WO2021039616A1 - 併用療法及びその有効性を示すバイオマーカー - Google Patents

併用療法及びその有効性を示すバイオマーカー Download PDF

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WO2021039616A1
WO2021039616A1 PCT/JP2020/031572 JP2020031572W WO2021039616A1 WO 2021039616 A1 WO2021039616 A1 WO 2021039616A1 JP 2020031572 W JP2020031572 W JP 2020031572W WO 2021039616 A1 WO2021039616 A1 WO 2021039616A1
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patient
cancer
substituted
group
combination
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French (fr)
Japanese (ja)
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孝之 吉野
恭利 久保木
彬人 川添
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National Cancer Center Japan
Sumitomo Pharma Co Ltd
National Cancer Center Korea
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Sumitomo Dainippon Pharma Co Ltd
National Cancer Center Japan
National Cancer Center Korea
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Priority to JP2021542830A priority patent/JPWO2021039616A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57535—Immunoassay; Biospecific binding assay; Materials therefor for cancer of the large intestine, e.g. colon, rectum or anus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/70521—CD28, CD152
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/70532—B7 molecules, e.g. CD80, CD86

Definitions

  • This disclosure relates to the field of cancer treatment.
  • Pembrolizumab a leading anti-PD-1 antibody
  • FDA US Food and Drug Administration
  • MSI-H high-frequency microsatellite instability
  • dMMR mismatch repair mechanism deficiency
  • pembrolizumab has not shown a promising antitumor effect in patients with microsatellite-stability (MSS) metastatic colorectal cancer, and there is still a high unmet medical need.
  • a method for treating a cancer patient with MSS with a specific combination of medicines, or a composition or combination for that purpose is provided.
  • Specific combinations of medications include combinations of cancer stem cell inhibitors (eg, napabucasin) and immune checkpoint inhibitors (eg, pembrolizumab).
  • Patients with MSS can be selected by having one or more patient characteristics. Patient characteristics include that the cancer is right colon cancer, that PD-L1 expression is positive on tumor cells, that PD-L1 expression is positive on immune cells, and that Consensus Molecular Subtypes (CMS). Is 1 or 4, and the like.
  • CMS Consensus Molecular Subtypes
  • Another aspect of the disclosure also provides a method of predicting a patient's responsiveness to cancer treatment based on one or more patient characteristics.
  • MSS microsatellite stability
  • a composition comprising being administered in combination with an immune checkpoint inhibitor to a patient having one or more patient characteristics indicating that.
  • a composition which is administered in combination with a cancer stem cell inhibitor, to a patient having one or more patient characteristics showing the above.
  • Item 5 The combination or composition according to Item 4, wherein the one or more patient characteristics include that the cancer is right colorectal cancer.
  • the one or more patient characteristics are (1) The cancer is right colon cancer, and PD-L1 expression is positive on the immune cells of the patient. (2) The cancer is right colon cancer and PD-L1 expression is positive on the tumor cells of the patient, or (3) the cancer is right colon cancer and the patient Item 3.
  • Item 12 The combination or composition according to any one of Items 1 to 11, wherein the cancer stem cell inhibitor is a STAT3 pathway inhibitor.
  • Each (R 1 ) is hydrogen, halogen, fluorine, cyano, nitro, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, alkenyl, substituted alkynyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Independently selected from the group consisting of substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, OR a , SR a , and NH 2.
  • R 3 is hydrogen, halogen, fluorine, cyano, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, halogen-substituted alkyl, hydroxyl-substituted alkyl, amine-substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Selected from the group consisting of substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, OR a , SR a , and NR b R c , where Ra is hydrogen, alkyl, substituted.
  • R b and independently selected from the group consisting of alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, and substituted aryl.
  • R c is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, and substituted aryl, or R b and R c are bound to them.
  • X is (1) Single bond, (2) C 1-6 alkylene (the alkylene may be substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group and -CO 2 R 6), or (3) C. 3-10 cycloalkylene, Y is a single bond, an oxygen atom, or -NR 4A- R 4A is a hydrogen atom Z is (1) single bond or (2) C 1-6 alkylene, n is 0 or 1, V is (1) -NHR 5 , (2) a 3- to 6-membered monocyclic or polycyclic heterocyclic group, or (3) a 3- to 6-membered cyclic amino group.
  • R 5 is (1) hydrogen atom or (2) C 1-6 alkyl group (the alkyl group is a halogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid group, a C 6-10 aryl group, C.
  • R 6 and R 7 are the same or Differently, each independently is a C 1-6 alkyl group which may be substituted with a hydrogen atom or one or two carboxyl groups , where R 6 and R 7 may be substituted together.
  • R 3C are hydrogen atoms.
  • R 1 is a hydrogen atom
  • R 2A , R 2B , R 2C and R 2D are all hydrogen atoms
  • R 8 is a methyl group, Item 2.
  • the combination comprises pembrolizumab and is characterized in that the combination is administered to a patient having one or more patient characteristics that indicate that the patient is responsive to the treatment, said one or more patient characteristics.
  • the cancer is right colon cancer, and PD-L1 expression is positive on the immune cells of the patient.
  • the cancer is right-sided colorectal cancer and PD-L1 expression is positive on the tumor cells of the patient, or (3)
  • the cancer is colorectal cancer and the cancer A combination comprising a patient's CMS of 1 or 4.
  • a composition comprising napabucasin or a prodrug thereof, or a pharmaceutically acceptable salt thereof for treating a cancer patient with microsatellite stability (MSS), said composition.
  • the patient is administered in combination with pembrolizumab to a patient having one or more patient characteristics that indicate that the patient is responsive to the procedure.
  • the cancer is right colorectal cancer and PD-L1 expression is positive on the patient's immune cells
  • the cancer is right side colorectal cancer and the patient's tumor
  • a composition comprising a positive PD-L1 expression on cells, or (3) the cancer being colorectal cancer, and a CMS of the patient being 1 or 4.
  • the cancer is right colorectal cancer and PD-L1 expression is positive on the patient's immune cells
  • the cancer is right side colorectal cancer and the patient's tumor
  • a composition comprising a positive PD-L1 expression on cells, or (3) the cancer being colorectal cancer, and a CMS of the patient being 1 or 4.
  • a composition for determining the responsiveness of a cancer patient with microsatellite stability (MSS) to a cancer treatment including a combination of a cancer stem cell inhibitor and an immune checkpoint inhibitor.
  • the composition comprises a detector for PD-L1 where PD-L1 expression is positive on tumor cells; or PD-L1 expression is positive on immune cells in the patient.
  • Item 19 The composition according to Item 18, wherein the detection agent for PD-L1 is an anti-PD-L1 antibody.
  • Item 20 A kit containing the composition according to item 18 or 19.
  • [Item 21] A method of using one or more patient characteristics as an index of the patient's responsiveness to cancer treatment in a cancer patient with microsatellite stability (MSS), wherein the cancer treatment is cancer.
  • a method comprising a combination of a stem cell inhibitor and an immune checkpoint inhibitor, wherein the presence of the one or more patient characteristics indicates that the patient is responsive to the cancer treatment.
  • the combination is characterized in that it is administered to a patient having one or more patient characteristics that indicate that the patient is responsive to the procedure.
  • a composition comprising an immune checkpoint inhibitor for treating a cancer patient with microsatellite stability (MSS), wherein the patient is responsive to the treatment.
  • MSS microsatellite stability
  • a composition which is administered in combination with an active oxygen species generator (ROS generator) to a patient having one or more patient characteristics showing the above.
  • ROS generator active oxygen species generator
  • Item 30 The combination or composition according to any one of Items 26 to 28, wherein the one or more patient characteristics are positive for PD-L1 expression on the immune cells of the patient.
  • the characteristics of the one or more patients are that the cancer is right-sided colon cancer, PD-L1 expression is positive on the tumor cells of the patient, and PD- on the immune cells of the patient.
  • Item 6. The combination or composition according to any one of Items 26 to 32, which comprises positive L1 expression or a CMS of 1 or 4 for the patient.
  • the one or more patient characteristics are that the cancer is right colon cancer and that PD-L1 expression is positive on the tumor cells of the patient or PD on the immune cells of the patient.
  • Item 35 The combination or composition according to any one of Items 26 to 34, wherein the immune checkpoint inhibitor is an inhibitor of PD-L1 or PD-1.
  • Item 36 The combination or composition according to any one of Items 26 to 35, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.
  • the active oxygen species-producing agent is a formula I: (During the ceremony Each (R 1 ) is hydrogen, halogen, fluorine, cyano, nitro, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, alkenyl, substituted alkynyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Independently selected from the group consisting of substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, OR a , SR a , and NH 2.
  • R 3 is hydrogen, halogen, fluorine, cyano, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, halogen-substituted alkyl, hydroxyl-substituted alkyl, amine-substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Selected from the group consisting of substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, OR a , SR a , and NR b R c , where Ra is hydrogen, alkyl, substituted.
  • R b and independently selected from the group consisting of alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, and substituted aryl.
  • R c is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, and substituted aryl, or R b and R c are bound to them.
  • X is (1) Single bond, (2) C 1-6 alkylene (the alkylene may be substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group and -CO 2 R 6), or (3) C. 3-10 cycloalkylene, Y is a single bond, an oxygen atom, or -NR 4A- R 4A is a hydrogen atom Z is (1) single bond or (2) C 1-6 alkylene, n is 0 or 1, V is (1) -NHR 5 , (2) a 3- to 6-membered monocyclic or polycyclic heterocyclic group, or (3) a 3- to 6-membered cyclic amino group.
  • R 5 is (1) hydrogen atom or (2) C 1-6 alkyl group (the alkyl group is a halogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid group, a C 6-10 aryl group, C.
  • R 6 and R 7 are the same or Differently, each independently is a C 1-6 alkyl group which may be substituted with a hydrogen atom or one or two carboxyl groups , where R 6 and R 7 may be substituted together.
  • R 3C are hydrogen atoms.
  • R 1 is a hydrogen atom
  • R 2A , R 2B , R 2C and R 2D are all hydrogen atoms
  • R 8 is a methyl group, Item 6.
  • Item 39 The combination according to any one of Items 26 to 38, wherein the reactive oxygen species generator (ROS generator) is napabucasin or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Composition.
  • ROS generator reactive oxygen species generator
  • composition comprising a detection agent for PD-L1, where PD-L1 expression is positive on tumor cells; or PD-L1 expression on immune cells in the patient.
  • a positive composition indicates that the patient is responsive to the cancer treatment.
  • a method comprising a combination of a seed-producing agent (ROS generator) and an immune checkpoint inhibitor, wherein the presence of the one or more patient characteristics indicates that the patient is responsive to the cancer treatment.
  • ROS generator seed-producing agent
  • the method of item 49, wherein the cancer stem cell inhibitor is administered separately from the immune checkpoint inhibitor.
  • 51. The method of item 49, wherein the cancer stem cell inhibitor is administered together with the immune checkpoint inhibitor.
  • 52. The method of any one of Items 49-51, wherein the one or more patient characteristics include that the cancer is colorectal cancer. 53.
  • the one or more patient characteristics are (1) The cancer is right colon cancer, and PD-L1 expression is positive on the immune cells of the patient.
  • the cancer is right colon cancer and PD-L1 expression is positive on the tumor cells of the patient, or (3) the cancer is right colon cancer and the patient Item 4.
  • the method according to any one of Items 49 to 51 which comprises having a CMS of 1 or 4.
  • Item 58. The method according to any one of Items 49 to 57, wherein the immune checkpoint inhibitor is an inhibitor of PD-L1 or PD-1.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody.
  • the cancer stem cell inhibitor is a STAT3 pathway inhibitor.
  • each (R 1 ) is hydrogen, halogen, fluorine, cyano, nitro, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, alkenyl, substituted alkynyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Independently selected from the group consisting of substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, OR a , SR a , and NH 2.
  • R 3 is hydrogen, halogen, fluorine, cyano, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, halogen-substituted alkyl, hydroxyl-substituted alkyl, amine-substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Selected from the group consisting of substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, OR a , SR a , and NR b R c , where Ra is hydrogen, alkyl, substituted.
  • R b and independently selected from the group consisting of alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, and substituted aryl.
  • R c is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, and substituted aryl, or R b and R c are bound to them.
  • X is (1) Single bond, (2) C 1-6 alkylene (the alkylene may be substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group and -CO 2 R 6), or (3) C. 3-10 cycloalkylene, Y is a single bond, an oxygen atom, or -NR 4A- R 4A is a hydrogen atom Z is (1) single bond or (2) C 1-6 alkylene, n is 0 or 1, V is (1) -NHR 5 , (2) a 3- to 6-membered monocyclic or polycyclic heterocyclic group, or (3) a 3- to 6-membered cyclic amino group.
  • R 5 is (1) hydrogen atom or (2) C 1-6 alkyl group (the alkyl group is a halogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid group, a C 6-10 aryl group, C.
  • R 6 and R 7 are the same or Differently, each independently is a C 1-6 alkyl group which may be substituted with a hydrogen atom or one or two carboxyl groups , where R 6 and R 7 may be substituted together.
  • the combination comprises the step of administering to the patient, wherein the combination is administered to a patient having one or more patient characteristics indicating that the patient is responsive to the treatment.
  • Multiple patient characteristics (1) The cancer is right colon cancer, and PD-L1 expression is positive on the immune cells of the patient.
  • the cancer is right-sided colorectal cancer and PD-L1 expression is positive on the tumor cells of the patient, or (3)
  • the cancer is colorectal cancer and the cancer A method comprising having a patient's CMS of 1 or 4.
  • the composition comprises the step of administration, wherein the composition is administered in combination with pembrolizumab to a patient having one or more patient characteristics indicating that the patient is responsive to the treatment.
  • One or more patient characteristics (1)
  • the cancer is right colorectal cancer and PD-L1 expression is positive on the patient's immune cells (2)
  • the cancer is right side colorectal cancer and the patient's tumor
  • a method comprising that PD-L1 expression is positive on cells, or (3) the cancer is colorectal cancer, and the patient has a CMS of 1 or 4.
  • [Item 65] A method for treating cancer patients with microsatellite stability (MSS), in which pembrolizumab and napabucasin or a prodrug thereof, or a pharmaceutically acceptable salt thereof are used in an effective amount.
  • the one or more patient characteristics comprising the step of administering in combination to the patient and indicating that the patient is responsive to the treatment.
  • the cancer is right colorectal cancer and PD-L1 expression is positive on the patient's immune cells
  • the cancer is right side colorectal cancer and the patient's tumor
  • a method comprising that PD-L1 expression is positive on cells, or (3) the cancer is colorectal cancer, and the patient has a CMS of 1 or 4.
  • [Item 66] The use of cancer stem cell inhibitors and immune checkpoint inhibitors to produce a combination for treating a cancer patient with microsatellite stability (MSS), wherein the combination is , The use, characterized in that it is administered to a patient having one or more patient characteristics that indicate that the patient is responsive to the procedure.
  • MSS microsatellite stability
  • MSS microsatellite stability
  • [Item 68] The use of a composition comprising an immune checkpoint inhibitor for producing a drug for treating a cancer patient with microsatellite stability (MSS), wherein the composition is used by the patient.
  • Use characterized by administration in combination with a cancer stem cell inhibitor, to a patient having one or more patient characteristics that are responsive to the procedure.
  • ROS generators reactive oxygen species generators
  • immune checkpoint inhibitors to produce combinations for treating microsatellite stability (MSS) cancer patients.
  • the combination is used, characterized in that it is administered to a patient who has one or more patient characteristics that indicate that the patient is responsive to the procedure.
  • [Item 70] The use of a composition containing a reactive oxygen species generator (ROS generator) for treating a cancer patient with microsatellite stability (MSS), wherein the patient is the treatment. Use, characterized in that it is administered in combination with an immune checkpoint inhibitor to a patient having one or more patient characteristics that are responsive to.
  • a composition comprising an immune checkpoint inhibitor for treating a cancer patient with microsatellite stability (MSS), wherein the patient is responsive to the treatment.
  • Use characterized in that it is administered in combination with a reactive oxygen species generator (ROS generator) to a patient with one or more patient characteristics indicating that it is present.
  • ROS generator reactive oxygen species generator
  • a cancer stem cell inhibitor characterized in that it is administered in combination with an immune checkpoint inhibitor to a patient having one or more patient characteristics that are responsive to the procedure.
  • An immune checkpoint inhibitor which is administered in combination with a cancer stem cell inhibitor, to a patient having one or more patient characteristics showing responsiveness to.
  • a reactive oxygen species generator for use in treating a cancer patient with microsatellite stability (MSS), the composition containing the reactive oxygen species generator (ROS generator).
  • Reactive oxygen species production characterized in that the substance is administered in combination with an immune checkpoint inhibitor to a patient having one or more patient characteristics indicating that the patient is responsive to the treatment.
  • Agent ROS generator.
  • Item 75 An immune checkpoint inhibitor for use in treating a cancer patient with microsatellite stability (MSS), the composition comprising the immune checkpoint inhibitor being treated by the patient.
  • An immune checkpoint inhibitor characterized in that it is administered in combination with a reactive oxygen species generator (ROS generator) to a patient having one or more patient characteristics that are responsive to.
  • a method comprising the step of administering and having one or more patient characteristics indicating that the patient is responsive to the procedure.
  • the composition comprising the reactive oxygen species generator (ROS generator) is administered separately from the immune checkpoint inhibitor.
  • the composition comprising the reactive oxygen species generator (ROS generator) is administered together with the immune checkpoint inhibitor.
  • effective cancer treatment can be provided for cancer patients with MSS whose therapeutic effect is difficult to appear.
  • FIG. 1 is a diagram showing an outline of a clinical trial.
  • FIG. 2 is a Waterfall plot showing the tumor shrinkage effect of napabucasin and pembrolizumab combination therapy for MSS colorectal cancer patients.
  • For subjects enrolled in this study chest and abdomen before the start of treatment and at 6, 12, 18, and 24 weeks after the start of treatment (every 9 weeks until the 42nd week thereafter, and every 12 weeks after the 42nd week) , Pelvic CT / MRI examination was performed to evaluate the tumor shrinkage effect of this combination therapy.
  • Tumor shrinkage effect is irRECIST (immune-related response criteria), which is a new guideline for determining the therapeutic effect of solid cancer (RECIST guideline) ver1.1 or RECIST v1.1 applied to the evaluation method of tumor shrinkage effect seen in immunotherapy. Judgment was made based on. As a result, PR (Partial Response: defined as a reduction of the sum of target lesions by 30% or more compared to the sum of baseline diameters) was observed in 4 subjects with MSS colorectal cancer with the best overall effect. The objective response rate (ORR: Objective response rate) was 10%.
  • FIG. 3 is a diagram showing progression-free survival (PFS: Progression free survival) in patients with MSS colorectal cancer.
  • FIG. 4 is a diagram showing overall survival (OS: Overall survival) in patients with MSS colorectal cancer. Overall survival (OS: Overall Survival) was evaluated for FAS.
  • the OS defines the registration date as the starting date and the period until the death date due to any cause.
  • FIG. 5 is a diagram showing the frequency and grade of adverse events that occurred in subjects who received napabucasin and pembrolizumab combination therapy. Adverse events (subjective and objective symptoms) were observed and recorded during the period from the start of treatment to 30 days after the final administration of the protocol treatment. An adverse event is any unfavorable or unintended sign (including abnormal changes in laboratory test values), symptoms, or illness that occur in a subject who received the study drug and has a causal relationship with the study drug. It was defined as having or not having it.
  • FIG. 6 is a diagram showing an objective response rate (ORR) with respect to the presence or absence of PD-L1 expression.
  • PDs were cut out from a formalin-fixed paraffin-embedded (FFPE) tissue block of 40 MSS colon cancer and 10 MSI-High colon cancer subjects for whom tumor specimens could be submitted at baseline to a thickness of 5 ⁇ m. -Stained with L1 IHC 22C3 tumorDx "Dako". Of the 5 MSS colorectal cancer subjects whose PD-L1 expression was 1% or more on tumor cells, 4 had right colorectal cancer and 1 had left side colorectal cancer. The ORRs of MSS right and left colorectal cancers that were positive for PD-L1 on tumor cells were 3/4 (75%) and 0/1 (0%), respectively.
  • FFPE formalin-fixed paraffin-embedded
  • CMS1 including 2 with MSI colorectal cancer
  • CMS2 including 2 with MSI colorectal cancer
  • CMS3 6 were CMS4, unknown or unmeasurable.
  • the ORR and Clinical Benefit of MSS colorectal cancer patients classified as CMS1 or 4 were 3/9 cases (33%) and 4/9 cases (44%), respectively, and MSS colorectal cancer classified as CMS1 or 4 Among the patients, the ORR and Clinical Benefit of the patients whose primary lesion was on the right side were 3/5 (60%) and 4/5 (80%), respectively.
  • the ORRs of MSS colorectal cancer patients classified into CMS2 or CMS3 were 0 cases / 6 cases (0%) and 1 case / 4 cases (25%), respectively.
  • POLE polymerase ⁇
  • MSI polymerase ⁇
  • POLE mutations show a high mutation load phenotype in tumors and are therefore considered as promising predictor markers for immune checkpoint inhibitors in colon cancer patients with POLE genetic mutations.
  • Successful cases of pembrolizumab alone have been reported (Laetitia Nebot-Bral, et al. European Journal of Cancer 84 (2017) 290e303, J. Gong, et al, J. Natl. Compr. Canc. Netw. 15 (2). ) (2017) 142-147.). From this, it was speculated that one case that was successful with CMS3 may also be successful with pembrolizumab alone.
  • FIG. 8 is an exemplary schematic diagram of the system of the present disclosure.
  • FIG. 9 is an exemplary schematic diagram when the system of the present disclosure is physically separated, such as by using a cloud / server.
  • biomarker refers to a property that is objectively measured and evaluated as an indicator of a pharmacological response to a normal biological process, pathological process, or therapeutic intervention.
  • patient characteristics refers to any criterion that allows patients to be stratified.
  • Patient characteristics used as selection criteria in the present disclosure include, for example, that the cancer is right colorectal cancer; positive PD-L1 expression in patients (based on CPS score); PD-L1 on tumor cells. Expression is positive; PD-L1 expression is positive on immune cells; and CMS is 1 or 4.
  • immune cells examples include monocytes, neutrophils, eosinophils, basophils, T cells, B cells and NK cells.
  • biomarkers that correspond to specific "patient characteristics”. That is, by measuring a specific "biomarker” corresponding to a specific "patient characteristic”, the specific "patient characteristic" can be determined.
  • cancer or “cancer” is used interchangeably as a malignant tumor or a malignant tumor that is highly atypical, proliferates faster than normal cells, and can destructively infiltrate or metastasize surrounding tissues. A condition in which such a malignant tumor is present.
  • cancers include, but are not limited to, solid tumors and hematopoietic tumors.
  • microsatellite stability (MSS) cancer means a cancer in which the number of repeats of microsatellite repeats in the cancer tissue is not different from the number of repeats in normal tissue, or a mismatch in the cancer tissue.
  • MMR cancer without defects in repair
  • Microsatellite stability is determined by PCR microsatellite instability (MSI) testing or immunochemical staining (IHC) mismatch repair (MMR) -related protein testing.
  • MSI test PCR method can be performed using a known test method (brand name: MSI test kit (FARCO)) listed in the insurance.
  • the IHC method is a mismatch repair protein MLH1, MSH2, etc. This is a known test method for confirming the expression of MSH6 and PMS2.
  • being "responsive" means that the treatment results in tumor regression or suppression of long-term growth, eg, see RECIST and RECIST guidelines in immunotherapy. It can be judged by the criteria of complete response (CR), partial response (PR) or stable (SD) in ir RECIST applied to the evaluation method of the tumor shrinkage effect.
  • CR complete response
  • PR partial response
  • SD stable
  • being responsive to treatment with a combination of cancer stem cell inhibitors and immune checkpoint inhibitors and a combination of reactive oxygen species generators and immune checkpoint inhibitors is defined as a period of time after the combination of treatments.
  • CR complete response
  • PR partial response
  • SD stability
  • the positive PD-L1 expression means “positive for PD-L1 expression on the patient's immune cells” and / or “positive for PD-L1 expression on the patient's tumor cells”. It means “to be”.
  • the positive PD-L1 expression can be determined based on CPS (Combined Positive Score), which is a combined score of PD-L1 expression of tumor cells and immune cells in cancer tissue, and CPS. If the score is 1% or more, it can be determined to be positive. In this case, it means that PD-L1 expression is observed in 1% or more of the total surviving cells in the tumor tissue, including tumor cells or immune cells.
  • the proportion of PD-L1-expressing cells on any of the tumor cells and immune cells in the cancer tissue may be used.
  • CMS means the classification of colorectal cancer based on the consensus result of the colorectal cancer molecular type by the colorectal cancer subtyping consortium (CRCSC). CMS is determined by the subtype classification algorithm of Guinney et al. By measuring gene expression in tumor tissue by RNA sequencing, etc. (Guinney J, et al .: Nat Med. 21 (11): 1350-1356, 2015 ).
  • cancer stem cell inhibitor refers to any substance that inhibits the properties of cancer stem cells and the properties possessed by cancer stem cells.
  • cancer stem cells CSCs
  • CSCs cancer stem cells
  • CSCs have the ability to spread to other parts of the body by metastasis, and after metastasis CSCs can give rise to new tumors (Jordan CT et al., N. Engl. J. Med. 2006; 355 (12): 1253- 1261).
  • Cancer stem cell inhibitors target the expression of at least one pathway that results in cancer stem cell property, or at least one gene that results in cancer stem cell property (eg, production of functional products such as proteins). , Can be reduced, inhibited, interfered with, or regulated.
  • cancer stem cell biomarkers include, but are not limited to, ⁇ -catenin, NANOG, SMO, SOX2, STAT3, AXL, ATM, c-MYC, KLF4, survivin, or BMI-1. , These molecules are thought to be involved in cancer stem cell nature.
  • a cancer stem cell inhibitor is a small molecule that binds to a protein encoded by a cancer stem cell gene.
  • the cancer stem cell inhibitor is a recombinant binding protein or peptide that interacts with the cancer stem cell gene or the protein encoded by it (eg, APTSTAT3; Kim et al., Cancer Res. (2014). ) 74 (8): 2144-51) or nucleic acids (eg, STAT3 aiRNA; see US Pat. No. 9,328,345 whose contents are incorporated herein by reference in its entirety) or conjugates thereof.
  • the cancer stem cell inhibitor is a cell.
  • the cancer stem cell inhibitor is a STAT3 pathway inhibitor (eg, a STAT3 inhibitor) (eg, binds to and inhibits the biological activity of STAT3 (Furtek et al., ACS Chem. Biol. , 2016, 11 (2), pp308-318)).
  • STAT3 pathway inhibitor eg, a STAT3 inhibitor
  • binds to and inhibits the biological activity of STAT3 Furtek et al., ACS Chem. Biol. , 2016, 11 (2), pp308-318
  • STAT3 pathway inhibitor refers to any molecule that inhibits any of the constituents of the STAT3 pathway, including STAT3 itself.
  • the inhibition target protein of the STAT3 pathway inhibitor is not limited to STAT3 itself.
  • the cancer stem cell inhibitor is 2- (1-hydroxyethyl) -naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-chloro-naphtho [2].
  • the cancer stem cell inhibitor is of formula I: (During the ceremony Each (R 1 ) is hydrogen, halogen, fluorine, cyano, nitro, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, alkenyl, substituted alkynyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Independently selected from the group consisting of substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, OR a , SR a , and NH 2.
  • R 3 is hydrogen, halogen, fluorine, cyano, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, halogen-substituted alkyl, hydroxyl-substituted alkyl, amine-substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Selected from the group consisting of substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, OR a , SR a , and NR b R c , where Ra is hydrogen, alkyl, substituted.
  • R b and independently selected from the group consisting of alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, and substituted aryl.
  • R c is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, and substituted aryl, or R b and R c are bound to them. Forming a heterocycle or a substituted heterocycle together with the N Compounds, or prodrugs, derivatives thereof, pharmaceutically acceptable salts or solvates thereof.
  • each (R 1 ) is hydrogen, halogen, fluorine, cyano, nitro, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, alkenyl, substituted alkynyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cyclo.
  • Alkyl can contain, for example, a moiety having 1 to 8 carbon atoms linked by a single bond
  • alkenyl can contain, for example, 2 to 8 moieties linked by one or more double bonds. It can include a portion having a carbon atom
  • alkynyl can include, for example, a portion having 2 to 8 carbon atoms linked by one or more triple bonds.
  • Substituents can include moieties such as hydrogen, halogen, cyano, nitro, aryl, OR a , SR a , and NH 2.
  • each (R 1 ) is independent of the group consisting of hydrogen, methyl, F (fluorine), Cl (chlorine), Br (bromine), I (iodine), OH (hydroxyl), and NH 2 (amine). You can choose.
  • R 3 is hydrogen, halogen, fluorine, cyano, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, halogen substituted alkyl, hydroxyl substituted alkyl, amine substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyclo. It can be selected from the group consisting of alkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, OR a , SR a , and NR bR c.
  • R 3 can be selected from the group consisting of methyl and C (R 8 ) 3.
  • Each (R 8 ) can be independently selected from the group consisting of hydrogen, methyl, F (fluorine), Cl, Br, I, OH, and NH 2.
  • up to two of the independently selected (R 1 ) and (R 8 ) substituents can be selected to be F (fluorine) and the rest to be hydrogen. Fluorine.
  • the compounds of formula I are 2- (1-hydroxyethyl) -naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-chloro-naphtho [2, 3-b] furan-4,9-dione, 2-acetyl-7-fluoro-naphtho [2,3-b] furan-4,9-dione, 2-acetylnaphtho [2,3-b] furan-4 , 9-dione, 2-ethyl-naphtho [2,3-b] furan-4,9-dione, and their enantiomers, diastereomers, tautomers, and salts or solvates thereof.
  • each (R 1 ) can be selected to be hydrogen, as the compound of formula I is 2-acetylnaphtho [2,3-b] furan-4,9-dione, and R 3 can be selected to be methyl.
  • each Ra is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, and substituted aryl. It can be selected independently from the group consisting of.
  • each R b and R c can be independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, and substituted aryl.
  • R b and R c can be combined with the N to which they are attached to form a heterocycle or a substituted heterocycle.
  • the cancer stem cell inhibitor has the following formula: A compound represented by (napabucasin), or a prodrug, derivative thereof, pharmaceutically acceptable salt or solvate thereof.
  • the cancer stem cell inhibitor of the present disclosure may be any polymorph when present in crystalline form, and examples of polymorphs of compounds are described in WO2011 / 116399 and the like.
  • the cancer stem cell inhibitors of the present disclosure can be administered in an amount of about 300-about 700 mg. In certain embodiments, the cancer stem cell inhibitor can be administered in an amount of about 700 to about 1200 mg. In certain embodiments, the cancer stem cell inhibitor can be administered in an amount of about 800 to about 1100 mg. In certain embodiments, the cancer stem cell inhibitor can be administered in an amount of about 850 to about 1050 mg. In certain embodiments, the cancer stem cell inhibitor can be administered in an amount of about 960 to about 1000 mg.
  • the total amount of the cancer stem cell inhibitor is administered once daily. In certain embodiments, the cancer stem cell inhibitor is administered at a daily dose of about 480 mg. In certain embodiments, the cancer stem cell inhibitor is administered at a daily dose of about 960 mg. In certain embodiments, the cancer stem cell inhibitor is administered at a dose of about 1000 mg daily. In certain embodiments, the total amount of the cancer stem cell inhibitor is administered in divided doses greater than once daily, such as twice daily (BID) or more frequently. In certain embodiments, the cancer stem cell inhibitor is administered at a dose of about 240 mg twice daily. In certain embodiments, the cancer stem cell inhibitor is administered at a dose of about 480 mg twice daily. In certain embodiments, the cancer stem cell inhibitor is administered at a dose of about 500 mg twice daily. In certain embodiments, the cancer stem cell inhibitor is orally administered.
  • X is (1) Single bond, (2) C 1-6 alkylene (the alkylene may be substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group and -CO 2 R 6), or (3) C. 3-10 cycloalkylene, Y is a single bond, an oxygen atom, or -NR 4A- R 4A is a hydrogen atom Z is (1) single bond or (2) C 1-6 alkylene, n is 0 or 1, V is (1) -NHR 5 , (2) a 3- to 6-membered monocyclic or polycyclic heterocyclic group, or (3) a 3- to 6-membered cyclic amino group.
  • R 5 is (1) hydrogen atom or (2) C 1-6 alkyl group (the alkyl group is a halogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid group, a C 6-10 aryl group, C.
  • R 6 and R 7 are the same or Differently, each independently is a C 1-6 alkyl group which may be substituted with a hydrogen atom or one or two carboxyl groups , where R 6 and R 7 may be substituted together.
  • R 3C are hydrogen atoms.
  • R 1 is a hydrogen atom
  • R 2A , R 2B , R 2C and R 2D are all hydrogen atoms
  • R 8 is a methyl group
  • Examples include compounds or pharmaceutically acceptable salts or solvates.
  • the prodrug of napabucasin for a cancer stem cell inhibitor is a compound selected from the following compounds, or a pharmaceutically acceptable salt thereof: 2-Acetylnaphtho [2,3-b] furan-4,9-diylbis ((3-aminopropyl) carbamate), 2-Acetylnaphtho [2,3-b] furan-4,9-diylbis ((2-aminoethyl) carbamate), (2S, 2'S) -4,4'-((((2-Acetylnaphtho [2,3-b] furan-4,9-diyl) bis (oxy)) bis (carbonyl)) bis (Azandiyl) ) Bis (2- (methylamino) butanoic acid), 2,2'-(((((2-Acetylnaphtho [2,3-b] furan-4,9-diyl) bis (oxy)) bis (carbon
  • reactive Oxygen Species Generator The combination of drugs in the present disclosure may include reactive oxygen species generators.
  • reactive oxygen species generator means an agent that increases reactive oxygen species such as intracellular superoxide, hydroxyl radical, or hydrogen peroxide.
  • the reactive oxygen species-producing agent include compounds that inhibit the removal of intracellular reactive oxygen species such as benzyl isothiocyanate, phenylethyl isothiocyanate, and butionine sulfoximin, or compounds having a quinone skeleton. .. More preferred include lapachol, beta-rapachon, or napabucasin.
  • the reactive oxygen species generator is 2- (1-hydroxyethyl) -naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-chloro-naphtho [2, 3-b] furan-4,9-dione, 2-acetyl-7-fluoro-naphtho [2,3-b] furan-4,9-dione, 2-acetylnaphtho [2,3-b] furan-4 , 9-Dione (napabcasin), or 2-ethyl-naphtho [2,3-b] furan-4,9-dione, these prodrugs, derivatives of these, pharmaceutically acceptable salts of any of these , And at least one compound selected from any of these solvates.
  • the reactive oxygen species generator is of formula I: (During the ceremony Each (R 1 ) is hydrogen, halogen, fluorine, cyano, nitro, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, alkenyl, substituted alkynyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Independently selected from the group consisting of substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, OR a , SR a , and NH 2.
  • R 3 is hydrogen, halogen, fluorine, cyano, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, halogen-substituted alkyl, hydroxyl-substituted alkyl, amine-substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Selected from the group consisting of substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, OR a , SR a , and NR b R c , where Ra is hydrogen, alkyl, substituted.
  • R b and independently selected from the group consisting of alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, and substituted aryl.
  • R c is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, and substituted aryl, or R b and R c are bound to them. Forming a heterocycle or a substituted heterocycle together with the N Compounds, or prodrugs, derivatives thereof, pharmaceutically acceptable salts or solvates thereof.
  • each (R 1 ) is hydrogen, halogen, fluorine, cyano, nitro, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, alkenyl, substituted alkynyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cyclo.
  • Alkyl can contain, for example, a moiety having 1 to 8 carbon atoms linked by a single bond
  • alkenyl can contain, for example, 2 to 8 moieties linked by one or more double bonds. It can include a portion having a carbon atom
  • alkynyl can include, for example, a portion having 2 to 8 carbon atoms linked by one or more triple bonds.
  • Substituents can include moieties such as hydrogen, halogen, cyano, nitro, aryl, OR a , SR a , and NH 2.
  • each (R 1 ) is independent of the group consisting of hydrogen, methyl, F (fluorine), Cl (chlorine), Br (bromine), I (iodine), OH (hydroxyl), and NH 2 (amine). You can choose.
  • R 3 is hydrogen, halogen, fluorine, cyano, CF 3 , OCF 3 , alkyl, methyl, substituted alkyl, halogen substituted alkyl, hydroxyl substituted alkyl, amine substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyclo. It can be selected from the group consisting of alkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, substituted aryl, OR a , SR a , and NR bR c.
  • R 3 can be selected from the group consisting of methyl and C (R 8 ) 3.
  • Each (R 8 ) can be independently selected from the group consisting of hydrogen, methyl, F (fluorine), Cl, Br, I, OH, and NH 2.
  • up to two of the independently selected (R 1 ) and (R 8 ) substituents can be selected to be F (fluorine) and the rest to be hydrogen. Fluorine.
  • the compounds of formula I are 2- (1-hydroxyethyl) -naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-chloro-naphtho [2, 3-b] furan-4,9-dione, 2-acetyl-7-fluoro-naphtho [2,3-b] furan-4,9-dione, 2-acetylnaphtho [2,3-b] furan-4 , 9-dione, 2-ethyl-naphtho [2,3-b] furan-4,9-dione, and their enantiomers, diastereomers, tautomers, and salts or solvates thereof.
  • each (R 1 ) can be selected to be hydrogen, as the compound of formula I is 2-acetylnaphtho [2,3-b] furan-4,9-dione, and R 3 can be selected to be methyl.
  • each Ra is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycle, substituted heterocycle, aryl, and substituted aryl. It can be selected independently from the group consisting of.
  • each R b and R c can be independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, substituted heterocycle, aryl, and substituted aryl.
  • R b and R c can be combined with the N to which they are attached to form a heterocycle or a substituted heterocycle.
  • the reactive oxygen species generator has the following formula: A compound represented by (napabucasin), or a prodrug, derivative thereof, pharmaceutically acceptable salt or solvate thereof.
  • the reactive oxygen species generator of the present disclosure may be any polymorph when present in crystalline form, and examples of polymorphs of compounds are described in WO2011 / 116399 and the like.
  • the reactive oxygen species generator of the present disclosure can be administered in an amount of about 300 to about 700 mg. In certain embodiments, the reactive oxygen species generator can be administered in an amount of about 700 to about 1200 mg. In certain embodiments, the reactive oxygen species generator can be administered in an amount of about 800 to about 1100 mg. In certain embodiments, the reactive oxygen species generator can be administered in an amount of about 850 to about 1050 mg. In certain embodiments, the reactive oxygen species generator can be administered in an amount of about 960 to about 1000 mg.
  • the total amount of reactive oxygen species-producing agent is administered once a day. In certain embodiments, the reactive oxygen species generator is administered at a dose of about 480 mg daily. In certain embodiments, the reactive oxygen species generator is administered at a dose of about 960 mg daily. In certain embodiments, the reactive oxygen species generator is administered at a dose of about 1000 mg daily. In certain embodiments, the total amount of reactive oxygen species-producing agent is administered in divided doses greater than once daily, such as twice daily (BID) or more frequently. In certain embodiments, the reactive oxygen species generator is administered at a dose of about 240 mg twice daily. In certain embodiments, the reactive oxygen species generator is administered at a dose of about 480 mg twice daily. In certain embodiments, the reactive oxygen species generator is administered at a dose of about 500 mg twice daily. In certain embodiments, the reactive oxygen species generator is orally administered.
  • the prodrug of napabucasin according to the reactive oxygen species generator is of formula 1A :.
  • B is (1) 3- to 6-membered monocyclic or polycyclic heterocyclic groups, (2) 3- to 6-membered cyclic amino group, or formula (3)
  • B It is a group represented by Here, the 3- to 6-membered monocyclic heterocyclic group and the 3- to 6-membered cyclic amino group have at least one secondary nitrogen atom in the ring.
  • X is (1) Single bond, (2) C 1-6 alkylene (the alkylene may be substituted with 1 to 3 substituents selected from the group consisting of a carboxyl group and -CO 2 R 6), or (3) C. 3-10 cycloalkylene, Y is a single bond, an oxygen atom, or -NR 4A- R 4A is a hydrogen atom Z is (1) single bond or (2) C 1-6 alkylene, n is 0 or 1, V is (1) -NHR 5 , (2) a 3- to 6-membered monocyclic or polycyclic heterocyclic group, or (3) a 3- to 6-membered cyclic amino group.
  • R 5 is (1) hydrogen atom or (2) C 1-6 alkyl group (the alkyl group is a halogen atom, a hydroxyl group, a carboxyl group, a sulfinic acid group, a sulfonic acid group, a phosphoric acid group, a C 6-10 aryl group, C.
  • R 6 and R 7 are the same or Differently, each independently is a C 1-6 alkyl group which may be substituted with a hydrogen atom or one or two carboxyl groups , where R 6 and R 7 may be substituted together.
  • R 3C are hydrogen atoms.
  • R 1 is a hydrogen atom
  • R 2A , R 2B , R 2C and R 2D are all hydrogen atoms
  • R 8 is a methyl group
  • Examples include compounds or pharmaceutically acceptable salts or solvates.
  • the prodrug of napabucasin according to a reactive oxygen species generator is a compound selected from the following compounds, or a pharmaceutically acceptable salt thereof: 2-Acetylnaphtho [2,3-b] furan-4,9-diylbis ((3-aminopropyl) carbamate), 2-Acetylnaphtho [2,3-b] furan-4,9-diylbis ((2-aminoethyl) carbamate), (2S, 2'S) -4,4'-((((2-Acetylnaphtho [2,3-b] furan-4,9-diyl) bis (oxy)) bis (carbonyl)) bis (Azandiyl) ) Bis (2- (methylamino) butanoic acid), 2,2'-(((((2-Acetylnaphtho [2,3-b] furan-4,9-diyl) bis (oxy)) bis (
  • immuno checkpoint inhibitor The combination of drugs in the present disclosure may include an immune checkpoint inhibitor.
  • an "immune checkpoint inhibitor” is any molecule capable of completely or partially inhibiting the expression or function of one or more immune checkpoint molecules that control the activation or function of T cells. Point to.
  • Non-limiting examples of immune checkpoint molecules include cytotoxic T lymphocyte-related antigens (CTLA, eg CTLA4) and their ligands CD80 and CD86, programmed cell death proteins (PD, eg PD-1) and their ligands.
  • CTLA cytotoxic T lymphocyte-related antigens
  • PD programmed cell death proteins
  • IDO1 indolamine-pyrrole 2,3-dioxygenase-1
  • T cell membrane protein TIM, eg, TIM3
  • A2aR adenosine A2a receptor
  • LAG lymphocyte activation gene
  • KIR killer immunoglobulin receptor
  • B7-H3, B7-H4, B7-H5 VISTA
  • TIGIT T cell immunoreceptor with Ig and ITIM domain
  • Immune checkpoint inhibitors include, but are not limited to, the extracellular region of AMP-224 (PD-1 ligand, programmed cell death ligand 2 (PD-L2, B7-DC)) and PD-1.
  • PD-1 ligand PD-1 ligand, programmed cell death ligand 2 (PD-L2, B7-DC)
  • PD-1 programmed cell death ligand 2
  • B7-DC Fc fusion protein consisting of the Fc region of human immunoglobulin (Ig) G1 that binds to.
  • B7-DClg See, for example, PCT / US2009 / 054969 and PCT / US2010 / 057940.
  • Atezolizumab (combined with PD-L1; also referred to as MPDL3280A, RG7446, YW243.55.S70; see, eg, US Pat. No. 8,217,149. Its contents are incorporated herein by reference); BMS-936559, which binds to Programmed Cell Death-1 Ligand (PD-L1), also referred to as MDX-1105 or 12A4, eg, US Pat. No. 7,943. See 743, 9, 102, 725, and 9, 212, 224, the contents of which are incorporated herein by reference)); BMS-986016 (LAG3 (CD223)).
  • PD-L1 also referred to as MPDL3280A, RG7446, YW243.55.S70
  • BMS-936559 which binds to Programmed Cell Death-1 Ligand (PD-L1), also referred to as MDX-1105 or 12A4, eg, US Pat. No. 7,943. See 743, 9,
  • ipilimumab binds to CTLA4. Ipirimumab. Also referred to as Yervoy, MDX-010, MDX101, 10D1, BMS-734016. See US Pat. Nos. 6,984,720, 8,784,815, and 8,685,394 for their content. (Incorporated herein by reference); Lilylumab (which binds to the killer cell immunoglobulin-like receptor (KIR). Lilylumab binds to IPH 2101, IPH 2101, 1 It is also called -7F9, IPH 2102, IPH 2102, or BMS-986015. See U.S. Pat. Nos.
  • enobilituzumab a humanized mouse antibody that binds to B7-H3; enobilituzumab is Also referred to as MGA271; see, eg, US Pat. Nos. 8,802,091 and 9,150,656, the contents of which are incorporated herein by reference); nivolumab (combined with PD-1). Nivolumab is also referred to as Opdivo, ONO-4538, MDX-1106, BMS-936558, 5C4, see, eg, US Pat. Nos. 8,008,449, 9,084,776, and 8,168,179.
  • penbrolizumab (combined with PD-1; penbrolizumab is also referred to as Keytruda, MK-3475, SCH 900475, Rambrolizumab, eg, US Pat. No. 8,354,509. No. 9, 220,776, 8,952,136, and 8,900,587, the contents of which are incorporated herein by reference); Tremerimumab (combined with CTLA4). Tremerimumab is also referred to as ticilimumab, CP-675206, clone 11.2.1. For example, US Pat. Nos. 6,682,736, 8,685,394, 7,824,679, and 8, 143,379, the contents of which are incorporated herein by reference); and semipyrimab (combined with PD-1, also referred to as REGN2810).
  • the immune checkpoint inhibitor is an anti-PD-1 antibody (eg, pembrolizumab, nivolumab or semipyrimab), an anti-PD-L1 antibody (eg, atezolizumab (MPDL3280A), rambrolizumab (MK3475), durvalumab, or avelumab). ), And an anti-CTLA4 antibody (ipilimumab or tremelimumab (MEDI4736)).
  • an anti-PD-1 antibody eg, pembrolizumab, nivolumab or semipyrimab
  • an anti-PD-L1 antibody eg, atezolizumab (MPDL3280A), rambrolizumab (MK3475), durvalumab, or avelumab.
  • an anti-CTLA4 antibody ipilimumab or tremelimumab (MEDI4736)
  • the immune checkpoint inhibitor is a PD-1 / PD-L1 inhibitor (eg, anti-PD-1 antibody or anti-PD-L1 antibody).
  • pembrolizumab is administered intravenously, for example, at a dose of about 2 mg / kg once every 3 weeks for about 30 minutes.
  • ipilimumab can be administered, for example, at a dose of about 3 mg / kg once every three weeks, intravenously over a period of about 90 minutes, for a total of four doses.
  • nivolumab is administered intravenously, eg, at a dose of about 3 mg / kg, once every two weeks for about 60 minutes.
  • the combination of drugs in the present disclosure may be such that the two or more specified drugs are each formulated and administered as a separate composition or as an integral composition. When administered as separate compositions, they may be administered at the same time or at different times (but while the effects of other medications on the subject persist).
  • each drug can be administered in different dosage forms and / or methods, for example, one compound can be administered topically and the other compound can be administered orally.
  • the combinations in the present disclosure may be administered in a 21-day cycle.
  • the immune checkpoint inhibitors of the present disclosure may be administered on the first day of the 21-day cycle. Administration may be intravenous administration.
  • the dose of the immune checkpoint inhibitor may be about 200 mg / body.
  • the cancer stem cell inhibitor or reactive oxygen species-producing agent according to the present disclosure may be administered daily twice a day.
  • the administration may be oral administration.
  • the dose of the cancer stem cell inhibitor or reactive oxygen species generator may be about 480 mg at a time.
  • a cancer stem cell inhibitor or a reactive oxygen species-producing agent may be administered alone for a certain period of time before the 21-day cycle. For example, the cycle can be initiated after 7 days of administration of the cancer stem cell inhibitor or reactive oxygen species generator alone.
  • cancer The present disclosure provides a method of treating cancer with a particular combination of drugs, or compositions or combinations thereof.
  • the cancers covered in this disclosure are, but are not limited to, esophageal cancer, gastroesophageal junction cancer, renal cell cancer, lung cancer, gastrointestinal cancer, leukemia, lymphoma, myeloma, and brain.
  • cancer pancreatic cancer, endometrial cancer, prostate cancer, liver cancer, bladder cancer, gastroesophageal adenocarcinoma, chondrosarcoma, colonic rectal adenocarcinoma, colonic rectal cancer, breast cancer, renal cells Cancer, ovarian cancer, head and neck cancer, melanoma, gastric adenocarcinoma, sarcoma, urogenital cancer, gynecological cancer, and corticolytic cancer.
  • the cancer is colorectal cancer.
  • the cancer is colorectal cancer.
  • the cancer is melanoma.
  • the cancer is breast cancer.
  • the cancer is bladder cancer.
  • the cancer is renal cell carcinoma.
  • the cancer is pancreatic cancer.
  • the cancer is endometrial cancer.
  • the cancer can be unresectable. In certain embodiments, the cancer can be advanced. In certain embodiments, the cancer can be refractory. In certain embodiments, the cancer can be recurrent. In certain embodiments, the cancer can be metastatic.
  • a cancer patient means a patient suffering from the above-mentioned "cancer".
  • Cancer can be cancer without mismatch repair deficiencies.
  • colorectal cancer is mentioned as a cancer in which microsatellite stability is a problem.
  • colorectal cancer without microsatellite stability and / or mismatch repair deficiency may be targeted.
  • Microsatellite Stability Microsatellite refers to a place in genomic DNA where a short base sequence of about 1 to several bases is repeated.
  • Microsatellite instability is a phenomenon in which microsatellite repeats show a different number of repeats in tumor tissue than in non-tumor (normal) tissue due to a decrease in the ability to repair base sequence errors that occur during DNA replication. Is.
  • MSI / MSS can be determined by comparing the number of repeats of microsatellite sequences of genomic DNA in tumor and non-tumor tissues. For example, the region containing the microsatellite repeats can be amplified by the PCR method and the number of repeats of the microsatellite sequences can be compared. Compared to tumor tissue and non-tumor tissue, if the number of repetitions of the microsatellite marker in the tumor tissue is changed, it is judged to be microsatellite instability (MSI) positive, and if it is not changed, microsatellite stability ( It is determined to be MSS).
  • MSI microsatellite instability
  • MSI-H high frequency microsatellite instability
  • MSI-L Infrequent microsatellite instability
  • MSS microsatellite stability
  • MSI-H colorectal cancer 10-100 times more somatic mutations occur than in MSS colorectal cancer due to functional deterioration of DNA mismatch repair genes. Since the antigens (neoantigens) derived from these gene mutations are recognized as non-self, the immune response in the tumor tissue is enhanced, and it is considered that the expression of various immune checkpoint molecules is induced as negative feedback. There is.
  • the proportion of patients with high-frequency microsatellite instability colorectal cancer is said to be about 14 to 16%, of which 5 to 6% are predicted to be stage 4 colorectal cancer patients.
  • the frequency of high-frequency microsatellite instability is said to be higher in those who develop colorectal cancer at an early age. In addition to colorectal cancer, it is said that high-frequency microsatellite instability is common in intrauterine cancer, gastric cancer, and small intestine cancer.
  • Antineoplastic agents including immune checkpoint inhibitors, have tended to be more effective against types of cancer with many genetic damage, and are either deficient in mismatch repair mechanisms or deficient in mismatch repair mechanisms. It is often effective against microsatellite instability cancers, but is often ineffective against microsatellite-stable cancers.
  • the present disclosure may provide the treatment of microsatellite-stable cancer with a particular combination of drugs.
  • selecting patients based on one or more patient characteristics can result in good clinical response even in patients with microsatellite-stable cancer.
  • patient characteristics refers to any criterion by which patients can be stratified. Patient characteristics used as selection criteria in the present disclosure include, for example, that the cancer is right colorectal cancer; positive PD-L1 expression in patients (based on CPS score); PD-L1 on tumor cells. Expression is positive; PD-L1 expression is positive on immune cells; and CMS is 1 or 4.
  • PD-L1 expression is positive means “PD-L1 expression is positive on the patient's immune cells” and / or “PD-L1 expression is positive on the patient's tumor cells”. Being “is included.
  • patient characteristics described herein one or more patient characteristics may be used in combination, or other patient characteristics known in the art may be used in combination.
  • Examples of combinations of patient characteristics include "right-sided colorectal cancer with positive PD-L1 expression” and / or "colorectal cancer with CMS of 1 or 4". it can.
  • immune cells examples include monocytes, neutrophils, eosinophils, basophils, T cells, B cells and NK cells.
  • PD-L1 expression can be determined based on a positive CPS score, but in some embodiments PD-L1 expression is measured on tumor cells and PD-L1 expression is positive on the tumor cells (1). % Or more) may be used to determine PD-L1 expression.
  • CMS is determined by the subtype classification algorithm of Guinney et al. By measuring gene expression in tumor tissue by RNA sequencing or the like (Guinney J, et al .: Nat Med. 21 (11): 1350-1356, 2015). CMS refers to the classification of colorectal cancers based on the consensus results of colorectal cancer molecule types by the Colorectal Cancer Subtyping Consortium (CRCSC). It can be classified into CMS1 to 4 based on the gene expression pattern.
  • CRCSC Colorectal Cancer Subtyping Consortium
  • CMS1 has many gene mutations and has the characteristic of being a phenotype in which the immune system is activated.
  • CMS2 is epithelial and is characterized by a phenotype in which the WNT and MYC signaling pathways are activated.
  • CMS3 is epithelial and has the characteristic of being a phenotype associated with metabolic disorders.
  • CMS4 is mesenchymal and is characterized by phenotypes associated with epithelial-mesenchymal transition, cancer stem cellity and angiogenesis.
  • a CMS of 1 (colorectal cancer is classified as CMS1) can be used.
  • a CMS of 2 (colorectal cancer is classified as CMS2) can be used.
  • a CMS of 3 colonrectal cancer is classified as CMS3
  • a CMS of 4 colonrectal cancer is classified as CMS4 can be used.
  • one or more gene mutations of the patient can be used.
  • Gene mutations can use their presence or absence.
  • the presence or absence of an EGFR gene mutation, the presence or absence of an ALK fusion gene, the presence or absence of a gene mutation of polymerase ⁇ (POLE), and the like can be used.
  • POLE polymerase ⁇
  • the absence of a gene mutation in polymerase ⁇ (POLE) can be used as a patient characteristic.
  • POLE polymerase ⁇
  • POLE polymerase ⁇
  • POLE polymerase ⁇
  • the presence or absence of a gene mutation can be used in combination with other patient characteristics, if desired.
  • the large intestine is the digestive tract consisting of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum.
  • the term "right colon (rectal colon) cancer” refers to cancer whose primary site is the right side of the colon (cecum, ascending colon and transverse colon), and "left colon (rectal colon) cancer".
  • the left side of the colon (descending colon, sigmoid colon and cecum) is the primary site of cancer.
  • Right-sided colorectal cancer is less symptomatic until it grows, is often found as a mass, and has anemia due to chronic bleeding.
  • left colorectal cancer is often diagnosed by symptoms such as bleeding (melena, mucous stool), constipation / diarrhea, and thinning of stool.
  • the cause of the laterality is developmentally different from the middle intestine for the right (proximal) large intestine and the posterior intestine for the left (distal) large intestine. It is thought that the right large intestine has the superior mesenteric artery system and the left large intestine has the inferior mesenteric artery system, and that the mucosal structure differs between the ascending colon and the descending colon.
  • the composition of intestinal bacteria (flores) may be different on the left and right sides of the large intestine, and right-sided large intestine cancer may be caused by intestinal bacteria or inflammation in many cases.
  • One embodiment of the present disclosure is a method of using one or more patient characteristics as an indicator of a patient's responsiveness to cancer treatment in a microsatellite stability (MSS) cancer patient.
  • Cancer treatment may include a combination of a cancer stem cell inhibitor and an immune checkpoint inhibitor.
  • the presence and / or absence of the one or more patient characteristics may indicate that the patient is responsive and / or not responsive to cancer treatment.
  • One or more patient characteristics are that the cancer is right colorectal cancer, PD-L1 expression is positive in the patient (based on CPS score), and PD-L1 expression is positive on the patient's tumor cells. That is, PD-L1 expression is positive on the patient's immune cells, and CMS is 1 or 4.
  • patient characteristics described herein one or more patient characteristics may be used in combination, or other patient characteristics known in the art may be used in combination. Examples of combinations of patient characteristics include "right side colon cancer with positive PD-L1 expression” or "colon cancer with CMS of 1 or 4".
  • one or more patient characteristics in a cancer patient are used as indicators to predict whether or not the patient will achieve a complete or partial response to cancer treatment. In one embodiment of the present disclosure, whether one or more patient characteristics in a cancer patient are used as an index to achieve a complete response, a partial response, and maintenance of stability for 4 months or longer for cancer treatment. Predict whether or not. In one embodiment of the present disclosure, it may be determined whether or not cancer treatment should be given based on the prediction results.
  • One embodiment of the present disclosure is a response of a cancer patient with microsatellite stability (MSS) to a cancer treatment comprising a combination of a cancer stem cell inhibitor or ROS generator and an immune checkpoint inhibitor. It is a composition containing a detection agent for PD-L1 for determining the sex.
  • PD-L1 expression is positive in the patient (based on CPS score); PD-L1 expression is positive on tumor cells; or PD-L1 expression is positive on immune cells.
  • Patients can be shown to be responsive to the cancer treatment.
  • the detection agent include, but are not limited to, anti-PD-L1 antibody. Kits containing such compositions may also be provided.
  • the kit may include package inserts and labels provided to instruct treating healthcare professionals, such as physicians, to identify the above-mentioned patients for treatment, but these are official.
  • treating healthcare professionals such as physicians
  • a system for determining the patient's responsiveness to cancer treatment may be provided.
  • the system is composed of a storage unit for storing patient characteristic information of a plurality of patients and responsiveness information of the plurality of individuals, patient characteristics of the plurality of individuals, and responsiveness information of the plurality of individuals. , Predict the responsiveness of a patient from the patient characteristics of a patient based on the relationship between the information and responsiveness of the patient characteristics and the learning unit configured to learn the relationship between patient characteristics and responsiveness. It may be equipped with a calculation unit.
  • system refers to a configuration for executing the method or program of the present disclosure, and originally means a system or organization for accomplishing an object, and a plurality of elements are systematically configured. In the field of computers, it refers to the entire configuration of hardware, software, OS, network, etc. If necessary, the system may further include a display unit that displays information on the responsiveness predicted by the calculator.
  • the present disclosure can also be provided as a program, a method, or a recording medium in which the above system is realized. In one embodiment, learning using artificial intelligence (AI) is performed as learning.
  • AI artificial intelligence
  • the storage unit may be a recording medium stored in or detached from the system, such as a CD-R, DVD, Blu-ray, USB, SSD, or hard disk, or may be stored in a server, and may be stored in the cloud. It may be in a format that is appropriately recorded above.
  • linear regression, logistic regression, support vector machine, etc. can be used, and cross-validation (also called cross-validation or cross-validation; Cross Validation; CV) is performed to calculate the discrimination accuracy of each model. be able to.
  • machine learning linear regression, logistic regression, support vector machine, etc.
  • cross-validation can be performed to calculate the discrimination accuracy of each model. Thereby, the model with the highest accuracy can be selected.
  • any machine learning can be used, and linear, logistic, support vector machine (SVM) and the like can be used as supervised machine learning.
  • the system can distribute functions to terminals located in patients or hospitals.
  • the input is performed at the patient or at an information terminal such as a hospital (for example, a mobile phone or a smartphone).
  • the input patient characteristics may be transmitted via the Internet, the prediction model may be applied on the cloud, and the prediction result may be transmitted to the information terminal.
  • the disclosure also refers to the patient's responsiveness to cancer treatment of the medicament or combination thereof (cancer treatment) provided in this disclosure that is stored or mediated to function in a mobile device such as a smartphone, smartwatch.
  • a mobile device such as a smartphone, smartwatch.
  • the method for determining the responsiveness of the patient to the cancer treatment of the present disclosure is A) a step of providing a computer with information on the patient characteristics of a plurality of patients and information on the responsiveness of the plurality of individuals, B. ) A step of making a computer learn the relationship between the patient characteristics and the responsiveness from the patient characteristics of the plurality of individuals and the responsiveness information of the plurality of individuals, C) The relationship between the information of the patient characteristics and the responsiveness. Based on the above, a step of causing the computer to predict the responsiveness of the patient from the patient characteristics of a certain patient, D) a step of displaying the prediction result on the display unit of the mobile terminal as needed.
  • the information in A) may be stored in a recording medium isolated or included in the computer, may be provided at any time on the Internet or the like, or may be stored in the cloud.
  • the patient characteristic information and the responsiveness information may be stored in the same place or in different places.
  • a discriminant model may be created by machine learning.
  • sample amplification method is a technique for significantly increasing the number of samples by using the distribution characteristics even when the number of samples is small.
  • model creation for example, a large number of samples are used as training data, and the hyperparameters ( ⁇ ) of the logistic regression model are determined by Lasso and Bayesian optimization, and the weighting coefficients and model intercepts of the features are determined. be able to. For a large number of samples, amplified ones using normal random numbers and Pearson system random numbers can be used, if necessary.
  • the created model can be evaluated as a model. That is, the model is used to discriminate and estimate other sample test data.
  • the therapeutic suitability determination technique of the present disclosure can be provided as one system or device in a form including all (Fig. 7).
  • the treatment suitability determination device mainly measures the patient characteristics and responsiveness and displays the results, and the calculation and the calculation of the discrimination model are performed on a server or the cloud (FIG. 8).
  • IoT Internet of Things
  • AI artificial intelligence
  • the treatment suitability determination technology also stores the discrimination model and performs discrimination on the spot, but the main calculation such as the calculation of the discrimination model is assumed to be a semi-standalone type, which is a form performed on a server or the cloud. obtain. In some places such as hospitals, transmission and reception are not always possible, so a model that can be used even when shielded is assumed.
  • the disclosure is a program that causes a computer to perform a method of determining therapeutic suitability for a subject, the method of which is A) information on patient characteristics of multiple patients and of the plurality of individuals.
  • a step of providing responsiveness information to a computer B) a step of causing a computer to learn the relationship between patient characteristics and responsiveness from the patient characteristics of the plurality of individuals and the responsiveness information of the plurality of individuals.
  • a program including a step to be displayed on the display unit of the above, and a recording medium, a system and an apparatus for storing the program.
  • a system that realizes such a program may be realized in an embodiment in which the whole is regarded as a system.
  • the visualization unit may be any one as long as the user can recognize the determination result of the treatment suitability of the target, and an input / output device, a display device, a television, a monitor, or the like may be used. ..
  • another cognitive means such as voice may be used and may include a sound generator (eg, speaker), a vibrating device, electrodes, or other device capable of presenting a challenge to the subject. it can.
  • the recording medium may be, for example, a recording medium such as a CD-R, DVD, Blu-ray, USB, SSD, or hard disk, may be stored in a server, or may be appropriately recorded on the cloud.
  • SaaS Software as a service
  • the cancer stem cell inhibitor or reactive oxygen species generator and / or immune checkpoint inhibitor therapeutic agent disclosed herein can be in the form of a pharmaceutical composition.
  • the pharmaceutical composition may comprise at least one cancer stem cell inhibitor.
  • the pharmaceutical composition may comprise at least one compound of formula I and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may comprise at least one immune checkpoint inhibitor.
  • the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds are at least one compound of formula I in the subject.
  • the pharmaceutical composition may comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds inhibit at least one immune checkpoint in a subject.
  • the plurality of agents described in the present disclosure may be contained in a single composition (mixture) or may be contained in separate compositions.
  • the preparations are immune checkpoint inhibitors and cancer stem cell inhibitors using forms known in the art, including those exemplified herein.
  • it may be a preparation containing an active oxygen species generator or a prodrug thereof.
  • the term “carrier” relates to, or enables, for example, transporting or transporting a pharmaceutical compound of interest from one organ or part of the body to another organ or part of the body.
  • a pharmaceutically acceptable substance, composition, or excipient such as a solid bulking agent, diluent, additive, solvent, or encapsulating agent.
  • “Pharmaceutically acceptable” means that it is compatible with other ingredients in the formulation and is not harmful to the patient.
  • Non-limiting examples of pharmaceutically acceptable carriers, carriers, and / or diluents include sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, sodium carboxymethyl cellulose, ethyl cellulose, and.
  • Cellulose and derivatives thereof such as cellulose acetate, excipients such as powdered tragacanth, malt, gelatin, talc, cacao butter and suppository wax, peanut oil, cottonseed oil, benibana oil, sesame oil, olive oil, corn oil, and Of oils such as soybean oil, glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, magnesium hydroxide and aluminum hydroxide.
  • excipients such as powdered tragacanth, malt, gelatin, talc, cacao butter and suppository wax
  • peanut oil cottonseed oil
  • benibana oil sesame oil
  • olive oil corn oil
  • Of oils such as soybean oil
  • glycols such as propylene glycol
  • polyols such as glycer
  • buffers Includes such buffers, argicic acid, starch-free water, isotonic physiological saline, Ringer's solution, ethyl alcohol, phosphate buffer, and other non-toxic compatible substances used in pharmaceutical formulations. .. Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as colorants, release agents, coating agents, sweeteners, flavors and flavors, preservatives, And antioxidants can also be included in the composition.
  • wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as colorants, release agents, coating agents, sweeteners, flavors and flavors, preservatives, And antioxidants can also be included in the composition.
  • compositions disclosed herein that are suitable for oral administration are capsules, cachets, pills, tablets, rhombic tablets (usually using flavor bases that are syrup and acacia or tragant), powders, granules, aqueous or non-aqueous.
  • compositions disclosed herein can be administered as a bolus, lick, or paste.
  • Solid dosage forms for oral administration are one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or.
  • Fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid, binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, moisturizers such as glycerol.
  • Agents agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, disintegrants such as sodium carbonate and sodium glycolicate, dissolution retarders such as paraffin, absorption enhancers such as quaternary ammonium compounds , Wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polypropylene oxide copolymers, absorbents such as kaolin and bentonite clay, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and these. It can be mixed with any of the lubricants, such as mixtures, as well as colorants.
  • the pharmaceutical composition may also include a buffering agent.
  • Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules with additives such as lactose or lactose, as well as high molecular weight polyethylene glycol.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form can include inactive diluents used in the art, such as water or other solvents, solubilizers, emulsifiers, ethyl alcohol, isopropyl alcohol, etc.
  • oils especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil
  • glycerol Tetrahydrofuryl alcohol
  • polyethylene glycol fatty acid ester of sorbitan
  • cyclodextrins such as hydroxypropyl- ⁇ -cyclodextrin can be used to dissolve the compounds.
  • the composition can also include auxiliary agents such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents, and preservatives.
  • Suspensions can include suspending agents in addition to one or more compounds according to the present disclosure, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxydos, etc. Examples include bentonite, agar, and tragacant, as well as mixtures thereof.
  • compositions disclosed herein can be suppositories for rectal or vaginal administration and include one or more compounds according to the present disclosure, such as cocoa butter, polyethylene glycol, suppository wax, salicylate, etc. It can be prepared by mixing with more than a variety of suitable non-irritating additives or carriers and is solid at room temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity to release the compounds of the present disclosure.
  • Pharmaceutical compositions suitable for vaginal administration may also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the prior art.
  • Dosage forms for topical or transdermal administration of the compositions of the present disclosure can include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the pharmaceutical composition or tablet can be mixed under sterile conditions with a pharmaceutically acceptable carrier and possibly required preservatives, buffers, or high pressure gas.
  • Ointments, pastes, creams, and gels in addition to the compositions of the present disclosure, include animal and vegetable fats, oils, waxes, paraffins, starches, tragacants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc, and Additives such as zinc oxide or mixtures thereof can be included.
  • Powders and sprays include, in addition to the pharmaceutical compositions or tablets of the present disclosure, additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Can be done.
  • the spray can include common high pressure gases such as chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane. Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc. are also construed as being within the scope of this disclosure.
  • compositions suitable for parenteral administration can be in sterile isotonic or non-aqueous solutions, dispersions, suspensions, emulsions, or sterile injectable solutions or dispersions that are acceptable as at least one pharmaceutical product. It can contain sterile powders that can be reconstituted.
  • salt includes acids and / or base salts formed by inorganic and / or organic acids and bases.
  • pharmaceutically acceptable salt is used, within certain medical judgment, without undue toxicity, irritation, allergic reactions, and / or similar events. Means these salts, which are suitable for use in contact with the tissue of the subject and are balanced with a legitimate effect / risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. Pharmaceutical Sciences (1977) 66: 1-19 describes in detail pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts can be produced by inorganic or organic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid.
  • suitable organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid.
  • suitable pharmaceutically acceptable salts include adipates, alginates, ascorbates, asparaginates, benzenesulfonates, besilates, benzoates, bisulfates, boroides.
  • the organic acids that can produce salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartrate acid. , Citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.
  • Salts can be prepared in-situ or separately during the separation and purification of the disclosed compounds, such as by reacting the compounds with appropriate bases or acids, respectively.
  • suitable alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • non-limiting examples of suitable pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, as well as halide ions, hydroxide ions, carboxylic acid ions, sulfate ions, phosphorus, as required. Includes amine cations formed using counterions such as acid ions, nitrate ions, lower alkyl sulfonic acid ions, and aryl sulfonic acid ions.
  • Non-limiting examples of suitable organic bases that can give rise to salts include primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and isopropylamines, trimethylamines, diethylamines, Includes basic ion exchange resins such as triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the combination of drugs of the present disclosure may further comprise any additional drug.
  • Additional agents include "chemotherapeutic agents" which are useful compounds in the treatment of cancer, or "cytotoxic agents” which are substances that inhibit or prevent cell function and / or cause cell death or destruction. However, it is not limited to these. Additional agents may also be formulated and administered as a separate composition or as an integral composition with the other agents in the combination of agents of the present disclosure. When administered as separate compositions, they may be administered at the same time or at different times (but while the effects of other medications on the subject persist). In addition, each drug can be administered in different dosage forms and / or methods.
  • Cytotoxicants include, but are not limited to: radioactive isotopes (eg, At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P. 32 , radioactive isotopes of Pb 212 and Lu); chemotherapeutic agents; growth inhibitors; enzymes and fragments thereof (eg, nuclear degrading enzymes); and toxins (eg, small molecule toxins of bacterial, fungal, plant or animal origin) Or an enzyme-active toxin (including fragments and / or variants thereof).
  • radioactive isotopes eg, At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P. 32 , radioactive isotopes of Pb 212 and Lu
  • chemotherapeutic agents eg, growth inhibitors; enzymes and fragments thereof (eg
  • Exemplary cytotoxic agents include anti-microtube agents, platinum coordination complexes, alkylating agents, antibacterial agents, topoisomerase II inhibitors, metabolic antagonists, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptors.
  • Tyrosine kinase Angiogenesis inhibitors immunotherapeutic agents, apoptosis promoters, LDH-A inhibitors; fatty acid biosynthesis inhibitors; cell cycle signaling inhibitors; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors can be selected.
  • chemotherapeutic agents include: erlotinib (Tarceva®, Genentech / OSI Pharm.), Bortezomib (Velcade®, Millennium Pharma.), Disulfiram, epigalolicatekin gallate, salinosporamide.
  • calfilzomib 17-AAG (gerdanamycin), radisicol, lactic acid dehydrogenase A (LDH-A), flubestrant (faslodex®, AstraZeneca), snitib (sutent®, Pphizer / Sugen) ), Retrozol (Femara®, Novartis), Imatinib mesylate (Gleevec®, Novartis), finasunate (Bataranib®, Novartis), Oxaliplatin (Erlotinib®) , Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (silolims, rapamune®, Wyeth), rapatinib (Tykerb®, GSK572016, GlaxoSmith) Kline), Lonafarnib (SCH 66336), Soraphenib (Nexavar®, Bayer Labs), Gefitinib (Iressa
  • Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit hormonal action on tumors (eg, anti-estrogen and selective estrogen receptor modulators (SERMs) (eg, tamoxifen (eg, tamoxifen).
  • SERMs selective estrogen receptor modulators
  • tamoxifen eg, tamoxifen
  • Nolvadex® including tamoxifen citrate), laroxyphene, droroxyfen, iodoxifene, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapriston, and fairstone® (tremifen citrate) ));
  • Aromatase inhibitors that inhibit the enzyme aromatase that regulates estrogen production in the adrenal cortex (eg, 4 (5) -imidazole, aminoglutetimide, megues® (registered trademark) ), Aromasin (registered trademark) (Exemestane; Pphizer), Formestane (formestane), Fadrosol, Ribizol (registered trademark) (Borosol), Femara (registered trademark) (Retrosol; Novartis), and Arimidex (registered trademark) (Anastro).
  • Anti-androgen eg, flutamide, niltamide, bicartamide, leuprolide and gocerelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilvestrol, premarin, fluorixemesterone, all-trans Retinoic acid, fenretinide, and troxacitabin (1,3-dioxolanucleoside cytosine analog); (iv) protein kinase inhibitor; (v) lipid kinase inhibitor; (vi) antisense oligonucleotides (particularly involved in ectopic cell proliferation) Those that inhibit the expression of genes in the signaling pathway, such as PKC- ⁇ , Ralf and H-Ras; (vii) ribozymes (eg, VEGF expression inhibitors (eg, Angiozyme®) and HER2.
  • Anti-androgen eg, flutamide, niltamide,
  • vaccines eg, gene therapy vaccines such as allobectin®, leuvectin®, and tamoxifen®
  • proleukin® rIL-2
  • tamoxifenase 1 Inhibitors eg, Lulttecan®; Avalerix® rmR H
  • pharmaceutically acceptable salts, acids and derivatives of any of the above e.g, Lulttecan®; Avalerix® rmR H.
  • Chemotherapeutic agents also include: antibodies (eg, alemtuzumab (campus), bebasizumab (Avastin®, Genentech); cetuximab (Arbitux®, Imclone); panitumumab (Vectibix®). , Amen), rituximab (rituximab®, Genentech / BiogenIdec), pertuzumab (Omnitag®, 2C4, Genentech), trastuzumab (Herceptin®, Genentech), toshitsumomab (bexa), cox.
  • Gemtuzumab ozogamicin Myrotarg®, Wyeth
  • Additional humanized monoclonal antibodies that have therapeutic potential in combination with the compounds of the present disclosure include: apolizumab: , Acerizumab, Atlizumab, Bapinuzumab, Bibatsuzumab Meltansin, Kantuzumab Meltansin, Cedelizumab, Celtrizumab Pegor, Sidofushitsuzumab, Sidtsuzumab, Dakrizumab, Ecrizumab, Efarizumab, Ephrazmab Zumabu Ozogamycin, Inotsumab Ozogamycin, Ipirimumab, Rabetsuzumab, Linzzumab, Matsuzumab, Mepolizumab, Motabizumab, Motobizumab, Natarizumab, Nimotsuzumab, Norobizumab, Nimotsuzumab, Norobizumab, Numabizumab Raribizumabu, ranibizumab, Resuribizumabu
  • Chemotherapeutic agents also include "EGFR inhibitors,” which refer to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and instead. Also referred to as “EGFR antagonist”. Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include: MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB 8507), MAb. 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see US Pat. No. 4,943,533, Mendelson et al.) And variants thereof (eg, chimeric 225 (C225 or cetuximab; arbitux).
  • ERBUTIX® and a new form of human 225 (rehapped human 225) (H225) (WO 96/40210, Imclone Systems) Inc. (See))); IMC-11F8, fully human EGFR targeting antibody (Imclone); antibody that binds type II mutant EGFR (US Pat. No. 5,212,290); US Pat. No. 5,891,996.
  • EGFR-binding humanized and chimeric antibodies as described in; and EGFR-binding human antibodies eg, ABX-EGF or panitumumab (see WO98 / 50433, Abgenix / Amen)); EMD 55900 (Stragliotto).
  • EMD7200 Humanized EGFR antibody directed against EGFR (EMD / Merck) that competes with both EGF and TGF- ⁇ for EGFR binding. ); Human EGFR antibody, HuMax-EGFR (GenMab); known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3. , US Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279 (29): 30375-30384 (2004)).
  • the anti-EGFR antibody can be conjugated to a cytotoxic agent and thus produce an immunoconjugate (see, eg, EP659,439A2, Merck Patent GmbH).
  • Examples of the EGFR antagonist include the following US patents: US Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, and 5th. , 679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726. , No. 6,713,484, No. 5,770,599, No. 6,140,332, No. 5,866,572, No. 6,399,602, No. 6, No. 344,459, No. 6,602,863, No. 6,391,874, No.
  • Chemotherapeutic agents also include: "tyrosine kinase inhibitors" (including EGFR targeting drugs); small molecule HER2 tyrosine kinase inhibitors (eg, TAK165 available from Takeda); CP-724,714, ErbB2. Oral selective inhibitors of receptor tyrosine kinases (Psizer and OSI); dual HER inhibitors that preferentially bind to EGFR but inhibit both HER2 overexpressing cells and EGFR overexpressing cells (eg, EGFR overexpressing cells).
  • EKB-569 (available from Wyeth)); lapatinib (GSK572016; available from Glaxo-MithKline), oral HER2 and EGFR tyrosine kinase inhibitors; PKI-166 (available from Novartis); general-purpose HER inhibitor (pan-HER inhibitor) (Eg, canertinib (CI-1033; Pharmacia)); Raf-1 inhibitor (eg, antisense agent ISIS-5132 available from ISIS Pharmaceuticals that inhibits Raf-1 signaling); non-HER-targeted TK inhibitor (eg, For example, imatinib mesylate (Gleevec®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitor (eg, sunitinib (Sutent®, available from Psizer)); VEGF receptor tyrosine kinase inhibitor ( For example, bataranib (PTK787 / ZK222584, available from Novartis / Schering
  • pyridopyrimidine pyrimidopyrimidine
  • pyrrolopyrimidine eg, CGP 59326, CGP 60261 and CGP 62706
  • pyrazolopyrimidine 4- (phenylamino) -7H-pyrrolo [2,3-d] pyrimidine
  • curcumin Differuloyl methane, 4,5-bis (4-fluoroanilino) phthalimide
  • tylhostin containing a nitrothiophene moiety PD-0183805 (Warner-Lamber); antisense molecule (eg, HER coding nucleus) Acid-binding); quinoxalin (US Pat. No.
  • Chemotherapeutic agents also include: dexamethasone, interferon, corhitin, metoprin, cyclosporin, amphotelicin, metronidazole, alemtuzumab, aritretinoin, alloprinol, amihostin, diaroxide, asparaginase, BCG raw, bevacizumab (bevacizumab).
  • Chemotherapeutic agents also include: hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortor pivalate, triamsinolone acetonide, triamsinolone alcohol, mometazone, amcinonide, budesonide, desonide, fluosinonide, fluoronecetonide, betametasone , Betamethasone sodium phosphate, dexamethasone, sodium dexamethasone phosphate, fluortron, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, acromethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicalbate, clobetazone-17 -Butylate, clobetazol-17-propionate, fluocortron caproate, fluocortron pivalate and fluprednidene acetate; immunoselective anti-
  • Chlorokin ⁇ -9-tetrahydrocannabinol (dronavinol, marinol®); ⁇ -rapacon; lapacol; corhitin; vincristine; acetylcamptothecin, scopoletin, and 9-aminocamptothecin); podophylrotoxin Tegafur (UFTORAL®); Bexarotene (Targretine®); Bisphosphonates (eg, clodronicate (eg, Bonefos® or OSTAC®)), Ethidronate (Zidrocar (registered trademark)) DIDROCAL (registered trademark)), NE-58095, zoledronic acid / zoledronic acid (Zometa (registered trademark)), alendronate (Fosamax (registered trademark)), pamidronate (Aredia (registered trademark)), chilldronate (skeleid (registered trademark)) (Trademark)), or lys
  • Lonafarnib (SCH 6636, Salazar TM ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; and two or more combinations of the above (eg, CHOP (cyclo).
  • CHOP cyclo
  • Chemotherapeutic agents also include: non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects.
  • NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
  • Specific examples of NSAIDs include: aspirin, propionic acid derivatives (eg ibuprofen, phenoprofen, ketoprofen, flurubiprofen, oxaprozin and naproxen), acetic acid derivatives (eg indomethacin, sulindac, etdrac, diclofenac).
  • Enolic acid derivatives eg, pyroxycam, meroxycam, tenoxycam, droxycam, lornoxicum and isoxycam
  • phenamic acid derivatives eg, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid
  • COX-2 inhibitors eg, cerecoxib, Etricoxyb, Lumilacoxib, Parecoxib, Rofecoxib, Rofecoxib, and Valdecoxib).
  • NSAIDs include rheumatoid arthritis, osteoarthritis, inflammatory arthritis, tonic spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, menstrual difficulty, metastatic bone pain, headache and migraine pain, surgery It can be indicated for symptom relief of conditions such as post-pain, inflammation and tissue damage resulting in mild to moderate pain, fever, ileus, and rheumatoid arthritis.
  • Chemotherapeutic agents may also include: treatments for Alzheimer's disease (eg, donepezil hydrochloride and rivastigmin); treatments for Parkinson's disease (eg, L-dopa / carvidopa, interferon, ropinrole), pramipexol, bromocryptin, Pergolide, trihexefendyl, and amantadine; drugs for treating multiple sclerosis (MS) (eg, ⁇ interferon (eg, Avonex® and Levif®), glatiramer acetate) , And mitoxantrone); treatment of asthma (eg, albuterol and monotelcastoso); drugs for treating schizophrenia (eg, Zyprexa, Rispadal, Seroquel, and haloperidol); anti-inflammatory agents (eg, corticosteroids) , TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazin
  • chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of the chemotherapeutic agents described herein, as well as two or more combinations thereof. ..
  • Drugs for the treatment of unresectable advanced / recurrent colorectal cancer may be provided.
  • Pharmaceuticals for the treatment of unresectable advanced / recurrent colorectal cancer in PD-L1 positive patients may be provided.
  • Drugs for the treatment of unresectable advanced / recurrent right colorectal cancer in PD-L1 positive patients may be provided.
  • Drugs for the treatment of unresectable advanced / recurrent right colorectal cancer (microsatellite stability) in PD-L1 positive patients may be provided.
  • the drug may include napabucasin as an active ingredient.
  • the drug, in combination with pembrolizumab can usually be administered daily to adults at 240 mg / day as napabucasin.
  • PD-L1 IHC 22C3 pharm Dx "Dako" can be used.
  • the microsatellite stability test can be a microsatellite instability (MSI) test by PCR or a mismatch repair (MMR) -related protein test by immunohistochemical staining (IHC).
  • compositions for the treatment of colorectal cancer classified as unresectable advanced / recurrent CMS1 or CMS4 may be provided. Pharmaceuticals for the treatment of unresectable advanced / recurrent colorectal cancer classified as CMS1 or CMS4 may be provided. Pharmaceuticals for the treatment of unresectable advanced / recurrent colorectal cancer (microsatellite stability) classified as CMS1 or CMS4 may be provided. Pharmaceuticals for the treatment of unresectable advanced / recurrent colorectal cancer (microsatellite stability) classified as CMS1 or CMS4 may be provided.
  • the drug may include napabucasin as an active ingredient. The drug, in combination with pembrolizumab, can usually be administered daily to adults at 240 mg / day as napabucasin.
  • CMS Classification can be determined by the subtype classification algorithm of Guinney et al. By measuring gene expression in tumor tissues by RNA sequencing or microarray etc. (Guinney J, et al .: Nat Med. 21 (11): 1350- 1356, 2015).
  • the above-mentioned patient is specified as a treatment target, and such a feature gives an instruction to a medical professional who treats a doctor or the like. Therefore, it may be described in the package insert or label, but it is possible to give treatment guidelines to doctors and the like based on other sources other than these official documents.
  • Example 1 Effectiveness of concomitant drug in MSS patients
  • FIG. 1 An outline of the test design in this example is shown in FIG. This is an open-label, multicenter, phase Ib / II clinical trial, and is effective in combination with napabucasin and pembrolizumab in patients with standard chemotherapy refractory, intolerant unresectable, recurrent colorectal cancer, and rectal cancer. And safety was evaluated exploratively.
  • Phase Ib the safety of the combination of napabucasin and pembrolizumab was evaluated in patients with standard chemotherapy refractory, intolerant, unresectable, and recurrent gastrointestinal cancer, and the recommended dose of napabucasin was determined.
  • Chemotherapy history includes patients with gastrointestinal cancer who are refractory and intolerant to standard chemotherapy in Phase Ib, and have a history of standard chemotherapy of 1 or more regimens for metastatic colon / rectal cancer in Phase II. , Patients who are refractory or intolerant to those chemotherapy , 5. Patients with an ECOG performance status (PS) of 0 or 1, 6. Patients who can orally administer the drug, 7.
  • PS ECOG performance status
  • Phase II Cohort A Patients with evaluable lesions (Phase Ib and Phase II Cohort A) or measurable lesions (Phase II Cohort B) as defined in RECIST version 1.1, 8. Patients with sufficient organ function, 9. Pregnant women are negative on pregnancy tests within 7 days prior to enrollment.
  • phase Ib phase the study drug was administered for 21 days per course, 240 mg or 480 mg of napabucasin was taken twice daily, and pembrolizumab 200 mg / body was administered on day 1 of each cycle.
  • one course was 21 days, and 480 mg of napabucasin was taken orally twice a day every day and administered to day 1 of each cycle of pembrolizumab.
  • a total of 8 subjects were evaluated in Phase 1b, and 10 subjects in Cohort A and 40 subjects in Cohort B were evaluated in Phase 2.
  • Tumor shrinkage effect is shown in the Waterfall plot of FIG.
  • Tumor shrinkage effect is irRECIST (immune-related) that applies new guidelines (RECIST guidelines) ver1.1 or RECIST v1.1 for determining the therapeutic effect of solid tumors to the evaluation method of tumor shrinkage effect seen in immunotherapy. Judgment was made based on response criteria).
  • PR Partial Response: defined as a 30% or more reduction in the sum of target lesions compared to the sum of baseline diameters
  • ORR objective response rate
  • Progression free survival (PFS) in patients with MSS colorectal cancer is shown in FIG.
  • PFS progression-free survival rate
  • FAS Full Analysis Set
  • Progression free survival was evaluated.
  • the PFS is defined as the period from the date of registration to the date of exacerbation or the date of death due to any cause, whichever comes first.
  • PFS estimated the survival function using the Kaplan-Meier method. Median PFS for MSS colorectal cancer was 1.6 months.
  • FIG. 1 FAS showing overall survival (OS) in patients with MSS colorectal cancer is shown in FIG.
  • the overall survival (OS) was evaluated.
  • the OS uses the registration date as the starting date. It was defined as the period until the date of death due to any cause.
  • the OS also performed the same analysis as PFS. Results
  • the median OS for MSS colorectal cancer was 7.3 months.
  • Figure 5 shows the frequency and grade of adverse events that occurred in subjects who received napabucasin and pembrolizumab combination therapy.
  • Adverse events subjective and objective symptoms
  • An adverse event is any unfavorable or unintended sign (including abnormal changes in laboratory test values), symptoms, or illness that occur in a subject who received the study drug and has a causal relationship with the study drug. It was defined as having or not having it.
  • the incidence of adverse events is the worst grade in the entire course by CTCAE v4.03-JCOG for each adverse event for the population (SP: Safety Population) for which this study treatment was performed even once among all registered cases. The frequency was calculated.
  • the adverse events that occurred in 20% or more of the SPs of cohort A and cohort B were diarrhea, vomiting, loss of appetite, and vomiting. There were no significant differences in adverse events, frequency and severity of monotherapy with napabucasin and pembrolizumab, and the combination therapy was tolerable.
  • the ORR for the presence or absence of PD-L1 expression is shown in FIG. PDs were cut out from a formalin-fixed paraffin-embedded (FFPE) tissue block of 40 MSS colon cancer and 10 MSI-High colon cancer subjects for whom tumor specimens could be submitted at baseline to a thickness of 5 ⁇ m. -Stained with L1 IHC 22C3 tumorDx "Dako". Of the 5 MSS colorectal cancer subjects whose PD-L1 expression was 1% or more on tumor cells, 4 had right colorectal cancer and 1 had left side colorectal cancer. The ORRs of MSS right and left colorectal cancers that were positive for PD-L1 on tumor cells were 3/4 (75%) and 0/1 (0%), respectively.
  • FFPE formalin-fixed paraffin-embedded
  • FIG. 1 A classification method proposed by the Colon Cancer Subtyping Consortium (CRCSC) by extracting RNA from the tumor tissue of subjects for whom tumor specimens could be submitted at baseline and analyzing gene expression using RNA sequencing. Subjects were classified into CMS 1-4 by molecular subtype based on (Guinney J, et al .: Nat Med. 21 (11): 1350-1356, 2015). Of the 31 subjects for whom tumor specimens could be submitted at baseline, 5 were CMS1 (including 2 with MSI colon cancer), 6 were CMS2, 4 were CMS3, and 6 were CMS4, unknown or unmeasurable. Was 10 people.
  • CMS1 including 2 with MSI colon cancer
  • ORR and Clinical of MSS colorectal cancer patients classified as CMS 1 or 4 Benefits were 3/9 (33%) and 4/9 (44%), respectively, and the ORR and Clinical Benefit of MSS colorectal cancer patients classified as CMS 1 or 4 whose primary lesion was on the right side. was 3/5 cases (60%) and 4/5 cases (80%), respectively.
  • the ORRs of MSS colorectal cancer patients classified into CMS2 or CMS3 were 0 cases / 6 cases (0%) and 1 case / 4 cases (25%), respectively.
  • Successful cases of pembrolizumab alone have been reported (Laetitia Nebot-Bral, et al. European Journal of Cancer 84 (2017) 290e303, J. Gong, et al, J. Natl. Compr. Canc.
  • CMS3 may also be successful with pembrolizumab alone. From these results, it was suggested that CMS 1 or 4 may be useful as a factor predicting the therapeutic effect of this combination therapy in patients with MSS colorectal cancer.
  • Example 2 AI / IoT / cloud service (SaaS)
  • the storage unit for storing the patient characteristic information of a plurality of patients and the responsiveness information of the plurality of individuals, the patient characteristics of the plurality of individuals, and the responsiveness information of the plurality of individuals, the patient characteristics
  • a calculation that predicts the responsiveness of a patient from the patient characteristics of a patient based on the relationship between the information and the responsiveness of the patient characteristics and the learning unit configured to learn the relationship between the patient and the responsiveness.
  • Information such as microsatellite stability information, PD-L1 expression information, cancer primary site information and CMS information and information on responsiveness to cancer treatment are obtained from a plurality of patients and stored in the storage unit.
  • the obtained information is learned by machine learning to generate a discriminant model.
  • the obtained information is applied to a discrimination model in the calculation unit to predict the responsiveness to cancer treatment.
  • the information may be transmitted from a terminal installed in a hospital or the like to a calculation unit on the cloud that stores the discrimination model.
  • the result is returned to the terminal or the display is used to convey the result to the user.
  • the present disclosure can be used in cancer therapeutic agents or companion diagnostic agents for cancer therapeutic agents, or in any procedure using them.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002541481A (ja) * 1999-04-09 2002-12-03 リグズホスピタレット 癌マーカーとしての１型マトリクスメタロプロテイナーゼ組織阻害剤（ｔｉｍｐ−１）
JP2007224009A (ja) * 2006-01-26 2007-09-06 Takeda Chem Ind Ltd 癌の予防・治療剤
JP2018521979A (ja) * 2015-06-03 2018-08-09 ボストン バイオメディカル， インコーポレイテッド 癌の治療に使用するための癌幹細胞性阻害剤および免疫療法剤を含む組成物

Family Cites Families (4)

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WO2019023525A1 (en) * 2017-07-28 2019-01-31 Dana-Farber Cancer Institute, Inc. ENHANCED IMMUNOTHERAPY OF CANCER USING TARGETED TRANSCRIPTION MODULATORS
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Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002541481A (ja) * 1999-04-09 2002-12-03 リグズホスピタレット 癌マーカーとしての１型マトリクスメタロプロテイナーゼ組織阻害剤（ｔｉｍｐ−１）
JP2007224009A (ja) * 2006-01-26 2007-09-06 Takeda Chem Ind Ltd 癌の予防・治療剤
JP2018521979A (ja) * 2015-06-03 2018-08-09 ボストン バイオメディカル， インコーポレイテッド 癌の治療に使用するための癌幹細胞性阻害剤および免疫療法剤を含む組成物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KAWAZOE A. ET AL: "Multicenter phase 1/11 trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP trial", CLINICAL CANCER RESEARCH, vol. 29, no. 11, July 2020 (2020-07-01), pages 2240 - 2246, XP055796645, DOI: 10.1158/1078-0432.CCR-20-1803 *
KRYEZIU K. ET AL.: "Combination therapies with HSP90 inhibitors against colorectal cancer", BBA REVIEWS ON CANCER, vol. 71, 18 January 2019 (2019-01-18), pages 240 - 247, XP085692941, DOI: doi.org/10.1016/j.bbcan. 2019.01.00 2 *
MOOI J.K., WIRAPATI P., ASHER R., LEE C.K., SAVAS P., PRICE T.J., TOWNSEND A., HARDINGHAM J., BUCHANAN D., WILLIAMS D., TEJPAR S.,: "The prognostic impact of consensus molecular subtypes(CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial", ANNALS OF ONCOLOGY, vol. 29, 2018, pages 2240 - 2246, XP055796645 *
SHINOZAKI E. ET AL.: "Multicenter phase 1/11 trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP study):EPOC1503", JOURNAL OF CLINICAL ONCOLOGY, vol. 36, no. 15, 2018 *

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