Ab-DGN462, Group J).
  • mice were treated with a combination regimen of IMGN779 (QW x 3) and 1 mg/ kg quizartinib (QD x 14), according to one of three different dosing schedules for combining the two drugs: either i) the Day 21 schedule for IMGN779 and the Day 21 schedule for quizartinib (Group F), or ii) the Day 21 schedule for IMGN779 and the Day 25 schedule for quizartinib (Group G), or iii) the Day 25 schedule for IMGN779 and the Day 21 schedule for quizartinib (Group H).
  • Quizartinib single-agent administered at 1 mg/kg, QD x 14, according to either the Day 21 schedule (Group B) or the Day 25 schedule (Group C), was minimally active in this study, resulting in a tumor growth delay (T-C value) of 17 days and a 39.5% ILS (Increased Life Span) for each of the quizartinib single-agent regimens compared to vehicle treatment.
  • T-C value tumor growth delay
  • ILS Increased Life Span
  • Each of the two different treatment schedules for single-agent IMGN779 were minimally active in this study, resulting in the following T-C values and %ILS: i) the Day 21 schedule (Group D) generated a T-C of 17 days and a 39.5% ILS; ii) the Day 25 schedule (Group E) generated a T-C of 11 days and a 25.6 % ILS.
  • the three different quizartinib plus IMGN779 combination therapy regimens outlined above resulted in the following anti-tumor activity: i) a T-C value of 57.5 days and a 133.7% ILS (highly active) for the combination of the IMGN779 Day 21 schedule plus the quizartinib Day 21 schedule (Group F); ii) a T-C value of 56 days and a 130.2% ILS (highly active) for the combination of the IMGN779 Day 21 schedule plus the quizartinib Day 25 schedule (Group G); iii) a T-C value of 31 days and a 72% ILS (highly active) for the combination of the IMGN779 Day 25 schedule plus the quizartinib Day 21 schedule (Group H).
  • Each of the three combination therapy regimens obtained a clear survival benefit over the corresponding single-agent treatment groups.
  • Single-agent treatment with a QWx3 regimen of 1 pg/kg (by DGN462) of the non- targeted Ab-DGN462 control conjugate beginning treatment on Day 21 (Group I) resulted in a T-C value of 9.5 days and in a 22.1% ILS, which was inactive.
  • Single-agent treatment with a QWx3 regimen of 1 pg/kg (by DGN462) of Ab-DGN462 beginning treatment on Day 25 (Group J) was minimally active, resulting in a T-C value of 11 days and a 25.6% ILS. Table 4.
  • a disseminated tumor model was used as described in the protocol below.
  • Female NOD SCID mice were pre-treated with 150 mg/kg cyclophosphamide to partially ablate bone marrow in order to improve the engraftment of Mo lm- 13 cells.
  • the cyclophosphamide (Sigma, C0768, Lot # MKBX1822V) was dissolved in 0.9% NaCl and was administered intraperitoneally to the mice on day -2 prior to Molm-l3 cell inoculation on day 0.
  • mice were each injected intravenously in the lateral tail vein with 2xl0 5 Molm-l3 cells, a human AML cell line, in 100 pl of serum- free medium on day 0 in the study.
  • mice On day 6 post-Molm-l3 inoculation, mice were randomized into the study groups based on body weight.
  • the mice were injected intraperitoneally with 150 mg/kg of non-targeted chKTI antibody to block Fc receptors on the Molm-l3 AML cells, preventing non-specific up-take of conjugate.
  • Quizartinib was given once a day (QD) at a dose of 3 mg/kg for 14 consecutive days (xl4) according to two different quizartinib dosing schedules, either alone or in combination with IMGN779. These two different quizartinib dosing schedules were: either i) days 7 to 20 (referred to as“Day 7” for quizartinib); or ii) days 10 to 23 (referred to as“Day 10” for quizartinib).
  • Single-agent groups were included that received a QW x 3 dosing regimen of 0.2 pg/kg by DGN462 (0.011 mg/kg by antibody) of a non-targeted control conjugate, Ab- DGN462, according to two different dosing schedules which corresponded to the two different dosing schedules of IMGN779. These two different Ab-DGN462 dosing schedules were: either i) days 7, 14 and 21 (referred to as“Day 7” for Ab-DGN462, Group I); or ii) days 10, 17 and 24 (referred to as“Day 10” for Ab-DGN462, Group J).
  • mice were treated with a combination regimen of IMGN779 (QW x 3) and 3 mg/ kg quizartinib (QD x 14), according to one of three different dosing schedules for combining the two drugs: either i) the Day 7 schedule for IMGN779 and the Day 7 schedule for quizartinib (Group F), or ii) the Day 7 schedule for IMGN779 and the Day 10 schedule for quizartinib (Group G), or iii) the Day 10 schedule for IMGN779 and the Day 7 schedule for quizartinib (Group H).
  • Quizartinib single-agent administered at 3 mg/kg, QD x 14, according to either the Day 7 schedule (Group B) or the Day 10 schedule (Group C), was highly active or active, respectively, in this study, resulting in a tumor growth delay (T-C value) of either 11.5 or 9 days, respectively, and either a 54.8 or a 42.9% ILS (Increased Life Span), respectively, compared to vehicle treatment.
  • T-C value tumor growth delay
  • the two different treatment schedules of single-agent IMGN779 either highly active or minimally active, respectfully, in this study, resulting in the following T-C values and %ILS: i) the Day 7 schedule (Group D) generated a T-C of 15 days and a 71.4% ILS (highly active); ii) the Day 10 schedule (Group E) generated a T-C of 6.5 days and a 31 % ILS (minimally active).
  • the three different quizartinib plus IMGN779 combination therapy regimens outlined above resulted in the following anti-tumor activity: i) a T-C value of >105 days and a >500% ILS (highly active) for the combination of the IMGN779 Day 7 schedule plus the quizartinib Day 7 schedule (Group F); ii) a T-C value of 20.5 days and a 97.6% ILS (highly active) for the combination of the IMGN779 Day 7 schedule plus the quizartinib Day 10 schedule (Group G); iii) a T-C value of 24 days and a 114.3% ILS (highly active) for the combination of the IMGN779 Day 10 schedule plus the quizartinib Day 7 schedule (Group H).
  • Single-agent treatment with a QWx3 regimen of 0.2 pg/kg (by DGN462) of the non- targeted Ab-DGN462 control conjugate beginning treatment on Day 7 (Group I) resulted in a T-C value of 0 days and in a 0% ILS, which was inactive.
  • Single-agent treatment with a QWx3 regimen of 0.2 pg/kg (by DGN462) of Ab-DGN462 beginning treatment on Day 10 (Group J) was inactive, resulting in a T-C value of 1 day and a 4.8% ILS.
  • Example 4 In vitro studies of the combination of IMGN779 and quizartinib in FLT3- ITD-positive AML models
  • Mcl-l, p- Stat5, p-ERKl/2, and Rad5l were measured by flow cytometry at 24, 48, and 72 hours.
  • Treatment with quizartinib in Molm-l3 (FIG. 5A) and MV4-11 cells (FIG. 5B) decreased expression of Mcl-l, p-Stat5, p-ERKl/2, and Rad5l.
  • Treatment with IMGN779 increased Mcl-l levels in both Molm-l3 (FIG. 5A) and MV4-11 (FIG. 5B) cells.
  • MV4-11 cells were treated with treatment vehicle, or IMGN779 (77 pM), or quizartinib (4.5 nM), or the combination of IMGN779 and quizartinib for 72 hours. Viability was measured in FSC/SSC-gated cells with a viability dye (FIVE/DEAD Aqua Fixable Dye) by flow cytometry at 24, 48, and 72 hours. Percentages of cells positive for cleaved PARP (cPARP) and for cleaved caspase 3 (cCaspase3) were measured in viable cells by flow cytometry at 24, 48, and 72 hours. Molm-13 cells (FIG. 6A; 7A; 7C) and MV4-11 cells (FIG.

Abstract

La présente invention concerne un procédé de traitement d'un cancer chez un sujet comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un conjugué anticorps-médicament (ADC) ciblant CD33 et d'une quantité thérapeutiquement efficace de quizartinib ou d'un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également des compositions pharmaceutiques comprenant une quantité thérapeutiquement efficace d'un ADC ciblant CD33 et une quantité thérapeutiquement efficace de quizartinib ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2019/032090 2018-05-15 2019-05-14 Traitement combiné avec des conjugués anticorps-médicament et des inhibiteurs flt3 WO2019222130A1 (fr)

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