WO2022102731A1 - Ｅｐ４拮抗薬と免疫チェックポイント阻害物質との併用によるがん治療 - Google Patents

Ｅｐ４拮抗薬と免疫チェックポイント阻害物質との併用によるがん治療 Download PDF

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WO2022102731A1
WO2022102731A1 PCT/JP2021/041650 JP2021041650W WO2022102731A1 WO 2022102731 A1 WO2022102731 A1 WO 2022102731A1 JP 2021041650 W JP2021041650 W JP 2021041650W WO 2022102731 A1 WO2022102731 A1 WO 2022102731A1
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therapy
administered
administration
alkyl
cancer
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PCT/JP2021/041650
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French (fr)
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真紀 近藤
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小野薬品工業株式会社
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Priority to US18/035,608 priority Critical patent/US20230390303A1/en
Priority to KR1020237015423A priority patent/KR20230107228A/ko
Priority to JP2022562190A priority patent/JPWO2022102731A1/ja
Priority to EP21891976.9A priority patent/EP4245301A1/en
Publication of WO2022102731A1 publication Critical patent/WO2022102731A1/ja

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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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Definitions

  • the present disclosure relates to a cancer treatment method using a combination of standard treatment and an EP4 antagonist and an immune checkpoint inhibitor.
  • Prostaglandin E 2 is known as a metabolite in the arachidonic acid cascade, and has cytoprotective action, uterine contraction action, pain threshold lowering action, gastrointestinal peristaltic motility promoting action, wakefulness action, and gastric acid. It is known to have a secretory inhibitory effect, a blood pressure lowering effect, a diuretic effect, and the like.
  • Non-Patent Document 1 PGE2 receptors have subtypes with different roles. There are roughly four subtypes known at present, and they are called EP 1 , EP 2 , EP 3 , and EP 4 , respectively.
  • the EP4 receptor suppresses MCP-1 production from macrophages, suppresses TNF- ⁇ , IL-2, and IFN- ⁇ production from lymphocytes, and anti-inflammatory by enhancing IL-10 production. , Vascular dilation, angiogenesis, suppression of elastic fiber formation, and regulation of MMP-9 expression.
  • EP4 receptors are thought to be involved in cancer immunoregulation via bone marrow-derived immunosuppressive cells (Myeloid Derived Suppressor Cells), regulatory T cells and natural killer cells.
  • Non-Patent Document 2-7 compounds that strongly bind to the EP4 receptor and have an antagonistic effect are diseases caused by activation of the EP4 receptor, such as bone disease, cancer, systemic granuloma, immune disease, allergy, and atopy.
  • diseases caused by activation of the EP4 receptor such as bone disease, cancer, systemic granuloma, immune disease, allergy, and atopy.
  • Stress, endometriosis, uterine adenomyosis, neonatal arterial duct patency, cholelithiasis, etc. are considered to be useful for
  • Patent Document 1 discloses that the compound represented by the general formula (I) has an EP4 antagonism and is useful as a therapeutic agent for cancer (see Patent Document 1).
  • the immune checkpoint inhibitor is a new therapeutic method that cancels the immunosuppressive mechanism and activates the immune response to cancer.
  • anti-CTLA-4 cytotoxic T lymphocyte-associated antibody
  • anti-PD-1 programmed cell death-1 antibody nivolumab and pembrolizumab have been approved in Japan and overseas and are used in cancer treatment. ..
  • Patent Document 2 discloses that a combination of a compound represented by the general formula (I) and an immune checkpoint inhibitor is useful for cancer treatment (see Patent Document 2).
  • the main treatment for unresectable advanced / recurrent colorectal cancer is drug therapy, and standard treatment with fluorinated pyrimidine antineoplastic agents, oxaliplatin, irinotecan, etc. is one of them.
  • XELOX and bevacizumab (hereinafter, may be abbreviated as "XELOX + bevacizumab therapy").
  • FOLFIRINOX therapy using a regimen containing fluorouracil (5-FU) in combination with oxaliplatin and irinotecan (hereinafter, “. It may be abbreviated as "FFX therapy"), and in the hope of reducing toxicity from FFX therapy, rapid administration of fluorouracil may be omitted and modified FOLFIRINOX therapy (hereinafter, abbreviated as "mFFX therapy”) in which the dose of irinotecan is reduced. ) Or a combination of gemcitabine and nabpacritaxel (hereinafter, may be abbreviated as "GnP therapy”).
  • FFX therapy modified FOLFIRINOX therapy
  • GnP therapy a combination of gemcitabine and nabpacritaxel
  • drug therapy is the main treatment for stage IV or relapsed non-small cell lung cancer, and combination therapy with docetaxel and ramucirumab (hereinafter, may be abbreviated as "DTX + RAM therapy”) or docetaxel therapy as standard therapy. (Hereinafter, it may be abbreviated as "DTX therapy”).
  • An object of the present invention is to provide a new treatment method for cancer (for example, colorectal cancer, pancreatic cancer, lung cancer).
  • cancer for example, colorectal cancer, pancreatic cancer, lung cancer.
  • EP4 receptor antagonist and immune checkpoint inhibitor in standard treatment can be an effective cancer treatment method.
  • further administration of EP4 receptor antagonists or EP4 receptor antagonists and immune checkpoint inhibitors to patients who have undergone prechemoradiation therapy may be an effective cancer treatment (both).
  • the treatment method of the present invention may be abbreviated as the treatment method of the present invention.
  • [1] Standard therapies ((i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, (vi) docetaxel therapy, or (vi) dosetaxel and ramsilmab therapy), and A cancer progression-suppressing, recurrence-suppressing and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, characterized by administration in combination with administration of an immune checkpoint inhibitor, or [2] standard therapy (((2] standard therapy.
  • a cancer progression-suppressing, recurrence-suppressing and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, characterized by being administered in combination.
  • a cancer progression-suppressing, recurrence-suppressing and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, which is characterized by being administered.
  • the present invention provides a new cancer treatment method.
  • FIG. 1 evaluates the tolerability, safety, and efficacy of compound A, nivolumab, described below, in combination with XELOX + bevacizumab therapy in patients with unresectable advanced or recurrent colorectal cancer.
  • FIG. 2 shows the safety, efficacy and pharmacokinetics of compound A and nivolumab described below as neoadjuvant therapy after preoperative chemoradiotherapy for locally advanced rectal cancer that can be curatively resected.
  • FIG. 1 evaluates the tolerability, safety, and efficacy of compound A, nivolumab, described below, in combination with XELOX + bevacizumab therapy in patients with unresectable advanced or recurrent colorectal cancer.
  • FIG. 2 shows the safety, efficacy and pharmacokinetics of compound A and nivolumab described below as neoadjuvant therapy after preoperative chemoradiotherapy for locally advanced rectal cancer
  • FIG. 3 is a multicenter non-cooperative evaluation of the tolerability, safety and efficacy of compound A, nivolumab described below in combination with mFFX therapy or GnP therapy in patients with pancreatic cancer with distant metastasis. The outline of the blinded uncontrolled trial is shown.
  • FIG. 4 shows the compounds A, nivolumab and docetaxel described below in patients with advanced or recurrent non-small cell lung cancer refractory to combination therapy including anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparations.
  • the EP4 antagonist is not particularly limited as long as it is a compound having an EP4 antagonist action, but in one embodiment, the general formula (I):
  • R 1 represents COOR 8 , tetrazole, SO 3 H, SO 2 NH 2 , SO 2 NHR 8-1 , CONHSO 2 R 8-1 , SO 2 NHCOR 8-1 , or hydroxamic acid.
  • R 8 represents a hydrogen atom, C1-4 alkyl, or benzyl
  • R 8-1 represents C1-4 alkyl, C1-4 haloalkyl, C3-10 carbocycle, or 3-10 membered heterocycle, and the C3-10 carbocycle and 3-10 membered heterocycle, respectively, is C1.
  • L 1 represents C1-5 alkylene, C2-5 alkenylene, or C2-5 alkinylene, R2 is halogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C2-4alkenyl, C2-4alkynyl, -O (C1-4haloalkyl), -S (C1-4haloalkyl),- C (O) (C1-4 alkyl), -SO 2 (C1-4 alkyl), -CONH (C1-4 alkyl), -CON (C1-4 alkyl) 2 , -NHC (O) (C1-4 alkyl) ), -N (C1-4 alkyl) C (O) (C1-4 alkyl) (C1-4 alkyl) (C1-4 alkyl) (C1-4 alkyl)
  • the C1-4 alkyl may be substituted with halogen and may be substituted.
  • (C1-4alkyl) 2 in the R2 represents two independent C1-4 alkyls, each of which may be the same or different.
  • X 1 represents CR 6 or nitrogen atom
  • R 6 represents hydrogen atom or
  • X 2 represents CR 7 or nitrogen atom
  • R 7 represents hydrogen atom
  • R 2 or -L 3 -R 9 and L 3 represents methylene, oxygen atom or sulfur atom which may be oxidized.
  • R 9 represents a 4-10 membered heterocycle which may be substituted with a substituent selected from the group consisting of halogen, C1-4alkyl, and C1-4haloalkyl.
  • each said C1-4 alkyl may be substituted with a halogen.
  • ring represents a benzene ring or a 5-6 member monocyclic aromatic heterocycle.
  • R5 is ( 1 ) halogen, (2) C1-4alkyl, (3) carboxyl, (4) nitrile, (5) -CONHR 11 , (6) -C (O) R 12 , (7) -OR.
  • R 14 (8) -S (O) t R 15 , (9) -CH 2 R 16 , (10) -NR 17 R 17 , (11) -NHCOR 11 , (12) C4-10 carbocycle, or ( 13) Represents a 4-10 membered heterocycle, the C4-10 membered ring or the 4-10 membered heterocycle may be substituted with 1 to 3 R18s , and if there are multiple R18s , then R Each of the 18 may be the same or different independently.
  • R 11 represents a C1-6 alkyl, C3-6 cycloalkyl, phenyl, or 4-6 membered heterocycle, where R 11 may be substituted with 1 to 3 R 13s , wherein the R 13s are plural.
  • R 13 may be independently the same or different, respectively.
  • R 13 represents a halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, hydroxyl group, -NR 20 R 21 , benzene, or 4-6 membered heterocycle.
  • R 20 and R 21 independently represent a hydrogen atom or C1-4 alkyl, respectively.
  • R 12 represents a C1-6 alkyl, C3-6 cycloalkyl, benzene, or 4-6 membered heterocycle, and the C3-6 cycloalkyl, benzene, or 4-6 membered heterocycle is independent of each other. It may be substituted with halogen, C1-4alkyl, or C1-4alkoxy.
  • R 14 represents a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl, wherein the C1-6 alkyl may be substituted with 1 to 3 R 19s , where the R 19 is. When there are a plurality of R 19 , each of them may be independently the same or different. R 19 is substituted with a substituent selected from the group consisting of C1-4 alkoxy, -CONH (C1-4 alkyl), -CON (C1-4 alkyl) 2 , or C1-4 alkyl and C1-4 haloalkyl. Represents a 5-6 member monocyclic aromatic heterocycle which may be present.
  • the (C1-4 alkyl) 2 in the R 19 represents two independent C1-4 alkyls, each of which may be the same or different.
  • R 15 represents C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl.
  • R 16 represents a hydroxyl group or C1-4 alkoxy and represents R 17 independently represent a hydrogen atom, C1-6 alkyl, or C3-6 cycloalkyl, respectively.
  • R18 is halogen, C1-6alkyl, C3-6cycloalkyl , C1-4alkoxy, oxo, nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C1-4alkyl) SO 2- , Represents a 4-6 membered heterocycle, (C1-4 alkyl) NH-, or (C1-4 alkyl) 2 N-.
  • the (C1-4 alkyl) 2 in the R 18 represents two independent C1-4 alkyls, each of which may be the same or different.
  • m represents an integer of 1 to 4
  • n represents an integer of 0 to 4
  • p represents an integer of 0 to 2
  • q represents an integer of 0 to 6
  • r represents an integer of 0 to 6.
  • R 2 , R 3 , R 4 , and R 5 may be independent and may be the same or different. ), Or a salt thereof.
  • EP4 antagonist AN0025, E7046, IK-007, RMX-1002, grapprant, AAT-007, CR6086, INV-1120, BYD-001, TT-038, DT095895, P-001, ER-819762, MK-2894, MF498, animal page, CJ-042794, EP4A, BGC201531, CJ-023423, GW627368, AH23848, DT-9081, or WO2001 / 062708, WO2002 / 020462, WO2002 / 0232900, WO2002.
  • C1-4 alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl.
  • C1-3 alkyl is, for example, methyl, ethyl, n-propyl, and isopropyl.
  • C1-5 alkylene is, for example, methylene, ethylene, propylene, butylene, and pentylene.
  • C2-5 alkenylene means, for example, ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3 -Pentenylene, 4-pentenylen, etc.
  • C2-5 alkynylene means, for example, ethynylene, 1-propinilen, 2-propinilen, 1-butinilen, 2-butinilen, 3-butinilen, 1-pentinylene, 2-pentinylene, 3-pentinylene, and 4-Pentinylene, etc.
  • halogen is fluorine, chlorine, bromine, and iodine.
  • C1-4 alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, tert-butoxy, isobutoxy and the like.
  • C1-4 alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, tert-butylthio, isobutylthio and the like.
  • the "C2-4 alkenyl” is, for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and the like.
  • C2-4 alkynyl is, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.
  • C1-4 haloalkyl means C1-4 alkyl substituted with halogen, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-Difluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, 1 , 2,2,2-Tetrafluoroethyl, 1,1,2,2-Tetrafluoroethyl, Pentafluoroethyl, 1,2-Dibromo-1,2,2-Trifluoroethyl, 1-Chloro-1,2 , 2,2-Tetrafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2-fluoropropyl, 2-chloropropyl, 2-chloro
  • the "sulfur atom which may be oxidized" refers to sulfur (S), sulfoxide (S (O)), and sulfone (SO 2 ).
  • the "4-10-membered heterocycle” is a 4-10-membered monocyclic or bicyclic heterocycle containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • Means for example, oxetane, azetidine, pyrrolidine, pyrrol, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazin, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, Thiopirane, Thiepin, Oxazole, Isoxazole, Thiazol, Isothiazole, Frazan, Oxazole, Oxazole, Oxazole, Oxazolepine, Oxazolezepine, Thiasiazol, Thiazin, Thiasiazin, Thiazepine, Thiasiazepin
  • the "3-10 membered heterocycle” is a 3-10 membered monocyclic or bicyclic heterocycle containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • the "5-10-membered aromatic heterocycle” is a 5-10-membered monocyclic or bicyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. It means an aromatic heterocycle and means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, frazan, oxadiazole, thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, Indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, purine, benzoxazole, benzothiazole, benzoimidazole, benzoflazan, benzothiazole, benzotriazole,
  • the "5-6-membered monocyclic aromatic heterocycle” means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole. , Isothiazole, Frazan, Oxadiazole, and Thiadiazole rings.
  • C4-10 carbocycle means a monocyclic or bicyclic carbocycle of C4 to 10, for example, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene.
  • Cyclohexene Cycloheptene, Cyclooctene, Cyclopentadiene, Cyclohexadiene, Cycloheptadiene, Cyclooctane
  • Benzene Pentalene, Perhydropentalene, Azulene, Perhydroazulene, Inden, Perhydroinden, Indan, Naphthalene, Dihydronaphthalene, Tetrahydronaphthalene, perhydronaphthalene ring and the like.
  • C3-10 carbocycle means a monocyclic or bicyclic carbocycle of C3-10, for example, cyclopropane, the carbocycle described in the above-mentioned "C4-10 carbocycle", and the like. Is.
  • C1-6 alkyl means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3 -Methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 2-methyl-2-ethylpropyl, 1 -Ethylbutyl, 2-ethylbutyl and the like.
  • C3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the "4-6 membered heterocycle” means a 4-6 membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • R 1 is preferably COOR 8 .
  • R8 is preferably a hydrogen atom or a C1-4 alkyl, and more preferably a hydrogen atom.
  • R8-1 is preferably C1-4alkyl, benzene or pyridine, the benzene and pyridine being C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, -O (C1-4haloalkyl). ), C1-4 alkylthio, -S (C1-4 haloalkyl), halogen, or nitrile may be substituted.
  • L 1 is preferably C1-5 alkylene or C2-5 alkenylene, more preferably C1-5 alkylene, and particularly preferably propylene.
  • R 2 is preferably fluorine.
  • X 1 is preferably CR 6 .
  • R6 is preferably a hydrogen atom or fluorine, and more preferably a hydrogen atom.
  • X 2 is preferably CR 7 .
  • R 7 is preferably fluorine, nitrile, -CH 2 R 9 , or -OR 9 , and more preferably nitrile.
  • R9 is preferably a 4-10-membered heterocycle optionally substituted with methyl or trifluoromethyl
  • the 4-10-membered heterocycle is preferably a 5-10-membered aromatic heterocycle.
  • More preferably 5-10-membered nitrogen-containing aromatic heterocycles eg, pyrazole, imidazole, triazole, pyrrolopyridine, pyrrolopyrimidine, pyropyridazine, imidazolipyridazine, imidazolepyridine, imidazolipyrimidine, imidazolepyrazine, pyrazolopyridine, pyrazolo). (Pyrimidine, etc.).
  • R3 is preferably fluorine.
  • R4 is preferably methyl, ethyl, or trifluoromethyl, more preferably methyl.
  • X3 is preferably methylene or an oxygen atom, and more preferably an oxygen atom.
  • R10 is preferably methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl, ethylsulfonyl, or tert-butoxycarbonyl.
  • the ring is preferably a benzene, thiophene, or pyrazole ring, and more preferably a benzene ring.
  • R5 is preferably ⁇ CONHR 11 , fluorine, methoxy, benzene ring, or 4-10 membered heterocycle
  • the 4-10 membered heterocycle is preferably azetidine, pyrridine, piperidine, oxazolidine, oxadi.
  • R11 is preferably C1-6alkyl, C3-6cycloalkyl , pyran, pyrrolidine, piperidine, pyrazole, thiazole, oxazole, isoxazole, pyridine, pyridazine, or pyrimidine ring, and more preferably C1-. It is 6-alkyl.
  • R 13 is preferably halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, hydroxyl group, ⁇ NR 20 R 21 , benzene, oxetane, pyridine, pyrazole, or oxazole ring. More preferably, fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, cyclopentyl, cyclobutyl, oxetane, hydroxyl group, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, benzene. , Pyridine, pyrazole, or oxazole ring.
  • R20 is preferably a hydrogen atom or methyl.
  • R 21 is preferably a hydrogen atom or methyl.
  • R12 is preferably C1-3 alkyl, C3-6 cycloalkyl, benzene, or a 4-6 membered heterocycle.
  • the 4-6-membered heterocycle is preferably oxetane, azetidine, pyrrolidine, piperidine, pyrazine, pyrazine, thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, pyrrol, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, and the like.
  • the 4-6 membered heterocycle may be substituted with C1-4 alkoxy.
  • R14 is preferably a hydrogen atom, methyl, ethyl, benzene, or benzyl.
  • R 19 is preferably methoxy, -CONHCH 3 , -CON (CH 3 ) 2 , oxazole, thiazole, pyrazole, or a pyridine ring.
  • R15 is preferably methyl, cyclopropyl, or benzene.
  • R 16 is preferably a hydroxyl group.
  • R 17 is preferably methyl, ethyl, or cyclopropyl, and more preferably methyl.
  • R18 is preferably fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, oxo. , Nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, methylsulfonyl, pyridine, dimethylamino.
  • m is preferably an integer of 1 to 2, and more preferably 1.
  • n is preferably an integer of 0 to 1, and more preferably 1.
  • p is preferably 0.
  • q is preferably 0.
  • r is preferably an integer of 0 to 4, and more preferably an integer of 0 to 2.
  • s is preferably an integer of 0 to 2, and more preferably 1 or 2.
  • t is preferably an integer of 0 to 2.
  • X 3a is preferably an oxygen atom.
  • na is preferably an integer of 0 to 1, and more preferably 1.
  • qa is preferably 0.
  • ra is preferably an integer of 0 to 2.
  • the general formula (I) is preferably ring, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8-1 , R 9 , R. 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21, R 21 , L 1 , L 2 , L 3 , X 1 , X 2 , X 3 , a combination of preferred definitions of each of m, n, p, q, r, s, and t.
  • the compound represented by the general formula (I) is preferably the general formula (Ia).
  • na represents an integer of 0 to 1
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4, and other symbols have the same meanings as above.
  • a salt thereof more preferably the general formula (I-1).
  • na represents an integer of 0 to 1
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4
  • X 3a represents a methylene or oxygen atom, and other symbols represent the above. It has the same meaning as), or a salt thereof.
  • na represents an integer of 0 to 1
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4, and other symbols have the same meanings as above.
  • a salt thereof more preferably the general formula (Ic).
  • na represents an integer of 0 to 1
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4, and other symbols have the same meanings as above.
  • a salt thereof still more preferably the general formula (Id).
  • na represents an integer of 0 to 1
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4, and other symbols have the same meanings as above.
  • na represents an integer of 0 to 1
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4, and other symbols have the same meanings as above.
  • a salt thereof particularly preferably the general formula (I-2).
  • R 2a represents a halogen
  • R 6a represents a hydrogen atom or a halogen
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4
  • other symbols have the same meanings as above. Represented
  • a salt thereof most preferably the general formula (I-4).
  • R 2a represents a halogen
  • R 6a represents a hydrogen atom or a halogen
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4, and other symbols have the same meanings as above. Represented
  • a salt thereof or a salt thereof.
  • R 5a is a C4-10 carbocycle or a 4-10-membered heterocycle that may be substituted with 1 to 3 R 18 , and the R 18 is plural, then the R 18 is They may be the same or different independently, na represents an integer of 0 to 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, and other symbols have the same meanings as above. It is a compound represented by (1) or a salt thereof, and more preferably the general formula (Ig).
  • R 5a is a C4-10 carbocycle or a 4-10-membered heterocycle that may be substituted with 1 to 3 R 18 , and the R 18 is plural, then the R 18 is They may be the same or different independently, na represents an integer of 0 to 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, and other symbols have the same meanings as above. It is a compound represented by (1) or a salt thereof, and more preferably the general formula (Ih).
  • R 5a is a C4-10 carbocycle or a 4-10-membered heterocycle that may be substituted with 1 to 3 R 18 , and the R 18 is plural, then the R 18 is They may be the same or different independently, na represents an integer of 0 to 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, and other symbols have the same meanings as above. It is a compound represented by (1) or a salt thereof, and more preferably the general formula (Ii).
  • R 5a is a C4-10 carbocycle or a 4-10-membered heterocycle that may be substituted with 1 to 3 R 18 , and the R 18 is plural, then the R 18 is They may be the same or different independently, na represents an integer of 0 to 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, and other symbols have the same meanings as above. It is a compound represented by (1) or a salt thereof, and is particularly preferably the general formula (I-3).
  • R 2a represents a halogen
  • R 6a represents a hydrogen atom or a halogen
  • R 5a may be substituted with 1 to 3 R 18s , a C4-10 carbocycle or a 4-10 member complex.
  • R 18s when the R 18s are plural, the R 18s may be independently the same or different, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, and others.
  • the symbol has the same meaning as above.
  • Is a compound represented by the above, or a salt thereof, and most preferably the general formula (I-5).
  • R 2a represents a halogen
  • R 6a represents a hydrogen atom or a halogen
  • R 5a may be substituted with 1 to 3 R 18s , a C4-10 carbocycle or a 4-10 member complex.
  • R 18s when the R 18s are plural, the R 18s may be independently the same or different, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, and others.
  • the symbol has the same meaning as above.
  • It is a compound represented by) or a salt thereof.
  • L 1 is preferably propylene.
  • the compound described in the examples of WO2016 / 111347, or a salt thereof is more preferable as an EP4 antagonist. More preferably (1) 4- [4-Cyano-2-( ⁇ [(2'R, 4S) -6- (methylcarbamoyl) -2,3-dihydrospiro [chromen-4,1'-cyclopropane] -2' -Il] carbonyl ⁇ amino) phenyl] butanoic acid, (2) 4- ⁇ 4-Cyano-2-[( ⁇ (2'R, 4S) -6-[(cyclopropylmethyl) carbamoyl] -2,3-dihydrospiro [chromen-4,1'-cyclopropane] ] -2'-yl ⁇ carbonyl) amino] phenyl ⁇ butanoic acid, (3) 4- ⁇ 4-Cyano-2-[( ⁇ (2'R, 4S) -6-[(2-methoxyethyl) carb
  • the EP4 antagonist is preferably (1) 4- [ 4 -cyano-2-( ⁇ [(2'R, 4S) -6- (5-methyl-1,3,4-). Oxadiazole-2-yl) -2,3-dihydrospiro [chromen-4,1'-cyclopropane] -2'-yl] carbonyl ⁇ amino) phenyl] butanoic acid, (2) 4- [4-Cyano-2- ( ⁇ [(2'R, 4S) -6- (5-cyclopropyl-1,3,4-oxadiazole-2-yl) -2,3- Dihydrospiro [chromen-4,1'-cyclopropane] -2'-yl] carbonyl ⁇ amino) phenyl] butanoic acid, (3) 4- [4-Cyano-2-( ⁇ [(2'R, 4S) -6- (3-methyl-1,2,4-oxadiazole-5-yl) -2,3-dihydro
  • 4- [4-cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyran-4,1'- Cyclopropane] -2'-carbonyl ⁇ amino) phenyl] butane acid is 4- [4-cyano-2-( ⁇ [(2'R, 4S) -6- (isopropylcarbamoyl) -2,3-dihydrospiroyl). It may also be named [chromen-4,1'-cyclopropane] -2'-yl] carbonyl ⁇ amino) phenyl] butanoic acid.
  • Compound A can be produced according to a known method, for example, the method described in Example 2-13 of WO2016 / 111347.
  • compound B 4- ⁇ 4-cyano-2-[( ⁇ (2'R, 4S) -6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromen-4,1'-" Cyclopropane] -2'-yl ⁇ carbonyl) amino] phenyl ⁇ butanoic acid (hereinafter, may be abbreviated as compound B), or a salt.
  • Compound B can be produced according to a known method, for example, the method described in Example 2-2 of WO2016 / 111347.
  • isomers include all of them unless otherwise specified.
  • alkyl groups, alkoxy groups, alkylene groups and the like include linear and branched chains.
  • R S isomers, ⁇ , ⁇ isomers, enantiomers, diastereomers.
  • D D, L, d, l bodies
  • chromatographically separated polar bodies high polar and low polar
  • equilibrium compounds rotational isomers, mixtures of any proportions thereof
  • All chiral mixtures are included in the present invention.
  • the present invention also includes all isomers due to tautomerism.
  • the compound represented by the general formula (I) is converted into a salt by a known method.
  • the salt is preferably a pharmaceutically acceptable salt.
  • the salt is preferably water-soluble.
  • Pharmaceutically acceptable salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts and the like.
  • Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, inorganic acid salt such as nitrate, or acetate, lactate, tartrate, and benzoic acid.
  • Organic acid salts such as salts, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, isethionates, glucronates, or gluconates
  • alkali metal salt include salts with potassium and sodium.
  • alkaline earth metal salt include salts with calcium, magnesium and the like.
  • Examples of the ammonium salt include salts with tetramethylammonium and the like.
  • Amine salts include, for example, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, and N-methyl-D-. Examples include salt with glucamine.
  • the compound used in the present invention can be made into an N-oxide compound by any method.
  • the N-oxide compound represents a compound in which the nitrogen atom represented by the general formula (I) is oxidized.
  • the compound represented by the general formula (I) and a salt thereof may exist in a non-solvate form, or may exist in a form solvated with a pharmaceutically acceptable solvent such as water or ethanol. ..
  • the solvate is preferably a hydrate.
  • the compound represented by the general formula (I) can form a co-crystal with a suitable co-crystal forming agent.
  • a pharmaceutically acceptable one formed with a pharmaceutically acceptable co-crystal forming agent is preferable.
  • a co-crystal is typically defined as a crystal in which two or more different molecules are formed by an intramolecular interaction different from that of an ionic bond.
  • the co-crystal may be a complex of a neutral molecule and a salt.
  • Cocrystals can be prepared by known methods, eg, by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal forming agents include those described in WO2006 / 007448.
  • all references to the compound represented by the general formula (I) are the compound represented by the general formula (I), a salt thereof, an N-oxide form thereof, a solvate thereof (for example, a hydrate), or a hydrate thereof.
  • the co-crystal or N-oxide of a salt of the compound represented by the general formula (I), a solvate thereof (for example, a hydrate), or a co-crystal thereof is included. That is, in the present invention, the compound represented by the general formula (I) or a salt thereof is a solvent product (for example, a hydrate) of the compound represented by the general formula (I), an N-oxide form thereof, or a salt thereof. It includes a co-crystal or an N-oxide compound of a salt of a compound represented by the general formula (I), a solvate thereof (for example, a hydrate), or a co-crystal thereof.
  • the compound represented by the general formula (I) can be administered as a prodrug.
  • the prodrug of the compound represented by the general formula (I) means a compound converted into the compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body.
  • Examples of the prodrug of the compound represented by the general formula (I) include, for example, when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example,).
  • the amino group of the compound represented by the general formula (I) is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranyl. (Pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylated compound, etc.); When the compound represented by the general formula (I) has a hydroxyl group, the hydroxyl group is acylated or alkylated.
  • the carboxy group of the compound is ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, 1- ⁇ (ethoxycarbonyl) oxy ⁇ ethyl esterification, phthalidyl esterification, ( 5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, 1- ⁇ [(cyclohexyloxy) carbonyl] oxy ⁇ ethyl esterification, methylamidated compounds, etc.) and the like.
  • These compounds can be produced by methods known per se.
  • the prodrug of the compound represented by the general formula (I) may be either a hydrated substance or a non-hydrated substance.
  • the prodrug of the compound represented by the general formula (I) is a general formula under physiological conditions as described in Hirokawa Shoten 1990, "Development of Pharmaceuticals", Vol. 7, “Molecular Design", pp. 163 to 198. It may be changed to the compound represented by (I).
  • each atom constituting the compound represented by the general formula (I) is an isotope thereof (for example, 2H , 3H , 13C , 14C , 15N , 16N , 17O , 18O , 18F . , 35 S, 36 Cl, 77 Br, 125 I, etc.) and the like.
  • the EP4 antagonist can be produced by a known method, for example, the compound represented by the general formula (I) can be produced according to the method described in WO2016 / 111347.
  • the EP4 antagonist is usually formulated with a pharmaceutically acceptable carrier such as various additives or solvents and then administered systemically or topically, orally or parenterally.
  • a pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used for pharmaceutical preparations.
  • the pharmaceutically acceptable carrier preferably has no pharmacological action at the dose of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient.
  • the pharmaceutically acceptable carrier can also be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the formulation, stabilizing the quality, or improving the usability.
  • a substance as described in Yakuji Nippo Co., Ltd. 2016 "Pharmaceutical Additives Dictionary 2016" (edited by Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.
  • Examples of the dosage form used for administration include oral preparations (eg, tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, etc.), oral preparations (eg, oral tablets, etc.). Oral sprays, semi-solids for the oral cavity, gargling agents, etc.), injection formulations (eg, injections, etc.), dialysis formulations (eg, dialysis agents, etc.), inhalation formulations (eg, inhalants, etc.), Ophthalmic preparations (eg, eye drops, ointment, etc.), otologic preparations (eg, ear drops, etc.), nasal preparations (eg, nasal drops, etc.), rectal preparations (eg, suppositories, etc.) Semi-solid preparations for the rectal, intestinal injections, etc.), vaginal preparations (eg, vaginal tablets, suppositories for vagina, etc.), and skin preparations (eg, solids for external use, liquids for external
  • the dose of the EP4 antagonist used in the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of 1 ng to 1000 mg per adult. Orally administered once to several times daily, or parenterally administered once to several times daily in the range of 0.1 ng to 100 mg per adult, or 1 hour to 24 times daily. It is continuously administered intravenously over a period of time.
  • a dose smaller than the above dose may be sufficient, or administration beyond the range may be necessary.
  • one aspect of the dose is about 1-100 mg orally administered 1 to 3 times daily, preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg at a time. , 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg orally administered 1 to 3 times a day, more preferably 1 mg once.
  • 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg are orally administered 1 to 3 times a day, and more preferably 5 mg, 10 mg, 20 mg or 40 mg is orally administered once a day. It is administered, more preferably 20 mg or 40 mg orally once daily.
  • an immune checkpoint molecule means a molecule that exerts an immunosuppressive function by transmitting an inhibitory co-signal.
  • the immune checkpoint molecule include CTLA-4, PD-1, PD-L1 (programmed cell date-ligand 1), PD-L2 (programmed cell death-ligand 2), LAG-3 (Lymphometry activation 3), and T.
  • T cell immunoglobulin and mucin-3 T cell immunoglobulin and mucin-3
  • BTLA Band T lymphocyte attenuator
  • B7H3, B7H4 CD160, CD39, CD73
  • A2aR adenosine A2areceptor
  • IDO1 Indoreamine 2,3-dioxygenase
  • ArginaseI T cell immunoglobulin and ITIM doman
  • CD115 etc. 2012, Cancer Cell, 27, 450-461, 2015
  • the molecule is not particularly limited as long as it has a function consistent with the definition.
  • the immune checkpoint inhibitor is a substance that inhibits the function of the immune checkpoint molecule.
  • the immune checkpoint inhibitor is not particularly limited as long as it is a substance that can suppress the function (signal) of the immune checkpoint molecule.
  • immune checkpoint inhibitor examples include anti-PD-1 antibodies (eg, Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartanlizumab (PDR-001), Tremelimumab (BGB-A317)).
  • anti-PD-1 antibodies eg, Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartanlizumab (PDR-001), Tremelimumab (BGB-A317).
  • anti-PD-L2 antibody PD-L1 fusion protein, PD-L2 fusion protein (eg, AMP- 224), anti-Tim-3 antibody (eg, MBG453), anti-LAG-3 antibody (eg, BMS-986016, LAG525), anti-KIR antibody (eg, Lilylumab) and the like.
  • Antibodies comprising the heavy and light chain complementarity determining regions (CDRs) or variable regions (VR) of the known antibodies are also aspects of immune checkpoint inhibitors.
  • further embodiments of anti-PD-1 antibodies include antibodies comprising, for example, Nivolumab heavy and light chain complementarity determining regions (CDRs) or variable regions (VR).
  • the immune checkpoint inhibitor is preferably an anti-PD-1 antibody, an anti-PD-L1 antibody and an anti-CTLA-4 antibody, and more preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • the anti-PD-1 antibody is preferably Nivolumab, Cemiplimab, Pembrolizumab, Spartanismab, Tisslerizumab, Tremelimumab, Sintilimab and Camrelizumab
  • the anti-PD-L1 antibody is preferably AlibaB
  • Durvalumab -4 Antibodies are preferably Ipilimumab and Tremelimumab.
  • the anti-PD-1 antibody is more preferably Nivolumab, Cemiplimab and Pembrolizumab, and even more preferably Nivolumab.
  • the immune checkpoint inhibitor is preferably an anti-PD-1 antibody, more preferably Nivolumab.
  • the immune checkpoint inhibitor can be produced by a known method.
  • Nivolumab can be produced according to the method described in WO2006 / 121168
  • Pembrolizumab can be produced according to the method described in WO2008 / 156712
  • BMS-936559 can be produced according to WO2007 / 005874.
  • Ipilimumab can be produced according to the method described in WO2001 / 014424.
  • any one or any of these immune checkpoint inhibitors can be used in combination with administration of EP4 antagonists and standard therapy.
  • the dose of the immune checkpoint inhibitor used in the combination of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is adjusted to bring about the optimum desired effect.
  • about 1 to 10 mg / kg (body weight) or about 200 to 1200 mg once with an immune checkpoint inhibitor as an active ingredient is applied at intervals of 2 to 4 weeks for about 30 minutes to about 60 minutes or about 60 minutes or more.
  • the dose in terms of body weight per administration for example, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg.
  • the dose per dose includes, for example, 200 mg, 240 mg, 250 mg, 280 mg, 300 mg, 320 mg, 350 mg, 360 mg, 400 mg, 420 mg, 450 mg, 480 mg, 500 mg, etc. Included are 540 mg, 560 mg, 600 mg, 640 mg, 700 mg, 720 mg, 750 mg, 800 mg, 840 mg, 900 mg, 1000 mg, 1080 mg, 1100 mg, 1120 mg or 1200 mg.
  • the administration interval may be, for example, 2 weeks, 3 weeks or 4 weeks, and the single administration time may be, for example, about 30 minutes, about 60 minutes or about 60 minutes or more.
  • Nivolumab which is an anti-PD-1 antibody
  • the immune checkpoint inhibitor is Nivolumab
  • Nivolumab which is an anti-PD-1 antibody
  • it is administered at the following dosage and administration. That is, for patients with malignant melanoma, Nivolumab was administered by intravenous drip infusion at 3 mg / kg (body weight) once at 2 week intervals or 2 mg / kg (body weight) at 3 week intervals, or 240 mg once for 2 weeks. Intravenous infusion of 480 mg at intervals or once every 4 weeks.
  • nivolumab For patients with non-small cell lung cancer, renal cell cancer, classical Hodgkin lymphoma, head and neck cancer, gastric cancer and malignant pleural mesothelioma, 3 mg / kg (body weight) of nivolumab was instilled at 2-week intervals. Injection is administered.
  • malignant melanoma, non-small cell lung cancer, renal cell cancer, urinary tract epithelial cancer, MSI-H or dMMR-positive colorectal cancer including patients of children aged 12 years or older.
  • Gastric cancer, hepatocellular carcinoma, small cell lung cancer and malignant thoracic mesothelioma are administered by intravenous drip infusion of 240 mg of nivolumab at 2-week intervals or 480 mg at 4-week intervals. ..
  • 1 mg / kg (body weight) of Nivolumab is intravenously infused four times at 3 week intervals to patients with malignant melanoma, and then Nivolumab.
  • 3 mg / kg (body weight) is intravenously infused at 2-week intervals, or 80 mg of Nivolumab is infused 4 times at 3-week intervals, and then 240 mg of Nivolumab is infused at 2-week intervals. Or 480 mg once may be infused intravenously at 4-week intervals.
  • 240 mg of nivolumab is intravenously infused four times at 3 week intervals to patients with renal cell carcinoma or colorectal cancer, and then 240 mg of nivolumab is administered once for 2 weeks. Intravenous infusion of 480 mg at intervals or once every 4 weeks may be performed.
  • Pembrolizumab which is the same anti-PD-1 antibody
  • it is administered at the following dosage and administration. That is, malignant melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, MSI-H or dMMR-positive solid or colon cancer, urinary epithelial cancer, cervical cancer, primary mediastinct.
  • Patients with B-cell lymphoma, hepatocellular carcinoma, gastric cancer, and Merkel cell carcinoma receive 200 mg of pembrolizumab at 3-week intervals or 400 mg at 6-week intervals by intravenous drip infusion.
  • Pembrolizumab As another dosage and administration, for example, for patients with classical Hodgkin lymphoma, MSI-H or dMMR-positive solid tumor or colorectal cancer and primary mediastinal B-cell lymphoma in children over 2 years old, Pembrolizumab As a result, 2 mg / kg (body weight) (up to 200 mg once) is administered by intravenous drip infusion at intervals of 3 weeks.
  • Avelumab which is an anti-PD-L1 antibody
  • 10 mg / kg (body weight) of Avelumab is administered once for 2 weeks to each patient of Merkel cell cancer and urothelial cancer. It is administered by intravenous drip infusion at intervals.
  • Atezolizumab the same PD-L1 antibody, is administered to patients with non-small cell lung cancer, urinary tract epithelial cancer, and hepatocellular carcinoma by intravenous drip infusion of 1200 mg of atezolizumab at 3-week intervals, and triple-negative breast cancer.
  • Patients receive 840 mg of atezolizumab in combination with paclitaxel at 2-week intervals by intravenous drip infusion.
  • Durvalumab which is the same PD-L1 antibody, is administered to patients with non-small cell lung cancer and urinary tract epithelial cancer by intravenous drip infusion of 10 mg / kg (body weight) once as Durvalumab at 2-week intervals.
  • 1500 mg of Durvalumab is administered by intravenous drip infusion at 4-week intervals.
  • Ipilimumab which is an anti-CTLA-4 antibody
  • Intravenous drip infusion was given to patients with renal cell carcinoma and MSI-H or dMMR-positive colon cancer at 1 mg / kg (body weight) once daily as ipilimumab four times at 3-week intervals in combination with nivolumab.
  • Intravenous drip infusion is given to patients with non-small cell lung cancer at 1 mg / kg (body weight) of Ipilimumab at 6-week intervals.
  • the administration form of the immune checkpoint inhibitor in the present invention is preferably parenteral administration, and examples of parenteral administration include subcutaneous administration, intradermal administration, intraperitoneal administration, intramuscular administration, intravenous administration and the like. However, subcutaneous administration or intravenous administration is preferable. More preferably, it is administered intravenously. As the administration form of intravenous administration, intravenous drip infusion is preferable.
  • the above dosage can also be used in the therapeutic method of the present invention.
  • the "XELOX therapy” in the present invention is a cancer treatment method using a combination of capecitabine and oxaliplatin (L-OHP).
  • the "XELOX + bevacizumab therapy" in the present invention is a cancer treatment method using a combination of capesitabin, oxaliplatin and bevacizumab, and in one embodiment, bevacizumab 7.5 mg / kg intravenously over about 30 to 90 minutes.
  • oxaliplatin 130 mg / m 2 body surface area
  • bevacizumab 1000 mg / m 2 / time body surface area 1.36 m 2 or less.
  • Withdrawal, dose reduction, and resumption of XELOX + bevacizumab therapy will be carried out at the discretion of the doctor with reference to the latest package insert.
  • Compound A an EP4 antagonist in combination with XELOX + bevacizumab therapy, is, in one embodiment, 5 mg orally once daily, 10 mg orally once daily, 20 mg orally once daily or It is orally administered at 40 mg once a day. Preferably, 20 mg is orally administered once a day or 40 mg is orally administered once a day.
  • the dose of Compound A may be reduced or the administration itself may be discontinued. Further, if the criteria for resumption are satisfied, the administration of compound A can be resumed, and when resuming, the dose of compound A can be reduced step by step and resumed at the discretion of the doctor.
  • the one-step dose reduction is 20 mg
  • the two-step dose reduction is 10 mg
  • the administration of compound A as an EP4 antagonist is started.
  • the one-step dose reduction is 10 mg and the two-step dose reduction is 5 mg.
  • Nivolumab as an immune checkpoint inhibitor in combination with XELOX + bevacizumab therapy in one embodiment, is 240 mg once at 2-week intervals, 360 mg at 3-week intervals, or 480 mg at 4-week intervals as Nivolumab. It is administered by intravenous drip infusion. Preferably, 360 mg of nivolumab is administered by intravenous drip infusion at intervals of 3 weeks. The administration of nivolumab itself may be discontinued depending on the degree of side effects of the patient. In addition, administration of nivolumab can be resumed if the criteria for resumption are met.
  • the cancer to which this combination -1 can be applied is not particularly limited as long as it is a cancer to which this combination -1 can exert an effect, but in one embodiment, it is colorectal cancer, preferably colon / rectal cancer. More preferably, it is unresectable advanced or recurrent colorectal cancer.
  • This combination-1 is administered to a patient who has not been treated for colorectal cancer in one embodiment.
  • the EP4 antagonist preferably compound A
  • the immune checkpoint inhibitor preferably anti-PD-1 antibody (preferably nivolumab)
  • XELOX + bevasizumab therapy when administered on the same day, one embodiment.
  • EP4 antagonist and immune checkpoint inhibitor are administered first.
  • the EP4 antagonist and immune checkpoint inhibitor are administered followed by bevacizumab, oxaliplatin, and capecitabine in that order.
  • EP4 antagonist preferably compound A
  • an immune checkpoint inhibitor preferably anti-PD-1 antibody (preferably nivolumab)
  • XELOX + Bevasizumab therapy may be given first or at the same time as administration of EP4 antagonists and immune checkpoint inhibitors.
  • the order of administration of EP4 antagonist, immune checkpoint inhibitor, bevacizumab, oxaliplatin and capecitabine may be initiated from any agent unless otherwise defined, and two or more agents. It may be administered at the same time.
  • the "preoperative chemoradiotherapy” in the present invention is a combination of irradiation and chemotherapy such as fluorouracil (5-FU) or capecitabine. In the present invention, a combination of irradiation and capecitabine administration is preferred.
  • the preoperative chemoradiotherapy in the present invention in one embodiment, is 45 Gy / 25 doses of pelvic cavity irradiation and 5.4 Gy / 3 doses of boost to the primary lesion, and 825 mg / m 2 capecitabin (starting dose).
  • capecitabin is taken orally for a period equivalent to 75% of the 28 irradiations.
  • the dose can be appropriately reduced for 21 days or 42 times or more as oral administration in the morning and evening), depending on the degree of expression of side effects of the patient.
  • Compound A as an EP4 antagonist used as neoadjuvant therapy after preoperative chemoradiation therapy is, in one embodiment, 5 mg orally once daily, 10 mg orally once daily, 20 mg. It is orally administered once a day or 40 mg orally once a day. Preferably, 20 mg is orally administered once a day or 40 mg is orally administered once a day. More preferably, compound A is orally administered at 40 mg once daily. Depending on the degree of side effects of the patient, the dose of Compound A may be reduced or the administration itself may be discontinued.
  • the administration of compound A can be resumed, and when resuming, the dose of compound A can be reduced step by step and resumed at the discretion of the doctor.
  • the one-step dose reduction is 20 mg and the two-step dose reduction is 10 mg.
  • Nivolumab as an immune checkpoint inhibitor used as neoadjuvant therapy after preoperative chemoradiation therapy in one embodiment, is 240 mg once every 2 weeks, once 360 mg every 3 weeks, or 1 as Nivolumab.
  • a dose of 480 mg is administered by intravenous drip infusion at 4-week intervals.
  • 240 mg of nivolumab is administered by intravenous drip infusion at 2-week intervals.
  • the administration of nivolumab itself may be discontinued depending on the degree of side effects of the patient.
  • administration of nivolumab can be resumed if the criteria for resumption are met.
  • One embodiment of this combination-2 is administration of an EP4 antagonist, and one embodiment is a combination administration of an EP4 antagonist and an immune checkpoint inhibitor.
  • the cancer to which this combination-2 is applied is not particularly limited as long as it is a cancer for which this neoadjuvant therapy can be effective, but in one embodiment, it is colorectal cancer, preferably colon / rectal cancer. .. More preferably, it is locally advanced rectal cancer that can be curatively resected.
  • it is administered to a patient who can undergo curative resection without distant metastasis on diagnostic imaging after preoperative chemoradiotherapy.
  • it is administered to a patient who is capable of (curative) resection in neoadjuvant therapy.
  • FFX therapy is oxaliplatin (L-OHP), irinotecan hydrochloride hydrate (irinotecan, CPT-11), levofolinate calcium (levofolinate, l-LV). It is a cancer treatment method using a combination of 4 drugs of fluorouracil (5-FU), and as a recommended dosage, for example, oxaliplatin 85 mg / m 2 (body surface area) is intravenously administered over 2 hours, and then levofolinate 200 mg.
  • L-OHP oxaliplatin
  • irinotecan hydrochloride hydrate irinotecan, CPT-11
  • levofolinate calcium levofolinate calcium
  • / M 2 is intravenously administered over 2 hours
  • irinotecan 180 mg / m 2 is intravenously administered over 1.5 hours from 30 minutes after the start of levofolinate administration
  • fluorouracil 400 mg / m 2 is further administered after the end of levofolinate administration. Is a rapid intravenous administration, and then fluorouracil 2400 mg / m 2 is intravenously administered over 46 hours, and the series of administrations is carried out at 2-week intervals.
  • the "weight loss regimen" of the FFX therapy is to reduce the dose of any of the four drugs administered in the FFX therapy from the first administration or to discontinue the administration itself, or to administer any of the first cycle and thereafter. Depending on the degree of occurrence of side effects observed in the above, the dose is reduced in any of the subsequent administrations after the second cycle, or the administration of any of the four agents is discontinued. In that embodiment, for example, it is not necessary to perform rapid intravenous administration of fluorouracil from the first administration, and the dose of oxaliplatin is between 65 mg / m 2 , 50 mg / m 2 or 85 to 50 mg / m 2 .
  • the dose of irinotecan may be any dose between 150 mg / m 2 , 120 mg / m 2 , 90 mg / m 2 or 180-90 mg / m 2 .
  • the dose of fluorouracil administered intravenously may be any dose between 1800 mg / m 2 , 1200 mg / m 2 and 2400 to 1200 mg / m 2 .
  • rapid intravenous administration of fluorouracil may be discontinued depending on the degree of side effects of the patient in any administration after the second cycle in the FFX therapy.
  • the dose of oxaliplatin may be reduced to any dose between 65 mg / m 2 , 50 mg / m 2 or 85-50 mg / m 2 or discontinuation of oxaliplatin.
  • the dose of irinotecan may be reduced to any dose between 150 mg / m 2 , 120 mg / m 2 , 90 mg / m 2 or 180-90 mg / m 2 , depending on the extent of the patient's onset of side effects.
  • administration of irinotecan may be discontinued, and the dose of fluorouracil administered intravenously may be 1800 mg / m 2 , 1200 mg / m 2 or 2400 to 1200 mg / m 2 , depending on the degree of side effects of the patient.
  • the dose may be reduced to any dose during the period or administration of the fluorouracil may be discontinued.
  • mFFX therapy modified FOLFIRINOX therapy
  • the recommended dosage is, for example, oxaliplatin 85 mg / m 2 (body surface area) intravenously over 2 hours.
  • levoleucovorin 200 mg / m 2 was intravenously administered over 2 hours
  • irinotecan 150 mg / m 2 was intravenously administered over 1.5 hours from 30 minutes after the start of levoleucovorin administration
  • fluorouracil 2400 mg was further administered after the end of levoleucovorin administration.
  • This is a treatment method in which / m 2 is intravenously administered over 46 hours, and the series of administrations is performed at 2-week intervals.
  • the dose of oxaliplatin may be any dose between 65 mg / m 2 , 50 mg / m 2 or 85-50 mg / m 2 .
  • the dose of irinotecan may be any dose between 140 mg / m 2 , 120 mg / m 2 or 140-120 mg / m 2
  • the dose of fluorouracil administered intravenously continuously is 2400 mg. It may be any dose between / m 2 , 1800 mg / m 2 , 1200 mg / m 2 or 2400 to 1200 mg / m 2 .
  • the dose of oxaliplatin may be 65 mg / m 2 , 50 mg / m 2 or 85 to 50 mg / m 2 depending on the degree of the occurrence of side effects of the patient.
  • the dose may be reduced to any dose during the period or the administration of oxaliplatin may be discontinued, and the dose of irinotecan may be adjusted to 120 mg / m 2 , 90 mg / m 2 or 150 to 90 mg, depending on the degree of side effects of the patient.
  • the dose may be reduced to any dose between / m 2 or the administration of irinotecan may be discontinued, and the dose of fluorouracil administered intravenously may be 1800 mg / m 2 , depending on the degree of side effects of the patient.
  • the dose may be reduced to any dose between 1200 mg / m 2 or 2400 to 1200 mg / m 2 or administration of the fluorouracil may be discontinued.
  • the interval between a series of administrations of the FFX therapy or its weight loss regimen is set to a 3-week interval or a 4-week interval temporarily or continuously depending on the degree of side effect occurrence of the patient. You may. Withdrawal / reduction / resumption of FFX therapy or its weight loss regimen (eg, mFFX therapy) will be carried out at the discretion of the physician with reference to the latest package insert.
  • FFX therapy or its combination with a weight loss regimen (hereinafter, may be abbreviated as this combination-3).
  • the EP4 antagonist in combination with FFX therapy or a weight loss regimen thereof (eg, mFFX therapy) is administered in one embodiment at the dosages described in (1) EP4 antagonist.
  • compound A which is an EP4 antagonist, is orally administered at 5 mg once a day, at 10 mg once a day, at 20 mg once a day, or at 40 mg once a day. Will be done.
  • 20 mg is orally administered once a day or 40 mg is orally administered once a day. More preferably, it is orally administered at 20 mg once a day.
  • the dose of Compound A may be reduced or the administration itself may be discontinued. Further, if the criteria for resumption are satisfied, the administration of compound A can be resumed, and when resuming, the dose of compound A can be reduced step by step and resumed at the discretion of the doctor.
  • the one-step dose reduction is 20 mg
  • the two-step dose reduction is 10 mg
  • the administration of compound A as an EP4 antagonist is started.
  • the one-step dose reduction is 10 mg and the two-step dose reduction is 5 mg.
  • the immune checkpoint inhibitor in this combination-3 is administered in one embodiment at the dosage as described in (2) Immune checkpoint inhibitor.
  • nivolumab as an immune checkpoint inhibitor is administered by intravenous drip infusion of 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals.
  • 480 mg of nivolumab is administered by intravenous drip infusion at 4-week intervals.
  • the administration of nivolumab itself may be discontinued depending on the degree of side effects of the patient.
  • administration of nivolumab can be resumed if the criteria for resumption are met.
  • EP4 antagonist preferably compound A
  • immune checkpoint inhibitor preferably anti-PD-1 antibody (preferably Nivolumab)
  • FFX therapy or a weight loss regimen thereof eg, mFFX therapy
  • the EP4 antagonist and the immune checkpoint inhibitor are administered first.
  • FFX therapy or a weight loss regimen thereof eg, mFFX therapy
  • an EP4 antagonist preferably compound A
  • an immune checkpoint inhibitor preferably an anti-PD-1 antibody (preferably Nivolumab)
  • FFX therapy or a weight loss regimen thereof eg, mFFX therapy
  • FFX therapy or a weight loss regimen thereof may be given first, or may be co-administered with an EP4 antagonist and an immune checkpoint inhibitor.
  • the order of administration of the EP4 antagonist, immune checkpoint inhibitor, FFX therapy or a weight loss regimen thereof may be initiated from any drug unless otherwise defined. Further, two or more drugs may be administered at the same time.
  • GnP therapy in the present invention is a therapy in which gemcitabine and nabupaclitaxel are combined, and in one embodiment, the GnP therapy is, for example, 1000 mg / m 2 of gemcitabine as a recommended dosage.
  • Body surface area was intravenously administered over 30 minutes
  • nabupaclitaxel was intravenously administered at 125 mg / m 2 (body surface area) over 30 minutes
  • the series of administrations was performed at 1-week intervals and continued for 3 weeks. It is a therapy that takes a week off.
  • gemcitabine may be reduced to 800 mg / m 2 or 600 mg / m 2 depending on the degree of side effect of the patient in any administration after the second cycle in the GnP therapy.
  • the dose may be reduced to 100 mg / m 2 or 75 mg / m 2 .
  • Withdrawal, dose reduction, and resumption of GnP therapy will be carried out at the discretion of the doctor with reference to the latest package insert.
  • Combination with GnP therapy (hereinafter, may be abbreviated as this combination-4).
  • the EP4 antagonist in this combination- 4 is administered in one embodiment at the dosage as described in (1) EP4 antagonist.
  • compound A which is an EP4 antagonist, is orally administered at 5 mg once a day, at 10 mg once a day, at 20 mg once a day, or at 40 mg once a day. Will be done.
  • 20 mg is orally administered once a day or 40 mg is orally administered once a day. More preferably, compound A is orally administered at 40 mg once daily.
  • the dose of Compound A may be reduced or the administration itself may be discontinued.
  • the administration of compound A can be resumed, and when resuming, the dose of compound A can be reduced step by step and resumed at the discretion of the doctor.
  • the one-step dose reduction is 20 mg and the two-step dose reduction is 10 mg.
  • the one-step dose reduction is 10 mg and the two-step dose reduction is 5 mg.
  • the immune checkpoint inhibitor in this combination-4 is administered in one embodiment at the dosage as described in (2) Immune checkpoint inhibitor.
  • nivolumab as an immune checkpoint inhibitor is administered by intravenous drip infusion of 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals.
  • 480 mg of nivolumab is administered by intravenous drip infusion at 4-week intervals.
  • the administration of nivolumab itself may be discontinued depending on the degree of side effects of the patient.
  • administration of nivolumab can be resumed if the criteria for resumption are met.
  • the "docetaxel and ramucirumab therapy" in the present invention is a cancer treatment method using a combination of docetaxel and ramucirumab, and the recommended dosage is, for example, docetaxel 60 mg / m 2 (body surface area) for 60 minutes. It is a treatment method in which ramucirumab 10 mg / kg is intravenously administered over 60 minutes, and the series of administrations is carried out at 3-week intervals. As one embodiment, in any administration after the second cycle in the DTX + RAM therapy, docetaxel is increased or decreased to 75 mg / m 2 or 50 mg / m 2 or administration of docetaxel is discontinued depending on the degree of side effect of the patient.
  • the dose of ramucirumab may be reduced to 8 mg / kg or 6 mg / kg, or the administration of ramucirumab may be discontinued, or the administration time of ramucirumab may be shortened to 30 to 60 minutes. Withdrawal, dose reduction, and resumption of DTX + RAM therapy will be carried out at the discretion of the doctor with reference to the latest package insert. In one embodiment, administration of docetaxel and ramucirumab is started on the same day.
  • the EP4 antagonist in this combination-5 is administered in one embodiment at the dosages described in (1) EP4 antagonist.
  • compound A which is an EP4 antagonist, is orally administered at 5 mg once a day, at 10 mg once a day, at 20 mg once a day, or at 40 mg once a day. Will be done.
  • 20 mg is orally administered once a day or 40 mg is orally administered once a day.
  • the dose of Compound A may be reduced or the administration itself may be discontinued.
  • the administration of compound A can be resumed, and when resuming, the dose of compound A can be reduced step by step and resumed at the discretion of the doctor.
  • the one-step dose reduction is 20 mg
  • the two-step dose reduction is 10 mg
  • the administration of compound A as an EP4 antagonist is started.
  • the one-step dose reduction is 10 mg and the two-step dose reduction is 5 mg.
  • the immune checkpoint inhibitor in this combination-5 is administered in one embodiment at the dosage as described in (2) Immune checkpoint inhibitor.
  • nivolumab as an immune checkpoint inhibitor is administered by intravenous drip infusion of 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals.
  • 360 mg of nivolumab is administered by intravenous drip infusion at intervals of 3 weeks.
  • the administration of nivolumab itself may be discontinued depending on the degree of side effects of the patient.
  • administration of nivolumab can be resumed if the criteria for resumption are met.
  • administration of DTX + RAM therapy, immune checkpoint inhibitors and EP4 antagonists is initiated on the same day.
  • EP4 antagonist preferably compound A
  • immune checkpoint inhibitor preferably anti-PD-1 antibody (preferably Nivolumab)
  • DTX + RAM therapy is performed after administration of EP4 antagonists and immune checkpoint inhibitors.
  • EP4 antagonist preferably compound A
  • an immune checkpoint inhibitor preferably anti-PD-1 antibody (preferably Nivolumab)
  • DTX + RAM therapy May be performed first or at the same time as the administration of the EP4 antagonist and the immune checkpoint inhibitor.
  • the order of administration of EP4 antagonist, immune checkpoint inhibitor, docetaxel and ramucirumab may be started from any drug unless otherwise defined, and two or more drugs may be administered simultaneously. You may.
  • the "docetaxel therapy" in the present invention is a cancer treatment method using docetaxel, and in one embodiment, the recommended dosage is, for example, 60 mg / m 2 (body surface area) of docetaxel for 60 minutes. It is a therapy in which intravenous administration is performed over the above and the administration is performed at 3-week intervals. As one embodiment, in any administration after the second cycle in the DTX therapy, docetaxel may be increased or decreased to 75 mg / m 2 or 50 mg / m 2 or administration of docetaxel may be discontinued depending on the patient's condition. Withdrawal, dose reduction, and resumption of DTX therapy will be carried out at the discretion of the doctor with reference to the latest package insert.
  • the EP4 antagonist in this combination-6 is administered in one embodiment at the dosages described in (1) EP4 antagonist.
  • compound A which is an EP4 antagonist, is orally administered at 5 mg once a day, at 10 mg once a day, at 20 mg once a day, or at 40 mg once a day. Will be done.
  • 20 mg is orally administered once a day or 40 mg is orally administered once a day.
  • the dose of Compound A may be reduced or the administration itself may be discontinued.
  • the administration of compound A can be resumed, and when resuming, the dose of compound A can be reduced step by step and resumed at the discretion of the doctor.
  • the one-step dose reduction is 20 mg and the two-step dose reduction is 10 mg.
  • the one-step dose reduction is 10 mg and the two-step dose reduction is 5 mg.
  • nivolumab as an immune checkpoint inhibitor is administered by intravenous drip infusion of 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals.
  • 360 mg of nivolumab is administered by intravenous drip infusion at intervals of 3 weeks.
  • the administration of nivolumab itself may be discontinued depending on the degree of side effects of the patient.
  • administration of nivolumab can be resumed if the criteria for resumption are met.
  • administration of DTX therapy, immune checkpoint inhibitors and EP4 antagonists is initiated on the same day.
  • EP4 antagonists and immune checkpoint inhibitors are administered first.
  • DTX therapy is performed after administration of EP4 antagonists and immune checkpoint inhibitors.
  • EP4 antagonists and immune checkpoint inhibitors are administered on the same day, DTX therapy. May be performed first or at the same time as the administration of the EP4 antagonist and the immune checkpoint inhibitor.
  • the order of administration of the EP4 antagonist, immune checkpoint inhibitor, and docetaxel may be started from any drug unless otherwise defined, and two or more drugs may be administered simultaneously. May be good.
  • the "ramucirumab therapy (hereinafter, may be abbreviated as” RAM therapy ”)" in the present invention is a cancer treatment method using ramucirumab, and in one embodiment, as a recommended dosage.
  • it is a treatment method in which ramucirumab 10 mg / kg is intravenously administered over 60 minutes, and the series of administrations is carried out at 3-week intervals.
  • the dose of ramucirumab may be reduced to 8 mg / kg or 6 mg / kg or the administration of ramucirumab may be discontinued depending on the patient's condition in any of the administrations after the second cycle in the RAM therapy.
  • the administration time of ramucirumab may be shortened to 30 to 60 minutes.
  • the EP4 antagonist in this combination-7 is administered in one embodiment at the dosages described in (1) EP4 antagonist.
  • compound A which is an EP4 antagonist, is orally administered at 5 mg once a day, at 10 mg once a day, at 20 mg once a day, or at 40 mg once a day. Will be done.
  • 20 mg is orally administered once a day or 40 mg is orally administered once a day.
  • the dose of Compound A may be reduced or the administration itself may be discontinued.
  • the administration of compound A can be resumed, and when resuming, the dose of compound A can be reduced step by step and resumed at the discretion of the doctor.
  • the one-step dose reduction is 20 mg and the two-step dose reduction is 10 mg.
  • the one-step dose reduction is 10 mg and the two-step dose reduction is 5 mg.
  • the immune checkpoint inhibitor in this combination-7 is administered in one embodiment at the dosage as described in (2) Immune checkpoint inhibitor.
  • nivolumab as an immune checkpoint inhibitor is administered by intravenous drip infusion of 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals.
  • 360 mg of nivolumab is administered by intravenous drip infusion at intervals of 3 weeks.
  • the administration of nivolumab itself may be discontinued depending on the degree of side effects of the patient.
  • administration of nivolumab can be resumed if the criteria for resumption are met.
  • administration of RAM therapy, immune checkpoint inhibitors and EP4 antagonists is initiated on the same day.
  • EP4 antagonists and immune checkpoint inhibitors are administered first.
  • RAM therapy is performed after administration of EP4 antagonists and immune checkpoint inhibitors.
  • EP4 antagonists and immune checkpoint inhibitors are administered on the same day, RAM therapy. May be performed first or at the same time as the administration of the EP4 antagonist and the immune checkpoint inhibitor.
  • the order of administration of the EP4 antagonist, immune checkpoint inhibitor, and ramucirumab may be started from any drug unless otherwise defined, and two or more drugs may be administered simultaneously. May be good.
  • the disease to which the therapeutic method of the present invention is applied is cancer.
  • the cancers include, for example, leukemia (eg, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia), malignant lymphoma (hodgkin lymphoma, non-hodgkin lymphoma (eg, adult)).
  • leukemia eg, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia
  • malignant lymphoma hodgkin lymphoma, non-hodgkin lymphoma (eg, adult)
  • T-cell leukemia follicular lymphoma, diffuse large B-cell lymphoma)
  • multiple myeloma myelodystrophy syndrome, head and neck cancer
  • esophageal cancer esophageal adenocarcinoma
  • gastric cancer esophagogastric junction Cancer
  • duodenal cancer colon cancer, colon cancer, rectal cancer
  • liver cancer eg, hepatocellular carcinoma
  • bile sac / bile duct cancer biliary tract cancer
  • pancreatic cancer eg, pancreatic duct cancer
  • Insulinoma intraductal papillary mucinous tumor
  • thyroid cancer lung cancer
  • non-small cell lung cancer eg, flat epithelial non-small cell lung cancer, non-flat epithelial non-small cell lung cancer
  • small cell lung cancer breast cancer
  • ovary Cancer eg, serous ovarian cancer
  • cervical cancer uterine body cancer
  • endometrial cancer vagina
  • Diseases to which the therapeutic method of the present invention is applied are preferably colon cancer, pancreatic cancer, and lung cancer, and more preferably unresectable advanced or recurrent colon / rectal cancer, and curatively resectable locally advanced cancer.
  • Lung cancer that has undergone combination therapy including rectal cancer, pancreatic cancer with distant metastasis, anti-PD-1 antibody or anti-PD-L1 antibody, and platinum preparation, and has progressed or recurred refractory.
  • unresectable advanced or recurrent colorectal cancer curatively resectable locally advanced cancer, rectal cancer, pancreatic duct cancer with distant metastasis, and anti-PD-1 antibody or anti-PD- Non-small cell lung cancer with refractory progression or recurrence after receiving combination therapy including L1 antibody and platinum preparation.
  • treatment refers to, for example, (i) reducing the growth of tumor cells, (ii) reducing the symptoms caused by the cancer, and (iii) the quality of life of a cancer patient. Includes treatments performed to improve, (iv) reduce the dose of other anti-cancer drugs or cancer treatment aids already administered, and / or (v) prolong the survival of cancer patients.
  • “suppressing the progression” of a cancer means delaying the progression of the cancer, stabilizing the symptoms caused by the cancer, and slowing the progression of the symptoms.
  • “suppression of recurrence” of cancer means to prevent recurrence of cancer in patients whose cancer lesions have completely or substantially disappeared or have been completely or substantially eliminated by cancer treatment or excision surgery. do.
  • the treatment method of the present invention is described in the following cancer patients, that is, (a) patients whose therapeutic effect with an anticancer drug is insufficient or insufficient, or patients whose exacerbation after treatment with an anticancer drug, (b) curative or curative. Patients with unresectable, metastatic, recurrent, refractory and / or distant metastatic cancer, (c) Tumor Proportion Score (hereinafter abbreviated as "TPS”) is 50% or more, 25% or more, 10 % Or more, 5% or more or 1% or more of cancer patients, (d) Combined Positive Score (hereinafter abbreviated as "CPS”) is 20% or more, 10% or more, 5% or more or 1% or more.
  • TPS Tumor Proportion Score
  • CPS Combined Positive Score
  • TMB Tumor mutation load
  • the treatment method of the present invention comprises the following cancer patients, that is, (g) patients who have not been treated with an anticancer drug, (h) TPS is less than 50%, less than 25%, and less than 10%.
  • cancer patients with cancer less than 5% or less than 1%, (i) Patients with cancer having CPS less than 20%, less than 10%, less than 5% or less than 1%, (j) dMMR and / or MSI -Prescription for patients with cancer who do not have H or who have low-frequency microsatellite instability (hereinafter abbreviated as "MSI-L"), or (k) patients with cancer who have a low frequency of TMB. May be more required.
  • cancer patients for whom the treatment method of the present invention is required include (i) unresectable advanced or recurrent cancer patients, particularly colon / rectal cancer patients, and (ii) curative resectable topical cancer patients.
  • cancer patients with advanced cancer especially patients with rectal cancer, (iii) cancer patients who have not been treated with anticancer drugs and / or have distant metastases, especially patients with pancreatic cancer, or (iv). Cancer patients who have undergone combination therapy including anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparations and have progressed or relapsed refractory, especially patients with lung cancer.
  • a patient with unresectable advanced or recurrent colorectal cancer may be mentioned.
  • a patient who has not been treated for colorectal cancer may be mentioned.
  • a patient with rectal cancer which is locally advanced cancer that can be curatively resected, is mentioned.
  • One embodiment includes a patient who has not been treated for rectal cancer.
  • a patient with pancreatic cancer who has not been treated with an anticancer drug and / or has distant metastasis can be mentioned.
  • a patient who has not been treated for pancreatic cancer can be mentioned.
  • a patient who has not been treated with a systemic malignant tumor agent for pancreatic cancer is mentioned.
  • a systemic antineoplastic agent for pancreatic cancer having distant metastasis.
  • a lung cancer patient who has received combination therapy including an anti-PD-1 antibody or an anti-PD-L1 antibody and a platinum preparation and has shown refractory progression or recurrence.
  • a patient confirmed to have non-small cell lung cancer can be mentioned.
  • Patients with stage IV or recurrent non-small cell lung cancer are preferred. More preferably, there is a patient who has received a combination therapy including an anti-PD-1 antibody or an anti-PD-L1 antibody as a first-line treatment and a platinum preparation, and has shown refractory progression or recurrence.
  • the therapeutic method of the present invention maximizes its antitumor effect. It can be expected to be demonstrated. Further, according to the therapeutic method of the present invention, it is possible to reduce the dose of each drug and administer it, which is expected to reduce side effects.
  • the therapeutic method of the present invention exerts a synergistic effect.
  • the therapeutic effect of immune checkpoint inhibitors or EP4 receptor antagonists, or standard therapy alone, or immune checkpoint inhibitors and standard therapies, EP4 receptor antagonists and standard therapies, or immunity exerts a synergistic effect compared to the therapeutic effect of the combined use of checkpoint inhibitors and EP4 receptor antagonists.
  • the treatment method of the present invention reduces side effects. Also, in one embodiment, the therapeutic effect of immune checkpoint inhibitors or EP4 receptor antagonists, or standard therapy alone, or immune checkpoint inhibitors and standard therapies, EP4 receptor antagonists and standard therapies, or immunity. It reduces side effects compared to the therapeutic effect of combination with checkpoint inhibitors and EP4 receptor antagonists.
  • timing of administration of each drug used for concomitant administration in the combination of the present invention may be simultaneous or separate.
  • the therapeutic method of the present invention can be applied to the treatment of metastatic cancer and the suppression of metastasis.
  • the therapeutic method of the present invention in one aspect, suppresses recurrence.
  • treatment is associated with reduction in tumor size, suppression of tumor growth (delay or arrest), suppression of tumor metastasis (delay or arrest), suppression of recurrence (prevention or delay), and cancer. It means producing at least one of alleviations of one or more symptoms.
  • the therapeutic method of the present invention is used for (1) complementing and / or enhancing the therapeutic effect, (2) improving kinetics / absorption, reducing the dose, and / or (3) reducing side effects. May be used in combination with the following drugs (eg, known anti-cancer treatments).
  • standard therapy is a standard treatment method that is based on scientific evidence and is recommended for general patients in a certain condition, and examples thereof include chemotherapy.
  • One embodiment includes (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpaclitaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramsylmab therapy.
  • the present invention provides, for example, the following embodiments.
  • Standard therapies preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, or (v) docetaxel and / or ramsylumab therapy, more preferably.
  • bevasizumab and XELOX therapy preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, (vii) docetaxel therapy, or (vi) dosetaxel and ramsilmab therapy, more preferably (i).
  • Bevasizumab and XELOX therapy (iii) FOLFIRINOX therapy or its weight loss regimen, (iv) gemcitabine and nabpacritaxel therapy, or (vi) docetaxel and ramsilmab therapy), and administration in combination with immunocheckpoint inhibitor.
  • a characteristic therapeutic agent for suppressing the progression, suppressing recurrence, and / or suppressing the progression of cancer which comprises an EP4 antagonist as an active ingredient.
  • Standard therapy preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, or (v) docetaxel and / or ramsilmab therapy, more preferably.
  • a therapeutic agent for suppressing the progression, suppressing recurrence, and / or suppressing the progression of cancer which comprises an immune checkpoint inhibitor as an active ingredient.
  • EP4 antagonist is a general formula (I):
  • R 1 represents COOR 8 , tetrazole, SO 3 H, SO 2 NH 2 , SO 2 NHR 8-1 , CONHSO 2 R 8-1 , SO 2 NHCOR 8-1 , or hydroxamic acid.
  • R 8 represents a hydrogen atom, C1-4 alkyl, or benzyl
  • R 8-1 represents C1-4 alkyl, C1-4 haloalkyl, C3-10 carbocycle, or 3-10 membered heterocycle, and the C3-10 carbocycle and 3-10 membered heterocycle, respectively, is C1.
  • L 1 represents C1-5 alkylene, C2-5 alkenylene, or C2-5 alkinylene, R2 is halogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, C2-4alkenyl, C2-4alkynyl, -O (C1-4haloalkyl), -S (C1-4haloalkyl),- C (O) (C1-4 alkyl), -SO 2 (C1-4 alkyl), -CONH (C1-4 alkyl), -CON (C1-4 alkyl) 2 , -NHC (O) (C1-4 alkyl) ), -N (C1-4 alkyl) C (O) (C1-4 alkyl) (C1-4 alkyl) (C1-4 alkyl) (C1-4 alkyl)
  • the C1-4 alkyl may be substituted with halogen and may be substituted.
  • (C1-4alkyl) 2 in the R2 represents two independent C1-4 alkyls, each of which may be the same or different.
  • X 1 represents CR 6 or nitrogen atom
  • R 6 represents hydrogen atom or
  • X 2 represents CR 7 or nitrogen atom
  • R 7 represents hydrogen atom
  • R 2 or -L 3 -R 9 and L 3 represents methylene, oxygen atom or sulfur atom which may be oxidized.
  • R 9 represents a 4-10 membered heterocycle which may be substituted with a substituent selected from the group consisting of halogen, C1-4alkyl, and C1-4haloalkyl.
  • each said C1-4 alkyl may be substituted with a halogen.
  • ring represents a benzene ring or a 5-6 member monocyclic aromatic heterocycle.
  • R5 is ( 1 ) halogen, (2) C1-4alkyl, (3) carboxyl, (4) nitrile, (5) -CONHR 11 , (6) -C (O) R 12 , (7) -OR.
  • R 14 (8) -S (O) t R 15 , (9) -CH 2 R 16 , (10) -NR 17 R 17 , (11) -NHCOR 11 , (12) C4-10 carbocycle, or ( 13) Represents a 4-10 membered heterocycle, the C4-10 membered ring or the 4-10 membered heterocycle may be substituted with 1 to 3 R18s , and if there are multiple R18s , then R Each of the 18 may be the same or different independently.
  • R 11 represents a C1-6 alkyl, C3-6 cycloalkyl, phenyl, or 4-6 membered heterocycle, where R 11 may be substituted with 1 to 3 R 13s , wherein the R 13s are plural.
  • R 13 may be independently the same or different, respectively.
  • R 13 represents a halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, hydroxyl group, -NR 20 R 21 , benzene, or 4-6 membered heterocycle.
  • R 20 and R 21 independently represent a hydrogen atom or C1-4 alkyl, respectively.
  • R 12 represents a C1-6 alkyl, C3-6 cycloalkyl, benzene, or 4-6 membered heterocycle, and the C3-6 cycloalkyl, benzene, or 4-6 membered heterocycle is independent of each other. It may be substituted with halogen, C1-4alkyl, or C1-4alkoxy.
  • R 14 represents a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl, wherein the C1-6 alkyl may be substituted with 1 to 3 R 19s , where the R 19 is. When there are a plurality of R 19 , each of them may be independently the same or different. R 19 is substituted with a substituent selected from the group consisting of C1-4 alkoxy, -CONH (C1-4 alkyl), -CON (C1-4 alkyl) 2 , or C1-4 alkyl and C1-4 haloalkyl. Represents a 5-6 member monocyclic aromatic heterocycle which may be present.
  • the (C1-4 alkyl) 2 in the R 19 represents two independent C1-4 alkyls, each of which may be the same or different.
  • R 15 represents C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl.
  • R 16 represents a hydroxyl group or C1-4 alkoxy and represents R 17 independently represent a hydrogen atom, C1-6 alkyl, or C3-6 cycloalkyl, respectively.
  • R18 is halogen, C1-6alkyl, C3-6cycloalkyl , C1-4alkoxy, oxo, nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C1-4alkyl) SO 2- , Represents a 4-6 membered heterocycle, (C1-4 alkyl) NH-, or (C1-4 alkyl) 2 N-.
  • the (C1-4 alkyl) 2 in the R 18 represents two independent C1-4 alkyls, each of which may be the same or different.
  • m represents an integer of 1 to 4
  • n represents an integer of 0 to 4
  • p represents an integer of 0 to 2
  • q represents an integer of 0 to 6
  • r represents an integer of 0 to 6.
  • the EP4 antagonist is the general formula (I-2).
  • R 2a represents a halogen
  • R 6a represents a hydrogen atom or a halogen
  • qa represents an integer of 0 to 3
  • ra represents an integer of 0 to 4
  • other symbols are the same as in claim 1.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-].
  • the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody.
  • the immune checkpoint inhibitor is an anti-PD-L1 antibody
  • the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolyma).
  • Nivolumab 3 mg / kg (body weight) or 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 240 mg once for 2 weeks).
  • the agent according to the above [17] wherein 360 mg once at intervals is administered at intervals of 3 weeks, or 480 mg once at intervals of 4 weeks).
  • the bevacizumab and CAPOX therapy (I) Bevacizumab is administered once at 7.5 mg / kg at 3-week intervals. (Ii) Oxaliplatin 130 mg / m 2 is administered at 3-week intervals, and (iii) capecitabine 1000 mg / m 2 is orally administered twice daily for 14 days, followed by a 7-day rest period.
  • a cancer progression-suppressing, recurrence-suppressing and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, characterized by administration in combination with bevasizumab and XELOX therapy, as well as immune checkpoint inhibitors.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane]. -4,1'-cyclopropane] -2'-carbonyl ⁇ amino) phenyl] butane acid, or a salt thereof, 5 mg to 40 mg (preferably 20 mg or 40 mg once) as an EP4 antagonist daily.
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 360 mg once for 3 weeks).
  • a cancer progression-suppressing, recurrence-suppressing and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, characterized by administration in combination with bevasizumab and XELOX therapy, and EP4 antagonists.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 360 mg once for 3 weeks).
  • the colorectal cancer is unresectable advanced or recurrent colorectal cancer (preferably unresectable advanced or recurrent colorectal cancer without treatment history).
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiroyl].
  • Agent. [2-13] The agent according to the above [2-12], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.
  • Anti-PD-1 antibody is Nivolumab, Cemiplimab, Pembrolizumab, Spartanismab, Tissellizumab, AMP-514, Dostarlimab, Toriparimab, Toripalimab, Camrelizumab, Gen Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplelimab), BAT-1306, AK105, AK103, BI 754991, LZM009, CMAB819, Sym021, GB226 (Geptanolimab) ), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63722383 (Cemiplimab) or AB122 (Zimberelimab), the agent according to the above [2-13].
  • the immune checkpoint inhibitor is an anti-PD-L1 antibody
  • the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolima).
  • Nivolumab 3 mg / kg (body weight) or 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals (preferably 240 mg once).
  • the agent according to the above [2-17] wherein 360 mg is administered once at 2-week intervals, or 480 mg once at 4-week intervals).
  • 240 mg of Nivolumab is intravenously administered at intervals of 2 weeks for about 30 minutes.
  • Preoperative chemoradiotherapy includes 45 Gy / 25 doses of pelvic cavity and 5.4 Gy / 3 doses of boost to the primary lesion, and capecitabine at 825 mg / m 2 twice daily.
  • Cancer containing an EP4 antagonist as an active ingredient which is characterized by being administered to a cancer patient who has undergone preoperative chemoradiotherapy (preferably colorectal cancer, more preferably colon / rectum).
  • preoperative chemoradiotherapy preferably colorectal cancer, more preferably colon / rectum.
  • a suppressive, recurrence-suppressing and / or therapeutic agent for cancer preferably curatively resectable locally advanced rectal cancer.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • Preoperative chemoradiotherapy is a combination of radiation therapy and capecitabin (preferably 45 Gy / 25 doses to the pelvic cavity and 5.4 Gy / 3 doses to the primary lesion, and capecitabin. 825 mg / m 2 is administered twice a day for 21 days or 42 times or more), Agent.
  • the agent according to the above [2-39], which is further administered in combination with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is nivolumab, and 240 mg at a time as anti-Nivolumab is 2
  • Colorectal cancer containing an immune checkpoint inhibitor as an active ingredient which is characterized by being administered in combination with an EP4 antagonist to cancer patients who have undergone preoperative chemoradiotherapy. Progression suppression, recurrence suppression and / or therapeutic agent,
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is Nivolumab, 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals (preferably 240 mg once at 2-week intervals).
  • Intervals) and (iii) preoperative chemoradiotherapy is a combination of radiation therapy and capecitabin (preferably 45 Gy / 25 doses of pelvic cavity and 5.4 Gy / 3 doses to the primary lesion). Bost irradiation, and 825 mg / m 2 of capecitabin twice daily for 21 days or 42 times or more). Agent.
  • [3-1] The agent according to the above [1] or [2], wherein the standard therapy is FOLFIRINOX therapy or a weight loss regimen thereof.
  • [3-2] The agent according to the above [3-1], wherein the EP4 antagonist is the compound represented by the general formula (I) described in the above [3] or a salt thereof.
  • [3-3] The agent according to the above [3-1] or [3-2], wherein the cancer is pancreatic cancer (preferably pancreatic duct cancer, more preferably invasive pancreatic duct cancer).
  • [3-4] The agent according to the above [3-3], wherein the pancreatic cancer is pancreatic cancer having distant metastasis.
  • Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartanismab, Tissellizumab, AMP-514, Dostarlimab, Toriparimab, Toripalimab, Camrelizumab, Gen Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplelimab), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226 (Geptanolimab) ), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63722383 (Cemiplimab) or AB122 (Zimberelimab), the agent according to the above [3-11].
  • the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolima). , HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 and CX-072, in the above [3-10]. The agent described.
  • Nivolumab 3 mg / kg (body weight) or 240 mg once at 2-week intervals, 360 mg once at 3-week intervals, or 480 mg once at 4-week intervals (preferably 240 mg once).
  • the agent according to the above [3-15] wherein 360 mg is administered once at 2-week intervals, or 480 mg once at 4-week intervals).
  • 480 mg of Nivolumab is intravenously administered at intervals of 4 weeks for about 30 minutes.
  • FOLFIRINOX therapy or a weight loss regimen thereof is a therapy in which (i) oxaliplatin, (ii) levoleucovorinate calcium, (iii) irinotecan hydrochloride hydrate, and (iv) fluorouracil are administered in combination.
  • FOLFIRINOX therapy Intravenously administer oxaliplatin 50-85 mg / m 2 (preferably 50 mg / m 2 , 65 mg / m 2 , 85 mg / m 2 , more preferably 85 mg / m 2 ).
  • Ii Intravenously administer levoleucovorinate calcium 200 mg / m 2 .
  • Irinotecan hydrochloride hydrate 90-180 mg / m 2 preferably 90 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 , 180 mg / m 2 , more preferably 180 mg / m 2 ) intravenously.
  • the weight loss regimen for FOLFIRINOX therapy is (I) Intravenously administer oxaliplatin 50-85 mg / m 2 (preferably 50 mg / m 2 , 65 mg / m 2 , 85 mg / m 2 , more preferably 85 mg / m 2 ). (Ii) Intravenously administer levoleucovorinate calcium 200 mg / m 2 . (Iii) Irinotecan hydrochloride hydrate 120-140 mg / m 2 (preferably 140 mg / m 2 ) is administered intravenously.
  • Fluorouracil 1200-2400 mg / m 2 (preferably 1200 mg / m 2 , 1800 mg / m 2 , 2400 mg / m 2 , more preferably 2400 mg / m 2 ) is a therapy that is continuously administered intravenously.
  • [3-34] FOLFIRINOX therapy or a weight loss regimen thereof administers a series of doses at 2- to 4-week intervals (preferably 2-week intervals, 3-week intervals, 4-week intervals, more preferably 2-week intervals).
  • [3-35] FOLFIRINOX therapy Intravenously administer oxaliplatin 85 mg / m 2 over 2 hours.
  • levoleucovorinate calcium 200 mg / m 2 is intravenously administered over 2 hours.
  • levoleucovorinate calcium is intravenously administered over 1.5 hours.
  • fluorouracil 400 mg / m 2 is rapidly intravenously administered.
  • fluorouracil 2400 mg / m 2 is continuously administered intravenously over 46 hours, and the series of administrations is carried out at 2-week intervals.
  • the agent according to any one of [3-34].
  • the weight loss regimen for FOLFIRINOX therapy is (I) Intravenously administer oxaliplatin 85 mg / m 2 over 2 hours. (Ii) Levoleucovorinate calcium 200 mg / m 2 is intravenously administered over 2 hours. (Iii) From 30 minutes after the start of administration of levoleucovorinate calcium, irinotecan hydrochloride hydrate 150 mg / m 2 is intravenously administered over 1.5 hours.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 480 mg once at 4 week intervals). Administered at intervals)
  • the FOLFIRINOX therapy is (A) Oxaliplatin 85 mg / m 2 is intravenously administered over 2 hours.
  • C Intravenously administer irinotecan hydrochloride hydrate 180 mg / m 2 over 1.5 hours 30 minutes after the start of administration of levoleucovorinate calcium.
  • D Further, after the administration of the levoleucovorinate calcium is completed, fluorouracil 400 mg / m 2 is rapidly intravenously administered.
  • fluorouracil 2400 mg / m 2 is continuously administered intravenously over 46 hours, and the series of administrations is carried out at 2-week intervals.
  • A Oxaliplatin 85 mg / m 2 is intravenously administered over 2 hours.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 480 mg once at 4 week intervals). Administered at intervals)
  • the FOLFIRINOX therapy is (A) Oxaliplatin 85 mg / m 2 is intravenously administered over 2 hours.
  • C Irinotecan hydrochloride hydrate 180 mg / m 2 is intravenously administered over 1.5 hours from 30 minutes after the start of administration of levoleucovorinate calcium.
  • D Further, after the administration of the levoleucovorinate calcium is completed, fluorouracil 400 mg / m 2 is rapidly intravenously administered.
  • fluorouracil 2400 mg / m 2 is continuously administered intravenously over 46 hours, and the series of administrations is carried out at 2-week intervals.
  • A Oxaliplatin 85 mg / m 2 is intravenously administered over 2 hours.
  • pancreatic cancer pancreatic cancer having distant metastasis.
  • pancreatic cancer pancreatic cancer having distant metastasis.
  • [4-1] The agent according to the above [1] or [2], wherein the standard therapy is gemcitabine and nabupaclitaxel therapy.
  • [4-2] The agent according to the above [4-1], wherein the EP4 antagonist is the compound represented by the general formula (I) described in the above [3], or a salt thereof.
  • [4-3] The agent according to the above [4-1] or [4-2], wherein the cancer is pancreatic cancer (preferably pancreatic duct cancer, more preferably invasive pancreatic duct cancer).
  • [4-4] The agent according to the above [4-3], wherein the pancreatic cancer is pancreatic cancer having distant metastasis.
  • Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartanismab, Tissellizumab, AMP-514, Dostarlimab, Toriparimab, Toripalimab, Camrelizumab, GenMab, Camrelizumab, Gen Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplelimab), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226 (Geptanolimab) ), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63722383 (Cemiplimab) or AB122 (Zimberelimab), the agent according to the above [4-11].
  • the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolima). , HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 and CX-072, in the above [4-10]. The agent described.
  • [4-29] The agent according to the above [4-20], wherein 10 mg / kg (body weight) of Durvalumab is administered once at 2-week intervals.
  • [4-30] The above-mentioned [4-21], wherein 3 mg / kg (body weight) or 1 mg / kg (body weight) of Ipilimumab is intravenously administered four times at three-week intervals.
  • Agent. [4-31] Gemcitabine and nab-paclitaxel therapy, (I) Gemcitabine 600-1000 mg / m 2 (preferably 600 mg / m 2 , 800 mg / m 2 , 1000 mg / m 2 , more preferably 1000 mg / m 2 ) is administered intravenously.
  • Nabpaclitaxel 75-125 mg / m 2 (preferably 75 mg / m 2 , 100 mg / m 2 , 125 mg / m 2 , more preferably 125 mg / m 2 ) is administered intravenously.
  • Gemcitabine and nab-paclitaxel therapy is a therapy in which a series of administrations are administered at 1-week intervals, continued for 3 weeks, and then withdrawn for 1 week, as described above [4-1] to [4-31].
  • [4-33] Gemcitabine and nab-paclitaxel therapy (I) Gemcitabine 1000 mg / m 2 is intravenously administered over 30 minutes. (Ii) Nabpaclitaxel 125 mg / m 2 is intravenously administered over 30 minutes, and the series of administrations is performed at 1-week intervals, continued for 3 weeks, and then withdrawn for 1 week.
  • [4-35] The agent according to any one of the above [4-1] to [4-34], which is a therapy in which administration of gemcitabine, nabupaclitaxel, an immune checkpoint inhibitor and an EP4 antagonist is started on the same day. ..
  • [4-36] Gemcitabine and nab-paclitaxel therapy, as well as suppression, recurrence suppression and / or treatment of cancer comprising an EP4 antagonist as an active ingredient, characterized by administration in combination with an immune checkpoint inhibitor. It ’s an agent, (I) The EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 480 mg once at 4 week intervals).
  • the gemcitabine and nab-paclitaxel therapy is (a) gemcitabine 1000 mg / m 2 intravenously over 30 minutes, (b) nab-paclitaxel 125 mg / m 2 intravenously over 30 minutes, the series. This is a therapy in which the drug is administered at 1-week intervals, continued for 3 weeks, and then withdrawn for 1 week.
  • Gemcitabine and nab-paclitaxel therapy, as well as suppression, recurrence suppression and / or treatment of cancer comprising an immune checkpoint inhibitor as an active ingredient, characterized by administration in combination with an EP4 antagonist.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane]. -4,1'-cyclopropane] -2'-carbonyl ⁇ amino) phenyl] butane acid, or a salt thereof, 5 mg to 40 mg (preferably 20 mg or 40 mg once) as an EP4 antagonist daily.
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 480 mg once at 4 week intervals).
  • Administered at intervals) (Iii) The gemcitabine and nab-paclitaxel therapy is (a) gemcitabine 1000 mg / m 2 intravenously over 30 minutes, (b) nab-paclitaxel 125 mg / m 2 intravenously over 30 minutes, the series. This is a therapy in which the drug is administered at 1-week intervals, continued for 3 weeks, and then withdrawn for 1 week.
  • [4-38] The agent according to the above [4-36] or [4-37], wherein the cancer is pancreatic cancer (preferably pancreatic duct cancer, more preferably invasive pancreatic duct cancer).
  • pancreatic cancer preferably pancreatic duct cancer, more preferably invasive pancreatic duct cancer.
  • pancreatic cancer is pancreatic cancer having distant metastasis.
  • [5-1] The agent according to the above [1] or [2], wherein the standard therapy is docetaxel and / or ramucirumab therapy.
  • [5-2] The agent according to the above [5-1], wherein the standard therapy is docetaxel therapy.
  • [5-3] The agent according to the above [5-1], wherein the standard therapy is ramucirumab therapy.
  • [5-4] The agent according to the above [5-1], wherein the standard therapy is docetaxel and ramucirumab therapy.
  • [5-5] The agent according to the above [5-1] to [5-4], wherein the EP4 antagonist is the compound represented by the general formula (I) described in the above [3] or a salt thereof.
  • [5-6] The agent according to any one of the above [5-1] to [5-5], wherein the cancer is lung cancer (preferably non-small cell lung cancer).
  • lung cancer is non-small cell lung cancer with advanced or recurrent stage IV or recurrence (preferably non-small cell lung cancer with advanced or recurrent refractory to combination therapy including anti-PD-1 antibody or anti-PD-L1 antibody, and platinum preparations.
  • the agent according to the above [5-6] which is (cell lung cancer).
  • [5-8] The above-mentioned [5-8], which is administered to a patient who has received a combination therapy containing an anti-PD-1 antibody or an anti-PD-L1 antibody and a platinum preparation and has progressed or relapsed refractory.
  • the EP4 antagonist is any of the above-mentioned [5-1] to [5-8], wherein the EP4 antagonist is the compound represented by the general formula (I-2) described in the above [8] or a salt thereof.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiroyl].
  • Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartanismab, Tissellizumab, AMP-514, Dostarlimab, Toriparimab, Toripalimab, Camrelizumab, Gen Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplelimab), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226 (Geptanolimab) ), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63722383 (Cemiplimab) or AB122 (Zimberelimab), the agent according to the above [5-14].
  • the immune checkpoint inhibitor is an anti-PD-L1 antibody
  • the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolima).
  • Ipilimumab is administered intravenously at a dose of 3 mg / kg (body weight) or 1 mg / kg (body weight) four times at 3-week intervals or at a dose of 1 mg / kg (body weight) at 6-week intervals.
  • Docetaxel therapy is a therapy in which docetaxel 50 to 75 mg / m 2 (preferably 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , more preferably 60 mg / m 2 ) is administered intravenously.
  • Docetaxel therapy is intravenous docetaxel 50-75 mg / m 2 (preferably 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , more preferably 60 mg / m 2 ) over 60 minutes.
  • Ramucirumab therapy is a therapy in which ramucirumab 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is intravenously administered.
  • Ramucirumab therapy is 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) of ramucirumab for 30-60 minutes (preferably 60 minutes). ), And the series of administrations is performed at 3-week intervals.
  • Docetaxel and ramucirumab therapy (I) Docetaxel 50-75 mg / m 2 (preferably 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , more preferably 60 mg / m 2 ) is administered intravenously. (Ii) Ramucirumab 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is administered intravenously.
  • the agent according to any one of the above-mentioned [5-1], [5-4] to [5-33], which is a therapy.
  • Docetaxel and ramucirumab therapy (I) Docetaxel 50-75 mg / m 2 (preferably 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , more preferably 60 mg / m 2 ) is administered intravenously over 60 minutes. (Ii) Ramucirumab 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) administered intravenously over 30-60 minutes (preferably 60 minutes). The series of doses will be given at 3-week intervals.
  • Agent. [5-41] A drug containing an EP4 antagonist as an active ingredient, which is characterized by being administered in combination with docetaxel therapy and an immune checkpoint inhibitor, for suppressing the progression, suppressing recurrence, and / or treating the cancer.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane]. -4,1'-cyclopropane] -2'-carbonyl ⁇ amino) phenyl] butane acid, or a salt thereof, 5 mg to 40 mg (preferably 20 mg or 40 mg once) as an EP4 antagonist daily.
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 360 mg once for 3 weeks).
  • Docetaxel therapy is intravenous administration of docetaxel 50-75 mg / m 2 (preferably 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , more preferably 60 mg / m 2 ) over 60 minutes.
  • a drug which is a therapy in which the administration is performed at 3-week intervals.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane]. -4,1'-cyclopropane] -2'-carbonyl ⁇ amino) phenyl] butane acid, or a salt thereof, 5 mg to 40 mg (preferably 20 mg or 40 mg once) as an EP4 antagonist daily.
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 360 mg once for 3 weeks).
  • Administered at intervals) (Iii) Docetaxel therapy is intravenous administration of docetaxel 50-75 mg / m 2 (preferably 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , more preferably 60 mg / m 2 ) over 60 minutes.
  • a drug which is a therapy in which the administration is performed at 3-week intervals.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 360 mg once for 3 weeks).
  • Ramucirumab therapy takes 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) over 30-60 minutes (preferably 60 minutes).
  • a drug that is administered intravenously and the series of administrations is performed at 3-week intervals.
  • a therapeutic agent for suppressing the progression, suppressing recurrence, and / or suppressing the progression of cancer containing an immune checkpoint inhibitor as an active ingredient which is characterized by being administered in combination with ramucirumab therapy and an EP4 antagonist.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 360 mg once for 3 weeks).
  • Ramucirumab therapy takes 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) over 30-60 minutes (preferably 60 minutes).
  • Ramsylumab 4- [4-cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyran-] 4,1'-Cyclopropane] -2'-carbonyl ⁇ amino) phenyl] butanoic acid, or a salt thereof, and Nivolumab are therapies that begin on the same day (preferably 4-when administered on the same day).
  • a cancer progression-suppressing, recurrence-suppressing and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, characterized by administration in combination with docetaxel and ramucirumab therapy and immune checkpoint inhibitors.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 360 mg once for 3 weeks).
  • Docetaxel and ramucirumab therapy (A) Docetaxel 50-75 mg / m 2 (preferably 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , more preferably 60 mg / m 2 ) is intravenously administered over 60 minutes. (B) Ramucirumab 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) administered intravenously over 30-60 minutes (preferably 60 minutes).
  • the agent which is a therapy in which the series of administrations is performed at 3-week intervals.
  • a cancer progression-suppressing, recurrence-suppressing and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, characterized by administration in combination with docetaxel and ramucirumab therapy, and EP4 antagonists.
  • the EP4 antagonist is 4- [ 4 -cyano-2-( ⁇ (2'R, 4S) -6-[(propane-2-yl) carbamoyl] -2,3-dihydrospiro [1-benzopyrane].
  • the immune checkpoint inhibitor is nivolumab, 240 mg once at 2 week intervals, 360 mg once at 3 week intervals, or 480 mg once at 4 week intervals (preferably 360 mg once for 3 weeks).
  • Docetaxel and ramucirumab therapy (A) Docetaxel 50-75 mg / m 2 (preferably 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , more preferably 60 mg / m 2 ) is intravenously administered over 60 minutes. (B) Ramucirumab 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) administered intravenously over 30-60 minutes (preferably 60 minutes).
  • the agent which is a therapy in which the series of administrations is performed at 3-week intervals.
  • Non-small advanced or recurrent lung cancer refractory to stage IV or recurrent non-small cell lung cancer preferably anti-PD-1 or anti-PD-L1 antibody, and combination therapy including platinum preparations
  • Standard therapy preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, or (v) docetaxel and / or ramsilmab therapy.
  • bevasizumab and XELOX therapy preferably, (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramsilmab therapy, more preferably (vi).
  • Standard therapy preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or its weight loss regimen, (iv) gemcitabine and nabpacritaxel therapy, or (vi) docetaxel and ramsilmab therapy, and administered in combination with immunocheckpoint inhibitor.
  • An EP4 antagonist used to control the progression, control and / or treatment of cancer.
  • Standard therapy preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, or (v) docetaxel and / or ramsilmab therapy.
  • bevasizumab and XELOX therapy Preferably, (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramsilmab therapy, more preferably (vi).
  • bevasizumab and XELOX therapy iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, or (vi) docetaxel and ramsilmab therapy
  • An immune checkpoint inhibitor used to control the progression, control and / or treatment of cancer.
  • Standard therapy preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, or (v) docetaxel and / or ramsylumab therapy.
  • bevasizumab and XELOX therapy preferably, (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramsilmab therapy, more preferably (vi).
  • Standard therapy preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, or (v) docetaxel and / or ramsylumab therapy.
  • bevasizumab and XELOX therapy preferably, (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramsilmab therapy, more preferably (vi).
  • Standard therapy preferably (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, or (v) docetaxel and / or ramsilmab therapy.
  • bevasizumab and XELOX therapy preferably, (i) bevasizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a weight loss regimen thereof, (iv) gemcitabine and nabpacritaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramsilmab therapy, more preferably (vi).
  • Example 1 An open-label, uncontrolled study in patients with unresectable advanced or recurrent colorectal cancer in combination with Compound A, Nivolumab as first-line treatment and XELOX + bevasizumab therapy as standard treatment.
  • the purpose of this study is to examine the tolerability, safety and efficacy of compound A, Nivolumab and XELOX + bevasizumab therapy as first-line treatment in patients with unresectable advanced or recurrent colorectal cancer. do.
  • the clinical trial can evaluate the combined effect of compound A, nivolumab and XELOX + bevacizumab therapy.
  • Target patients Patients with unresectable advanced or recurrent colon / rectal cancer (2) Patient selection criteria Treatment with systemic antineoplastic agents for unresectable advanced or recurrent colon / rectal cancer at the time of enrollment Patients with no history and who met all of the prescribed patient selection criteria determined in light of the patient selection criteria in each of the trials conducted so far for Compound A, Nivolumab and XELOX + bevasizumab therapy were selected. If it becomes clear that the criteria are not met from registration to before the initial administration of the investigational drug, administration of the investigational drug will not be started and the study will be discontinued.
  • Compound A was orally administered at 20 mg or 40 mg once daily, and continued to be administered until the prescribed discontinuation criteria for compound A were met.
  • compound A, nivolumab and XELOX + bevacizumab therapy were administered on the same day, compound A and nivolumab were administered first, compound A and nivolumab were administered, and then XELOX + bevacizumab therapy was started.
  • Nivolumab Nivolumab 360 mg was administered intravenously over 30 minutes at 3-week intervals and continued until the prescribed discontinuation criteria for nivolumab were met.
  • nivolumab The administration of nivolumab was carried out at least 14 days after the previous administration and after the 15th day.
  • Oxaliplatin was administered intravenously at 130 mg / m 2 (body surface area) over 2 hours.
  • Capecitabine was orally administered at 1000 mg / m 2 twice daily after breakfast and after dinner, and after oral administration for 14 days, the drug was withdrawn for 7 days.
  • Commercially available products were used for bevacizumab, oxaliplatin, and capecitabine.
  • Clinical trial schedule The study consists of a screening phase, a treatment phase and a follow-up phase.
  • the outline of the clinical trial schedule is shown in FIG.
  • the screening period was within 28 days before the administration of the study drug, and the investigator or investigator met the above selection criteria and did not violate the above exclusion criteria, and included patients who were judged to be eligible for this study.
  • the treatment period was 21 days per cycle, and the date of administration of the first investigational drug was the first day of cycle 1.
  • the first day of each cycle after the second cycle was set to [21X (number of cycles-1) + 1] days.
  • Administration of Compound A, Nivolumab and XELOX + bevacizumab therapy was started according to the above dosage and administration, respectively, and administration was continued according to the administration criteria, dose reduction criteria and dose at the time of dose reduction for Compound A, nivolumab and XELOX + bevacizumab therapy.
  • the end of the treatment period is the time when the evaluation at the end (discontinuation) of the administration of Compound A, nivolumab and XELOX + bevacizumab therapy is completed.
  • the subjects who discontinued or discontinued the administration of compound A, nivolumab and XELOX + bevacizumab therapy will be evaluated at the end of administration (discontinuation) and will shift to the follow-up period.
  • a follow-up survey will be conducted after the follow-up period.
  • CT / MRI imaging in the head fluorodeoxyglucose-positron emission tomography (FDG-PET) (or bone) Scinchography) etc. were performed to confirm the presence or absence of brain metastasis or bone metastasis.
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • the investigator or investigator measured the tumor diameter of the target lesion according to RECIST Guidelines 1.1, and determined the antitumor effect. Baseline evaluation was performed using the latest imaging tests within 28 days prior to study drug administration and confirmed to have one or more measurable lesions as defined in RECIST Guidelines version 1.1. The diagnostic imaging during the treatment period was performed at 6-week intervals from the 1st day of the first cycle to 6 weeks (+7 days) to 54 weeks (+7 days), and at 12-week intervals ( ⁇ 7 days) thereafter.
  • Progression-free survival (day) "the day when the overall effect was determined to be PD, or the earliest day of death due to any cause"-"the date when the investigational drug was started” + 1
  • PD progressing disease
  • the date on which the last evaluable diagnostic imaging was performed is the discontinuation date.
  • Subjects who have not undergone evaluable diagnostic imaging and have not died will have the study drug administration start date as the discontinuation date.
  • Subjects who receive post-treatment for cancer before the overall effect is determined to be PD or die will have the date of the last evaluable diagnostic imaging prior to the start of post-treatment for cancer as the termination date. ..
  • Response period The response period is calculated from the following formula.
  • Response period (day) "The day when the overall effect is judged to be PD for the first time after the response is confirmed or the earliest day of death due to any cause"-"The first judgment date of the confirmed CR or PR" + 1
  • the evaluation target is a subject who showed CR or PR confirmed through the clinical trial.
  • Period until response The period until response is calculated from the following formula.
  • Duration to response (day) "First determination date of confirmed CR or PR"-"Start date of study drug administration" + 1 (7)
  • Rate of change in the sum of tumor diameters of the target lesion The rate of change in the sum of tumor diameters of the target lesion was calculated using the following formula for subjects having the target lesion. However, the rate of change in the sum of tumor diameters of the target lesion after post-treatment is not calculated.
  • the maximum rate of change in the sum of tumor diameters of the target lesion is the rate of change at the time when the sum of tumor diameters of the target lesion becomes the smallest.
  • the sum of tumor diameters of the target lesion after the overall effect is determined to be PD or after post-treatment is not used to calculate the maximum rate of change.
  • Example 2 An open-label, uncontrolled study in which compound A or compound A and Nivolumab are used in combination as neoadjuvant therapy after preoperative chemoradiotherapy in curatively resectable locally advanced rectal cancer.
  • Effective as neoadjuvant therapy after preoperative chemoradiation therapy (CRT) for curatively resectable locally advanced rectal cancer when compound A is administered alone and / or compound A and Nivolumab are administered in combination.
  • CRT preoperative chemoradiation therapy
  • the purpose is to examine sex, pharmacokinetics and safety.
  • the study can evaluate the effect of compound A and / or the combination of compound A and nivolumab as neoadjuvant therapy.
  • Target curative resectable locally advanced rectal cancer (2) Patient selection criteria At the time of enrollment, the prescribed criteria for Nivolumab and Compound A were determined in consideration of the patient selection criteria in each clinical trial conducted so far. Patients who met all of the patient selection criteria were selected. If it becomes clear that the criteria are not met between registration and the initial administration of the investigational drug, administration of the investigational drug will not be started and the study will be discontinued.
  • preoperative CRT As preoperative CRT, it was administered to patients who were treated to meet the following conditions. -45 Gy / 25 times of irradiation to the pelvic cavity and 5.4 Gy / 3 times of bomb irradiation to the primary lesion were performed. It was started as capecitabine at a daily dose of 1,650 mg / m 2 (825 mg / m 2 twice daily). The starting dose is determined based on the usage / dose D method of Xeloda® Tablets 300.
  • capecitabine was taken orally for a period corresponding to 75% of the 28 times of radiation irradiation (eg, in the case of 50.4 Gy / 28 times irradiation, it was taken for 21 days or 42 times in the morning and evening. Oral administration more than once). It doesn't matter if you lose weight or not.
  • Compound A Compound A was orally administered at 40 mg once daily, and administration was continued until the prescribed discontinuation criteria for compound A were met.
  • Nivolumab Nivolumab was administered intravenously at 240 mg every 2 weeks for 30 minutes and continued until the prescribed discontinuation criteria for nivolumab were met. Nivolumab administration was performed at least 10 days after the day following the previous administration, and after the 11th day.
  • Clinical trial schedule The study consists of a screening phase, a therapeutic phase, a perioperative phase and a follow-up phase. The outline of the clinical trial design is shown in FIG.
  • perioperative period in principle, surgery is performed 7 days after the final administration date of compound A, 14 days after the final administration date of nivolumab, and within 14 weeks after the end of preoperative CRT.
  • the condition of the subject should be given top priority, and if surgery is required immediately, such as exacerbation of the underlying disease, or if surgery should be postponed, such as treatment for adverse events. Not limited.
  • various final examinations are performed starting from 30 days after the end of the surgical treatment or the time when the investigator or the investigator determines that the complications due to the surgery have been alleviated, whichever is later.
  • Imaging and endoscopy determined the presence or absence of tumor exacerbations from colonoscopy, CT or MRI images. The implementation period is not affected by the suspension of the investigational drug. In addition, if brain metastasis is suspected due to clinical symptoms during the screening period (within 14 days before administration of the investigational drug), CT / MRI imaging in the head, FDG-PET (or bone scintigraphy), etc. are performed to perform brain metastasis. Or, the presence or absence of bone metastasis was confirmed.
  • pCR rate The percentage of subjects judged to be AJCC Tumor regression grade 0 by the pathologist of each implementing medical institution is defined as the pCR rate. Calculated. The pCR was one in which no viable tumor cells were found not only in the primary lesion but also in the regional lymph nodes (ypT0N0).
  • MPR rate The percentage of subjects judged to be AJCC Tumor regression grade 0 or 1 by the pathologist of each implementing medical institution is calculated as the MPR rate.
  • Example 3 An open-label, uncontrolled study in patients with pancreatic cancer with distant metastasis using compound A, Nivolumab and standard therapies mFFX or GnP therapy as first-line therapy.
  • the purpose of this study is to examine the tolerability, safety and efficacy of compound A, Nivolumab and mFFX therapy or GnP therapy in combination as first-line treatment in patients with pancreatic cancer.
  • the clinical trial can evaluate the combined effect of compound A, nivolumab and mFFX therapy or GnP therapy.
  • Compound A was orally administered at 20 mg or 40 mg once daily, and continued to be administered until the prescribed discontinuation criteria for compound A were met.
  • compound A, nivolumab and mFFX therapy or GnP therapy were administered on the same day, compound A and nivolumab were administered first, compound A and nivolumab were administered, and then mFFX therapy or GnP therapy was started.
  • Nivolumab Nivolumab 480 mg was administered intravenously over 30 minutes at 4-week intervals and continued until the prescribed discontinuation criteria for nivolumab were met.
  • nivolumab The administration of nivolumab was carried out at least 24 days after the previous administration and after the 25th day.
  • Oxaliplatin was administered intravenously at 85 mg / m 2 (body surface area) over 2 hours.
  • Irinotecan was administered intravenously at 150 mg / m 2 (body surface area) over 90 minutes.
  • Levoleucovorinate was administered intravenously at 200 mg / m 2 (body surface area) over 2 hours.
  • Fluorouracil was administered intravenously at 2400 mg / m 2 (body surface area) over 46 hours. The series of administrations was performed at 2-week intervals.
  • Commercially available products were used for oxaliplatin, irinotecan, levofolinate, and fluorouracil.
  • [GnP therapy] Gemcitabine was administered intravenously at 1000 mg / m 2 (body surface area) over 30 minutes and was withdrawn for at least 6 days.
  • Nabpaclitaxel was administered intravenously at 125 mg / m 2 (body surface area) over 30 minutes and was withdrawn for at least 6 days. The series of administrations was performed at 1-week intervals, continued for 3 weeks, and then withdrawn for 1 week.
  • the treatment period was 28 days per cycle, and the date of administration of the first investigational drug was the first day of cycle 1.
  • the first day of each cycle after the second cycle was set to [28 ⁇ (number of cycles-1) + 1] days.
  • Start administration of compound A, nivolumab and mFFX therapy or GnP therapy according to the above dosage and administration and continue administration according to the administration criteria, dose reduction criteria and dose at the time of dose reduction for compound A, nivolumab and mFFX therapy or GnP therapy. bottom.
  • the end of the treatment period was defined as the time when the evaluation at the end (discontinuation) of the administration of compound A, nivolumab and mFFX therapy or GnP therapy was completed.
  • the administration should be postponed until the clinical laboratory test values on the scheduled administration date recover to the condition satisfying the criteria, and the administration should be confirmed after confirming that the contraindications for each drug do not apply.
  • Weight loss and weight loss criteria for mFFX therapy Weight loss will be implemented according to the latest package insert.
  • [Criteria for discontinuing mFFX therapy] During the treatment phase, subjects who meet any of the prescribed discontinuation criteria determined in consideration of the discontinuation criteria in each clinical trial conducted so far for mFFX therapy will discontinue administration of mFFX therapy.
  • the administration should be postponed until the clinical laboratory test values on the scheduled administration date recover to the condition satisfying the criteria, and the administration should be confirmed after confirming that the contraindications for each drug do not apply.
  • Weight loss and weight loss criteria for GnP therapy Weight loss will be implemented according to the latest package insert.
  • [Criteria for discontinuing GnP therapy] During the treatment period, subjects who meet any of the prescribed discontinuation criteria determined in consideration of the discontinuation criteria in each clinical trial conducted so far for GnP therapy discontinue administration of GnP therapy.
  • Effectiveeness evaluation criteria (Diagnostic imaging) CT / magnetic resonance imaging (MRI) imaging of the chest, abdomen and pelvis was performed.
  • CT / MRI imaging in the head fluorodeoxyglucose-positron emission tomography (FDG-PET) (or bone) Scinchography) etc. were performed to confirm the presence or absence of brain metastasis or bone metastasis.
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • the investigator or investigator measured the tumor diameter of the target lesion according to RECIST Guidelines 1.1, and determined the antitumor effect. Baseline evaluation was performed using the latest imaging tests within 28 days prior to study drug administration and confirmed to have one or more measurable lesions as defined in RECIST Guidelines version 1.1. The diagnostic imaging during the treatment period was performed 8 weeks after the 1st day of the first cycle (+7 days), and the tumor diameter was measured.
  • the response rate indicates the proportion of subjects whose best overall effect was determined to be CR or PR.
  • Disease control rate indicates the proportion of subjects whose best overall effect was determined to be CR, PR or SD.
  • Progression-free survival The progression-free survival is calculated from the following formula.
  • Progression-free survival (day) "the day when the overall effect was determined to be PD, or the earliest day of death due to any cause"-"the date when the investigational drug was started” + 1
  • the day on which the last evaluable diagnostic imaging was performed is set as the discontinuation date.
  • Subjects who have not undergone evaluable diagnostic imaging and have not died will have the study drug administration start date as the discontinuation date.
  • Subjects who receive post-treatment for cancer before the overall effect is determined to be PD or die will have the date of the last evaluable diagnostic imaging prior to the start of post-treatment for cancer as the termination date. .. (5) Response period
  • the response period is calculated from the following formula.
  • Response period (day) "The day when the overall effect is judged to be PD for the first time after the response is confirmed or the earliest day of death due to any cause"-"The first judgment date of the confirmed CR or PR" + 1
  • the evaluation target is a subject who showed CR or PR confirmed through the clinical trial.
  • Duration to response (day) "First determination date of confirmed CR or PR"-"Start date of study drug administration" + 1 (7)
  • Rate of change in the sum of tumor diameters of the target lesion The rate of change in the sum of tumor diameters of the target lesion was calculated using the following formula for subjects having the target lesion. However, the rate of change in the sum of tumor diameters of the target lesion after post-treatment is not calculated.
  • the maximum rate of change in the sum of tumor diameters of the target lesion is the rate of change at the time when the sum of tumor diameters of the target lesion becomes the smallest.
  • the sum of tumor diameters of the target lesion after the overall effect is determined to be PD or after post-treatment is not used to calculate the maximum rate of change.
  • Example 4 Compound A, nivolumab and standard as second-line treatment in patients with advanced or recurrent non-small cell lung cancer refractory to combination therapy with anti-PD-1 or anti-PD-L1 antibodies and platinum preparations.
  • An open-label, uncontrolled study with the therapy docetaxel and ramucirumab This study is an advanced or recurrent non-small cell lung cancer refractory to combination therapy with anti-PD-1 or anti-PD-L1 antibodies and platinum. The purpose of this study is to examine the tolerability, safety and efficacy of compound A, nivolumab, docetaxel and ramucirumab in combination as second-line treatment in patients.
  • the clinical trial can evaluate the combined effect of compound A, nivolumab, docetaxel and ramucirumab.
  • Target patients Patients with stage IV or recurrent non-small cell lung cancer
  • Patient selection criteria At the time of enrollment, received combination therapy including anti-PD-1 antibody or anti-PD-L1 antibody as first-line treatment, and platinum preparations.
  • Prescribed patient selection criteria determined in consideration of the patient selection criteria in each of the trials conducted so far for patients with refractory progression or recurrence and for Compound A, Nivolumab, docetaxel and ramucirumab. Patients who meet all were selected. If it became clear that the study drug did not meet the criteria from registration to before the first administration, administration of the study drug was not started and the study was discontinued.
  • Patient exclusion criteria At the time of enrollment, patient exclusion criteria in each clinical trial for compound A, Nivolumab, docetaxel and ramucirumab, or patient selection in each proper use guide or proper use information for compound A, Nivolumab and docetaxel and ramucirumab. Patients who were considered to meet any of the prescribed patient exclusion criteria determined in consideration of the precautions were excluded. If it became clear that the study drug did not meet the criteria from registration to before the first administration, administration of the study drug was not started and the study was discontinued.
  • Compound A was orally administered at 20 mg or 40 mg once daily, and continued to be administered until the prescribed discontinuation criteria for compound A were met.
  • compound A, nivolumab, docetaxel and ramucirumab were administered on the same day, administration of compound A and nivolumab was first followed by administration of docetaxel and ramucirumab.
  • Nivolumab Nivolumab 360 mg was administered intravenously over about 30 minutes at 3-week intervals and continued until the prescribed discontinuation criteria for nivolumab were met. The administration of nivolumab was carried out at least 14 days after the previous administration and after the 15th day.
  • Docetaxel and ramucirumab The dosage of docetaxel and ramucirumab follows the procedure of the implementing medical institution, but the recommended dosage of docetaxel is 60 mg / m 2 (body surface area) intravenously over 60 minutes at 3-week intervals.
  • Ramucirumab was administered intravenously at 10 mg / kg over 60 minutes at 3-week intervals.
  • the 3-week interval means that the drug is administered between the 22nd and 29th days, with the previous administration day of docetaxel or ramucirumab as the 1st day.
  • Commercially available products were used for docetaxel and ramucirumab.
  • the treatment period was 21 days per cycle, and the date of administration of the first investigational drug was the first day of cycle 1.
  • the first day of each cycle after the second cycle is [21 ⁇ (number of cycles-1) + 1] days.
  • Administration of compound A, nivolumab, docetaxel and ramucirumab was started according to the above dosage and administration, respectively, and administration was continued according to the administration criteria, dose reduction criteria and dose at the time of dose reduction for compound A, nivolumab, docetaxel and ramucirumab.
  • the end of the treatment period was defined as the time when the evaluation at the end (discontinuation) of the administration of compound A, nivolumab, docetaxel and ramucirumab was completed.
  • the investigator or investigator measured the tumor diameter of the target lesion according to RECIST Guidelines 1.1, and determined the antitumor effect. Baseline evaluation was performed using the latest imaging tests within 28 days prior to study drug administration and confirmed to have one or more measurable lesions as defined in RECIST Guidelines Version 1.1. The diagnostic imaging during the treatment period was performed at 6-week intervals ( ⁇ 7 days) from the first day to 54 weeks after the first cycle, and at 12-week intervals ( ⁇ 7 days) thereafter, and the tumor diameter was measured.
  • the overall effect and the best overall effect were the results of diagnostic imaging evaluated based on RECIST Guidelines Version 1.1.
  • Evaluation item (1) Response rate (ORR), (2) Disease control rate (DCR), (3) Overall survival (OS), (4) Progression-free survival (PFS), (5) Duration of response (DOR), ( 6) Duration to response (TTR), (7) Best overall effect (BOR), (8) Rate of change in tumor diameter of target lesion, (9) Maximum rate of change in tumor diameter of target lesion, (9) 10) Changes in tumor markers
  • ORR Response rate
  • DCR Disease control rate
  • DCR Disease control rate
  • OS Overall survival
  • PFS Progression-free survival
  • DOR Duration of response
  • TTR Duration to response
  • BOR Best overall effect
  • Rate of change in tumor diameter of target lesion (9) Maximum rate of change in tumor diameter of target lesion, (9) 10) Changes in tumor markers
  • Response rate Response rate indicates the proportion of subjects whose best overall effect was determined to be CR or PR.
  • (2) Disease control rate The disease control rate indicates the proportion
  • Subjects who have not undergone evaluable diagnostic imaging and have not died will have the study drug administration start date as the discontinuation date.
  • Subjects who receive post-treatment for cancer before the overall effect is determined to be PD or die will have the date of the last evaluable diagnostic imaging prior to the start of post-treatment for cancer as the termination date. .. (5)
  • Response period The response period is calculated from the following formula.
  • Response period (day) "The day when the overall effect is judged to be PD for the first time after the response is confirmed or the earliest day of death due to any cause"-"The first judgment date of the confirmed CR or PR" + 1
  • the evaluation target is a subject who showed CR or PR confirmed through the clinical trial.
  • (6) Period until response The period until response is calculated from the following formula.
  • Duration to response (day) "First determination date of confirmed CR or PR"-"Start date of study drug administration" + 1 (7)
  • Rate of change in the sum of tumor diameters of the target lesion was calculated using the following formula for subjects having the target lesion. However, the rate of change in the sum of tumor diameters of the target lesion after post-treatment is not calculated.
  • the maximum rate of change in the sum of tumor diameters of the target lesion is the rate of change at the time when the sum of tumor diameters of the target lesion becomes the smallest.
  • the sum of tumor diameters of the target lesion after the overall effect is determined to be PD or after post-treatment is not used to calculate the maximum rate of change.
  • the present invention provides a new cancer treatment method and is useful.

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