WO2020175704A1 - 3,5-二置換ベンゼンアルキニル化合物と免疫チェックポイント阻害薬とを用いた癌治療法 - Google Patents
3,5-二置換ベンゼンアルキニル化合物と免疫チェックポイント阻害薬とを用いた癌治療法 Download PDFInfo
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- WO2020175704A1 WO2020175704A1 PCT/JP2020/008527 JP2020008527W WO2020175704A1 WO 2020175704 A1 WO2020175704 A1 WO 2020175704A1 JP 2020008527 W JP2020008527 W JP 2020008527W WO 2020175704 A1 WO2020175704 A1 WO 2020175704A1
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- nivolumab
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present disclosure relates to an antitumor agent, an antitumor effect enhancer, and a kit preparation.
- Fibroblast growth factor (FG F; fibroblast growth factor) is expressed in a wide range of tissues and is one of the growth factors that governs proliferation and differentiation of cells.
- the physiological activity of FG F is mediated by a specific cell surface receptor, the fibroblast growth factor receptor (FG FR).
- FGFR belongs to the receptor-type protein tyrosine kinase family and is composed of an extracellular ligand binding domain, a single transmembrane domain and an intracellular tyrosine kinase domain, and four types of FGFR have been identified so far. (FG FR 1, FG FR 2, FGFR 3 and FGFR 4).
- FGFR forms a dimer upon binding of FGF and is activated by phosphorylation.
- Receptor activation induces the recruitment and activation of specific downstream signaling molecules and exerts physiological functions.
- Abnormal FGF/FGFR signaling has been reported to be associated with various human tumors.
- Abnormal activation of FGF/FGFR signals in human tumors is caused by overexpression of FG FR and/or gene amplification, gene mutation, chromosomal translocation/insertion/inversion, gene fusion or FGF as a ligand.
- overproduction ⁇ 02020/175704 2 (: 17 2020/008527
- Non-Patent Documents 1, 2, 3 and 4 are non-Patent Documents 1, 2, 3 and 4.
- cancer immunotherapy is being developed as one of new cancer treatment methods.
- Nivolumab (human type 9084 monoclonal antibody against human oral cavity _ 1) is used as an immune checkpoint inhibitor that activates Ding cells by inhibiting the binding of Escherichia coli to the treatment of malignant melanoma (Patent Document 1, Non-Patent Document 6). Further, bembrolizumab is an immune checkpoint inhibitor having a different antibody type from nivolumab, and is used for the treatment of malignant melanoma, non-small cell lung cancer, etc. (Non-Patent Document 6).
- Examples of the use of immune checkpoint inhibitors and FGFR inhibitors include, for example, Pd-1 or P in the phase I clinical trial (NCTO 2365597) of erdafitinib (JNJ-42756493) for urothelial cancer.
- Studies of FGFR inhibitors in subjects with DL 1 pretreatment have been reported.
- a combined use trial of anti-FGFR3 antibody V ⁇ fatamab and pembrolizumab is in progress (NCT 03 1 23055).
- Non-Patent Document 1 2 As continuous administration, there are reports of combined use of pazopanib, which is a multikinase inhibitor with FGFR inhibitory effect, and everolimus, combined use of V ⁇ datamab and docetaxel, and continuous administration of atezolizumab (Non-Patent Document 1 2 ).
- Patent Document 1 International Publication 2004/00477 No. 1
- Patent Document 2 International Publication 201 3/1 08809
- Patent Document 3 International Publication 201 7/1 50725
- Patent Document 4 International Publication 201 6/1 6 1 239
- Non-Patent Document 1 N a t .R e v. C a n c e r 1 0 :1 1 6— 1 29 (20
- Non-Patent Document 3 Mo l .C a n c e r R e s. 3, 655— 667
- Non-Patent Document 4 C a n c e r R e s. 70, 2085 -2094 (20
- Non-Patent Document 5 N a t .R e v. C a n c e r, 1 2 :252-264 (20 1 2)
- Non-Patent Document 6 N. E n g l .J .Me d., 366: 2443-2454 (201 2)
- Non-Patent Document 7 T h e B r e a s t .37, 1 26-1 33 (201 8)
- Non-Patent Document 8 ⁇ n c o t a r g e t .8: 1 6052 — 1 6074 (20
- Non-Patent Document 9 Cel I .1 68: 707 -723 (201 7)
- Non-Patent Document 10 N. E n g l .J .Me d., 375: 81 9-829 (2 01 6)
- Non-Patent Document 11 S c i .T r a n s I .Me d. 9, e a a I 3604 (2 01 7)
- Non-Patent Document 12 J C ⁇ P r e c i s i o n ⁇ n e o l o g y (D ⁇ l:
- Non-Patent Document 13 Ce l I u I a r P h y s i o l o g y a n d B i o c h e m i s t r y, 33, p .633— 645 (201 4)
- Non-Patent Document 14 f r o n t i r s i n I mm u n o l o g y, 9, 20 1 8, A r t i c l e 1 3 1 0.d o i :1 0. 3389/f i mm u. 2 01 8. 01 3 1 0
- the present disclosure provides (S) — 1 — (3 — (4-amino-3_ ((3, 5-dimethoxyphenenyl) ethynyl) _ 1 H-pyrazolo [3, 4-d] pyrimidine-1 _. ⁇ 2020/175704 5 ⁇ (:171? 2020 /008527
- a compound having an inhibitory activity is (3)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl). ) 1 1 to 1—pyrazolo [3, 4—] pyrimidin-1-yl) pyrrolidin-1-yl) proper-2-en-1-one (hereinafter also referred to as “compound 1”) or a salt thereof is used as an immune checkpoint. It was found that the above problem can be solved by using it together with an inhibitor.
- the present disclosure provides the following items 1 to 77.
- Item 1 (3)-1-(3- (4-amino-3-((3,5-dimethoxyphenyl)ethynyl)) Pyrazolo [3, 4_] Pyrimidin-1-yl) Pyrrolidin-1-yl) Proper-2-en-1-one or salts thereof as an active ingredient
- Antitumor agent that is co-administered with point inhibitors (excluding bembrolizumab).
- the immune checkpoint inhibitor is at least one member selected from the group consisting of 0_1 pathway antagonists, I ⁇ 003 pathway agonists, ⁇ chome !_ _4 pathway antagonists and ⁇ ⁇ 28 pathway agonists.
- the antitumor agent according to 1.
- Item 3 The antitumor agent according to item 1 or 2, wherein the immune checkpoint inhibitor is an oral 1 pathway antagonist.
- Item 4 Oral 1 pathway antagonist Antibodies, anti 0-!_ 1 antibodies and anti Item 2.
- Item 5 Oral 1 pathway antagonist The antitumor agent according to any one of items 2 to 4, which is an antibody. ⁇ 2020/175704 6 ⁇ (: 171-1? 2020/008527
- the anti-0 _ 1 antibody is nivolumab, semi-primab, spartalizumab, taethrelizumab, 6 1 75409 1, dostalizumab, sasanlimab, IV! Item 6.
- Item 7. Item 5. The antitumor agent according to any one of items 2 to 4, wherein the antagonist is an anti-0-!_1 antibody.
- Item 8 The antitumor agent according to item 7, wherein the anti- ⁇ _!_ 1 antibody is atezolizumab, durvalumab or avelumab.
- Item 9. The item that the 0_!_81_4 pathway antagonist is an anti_0!_81_4 antibody.
- the antitumor agent according to 2.
- Item 1 Item in which the anti-Cha!_8_14 antibody is ipilimumab or tremelimumab
- the antitumor agent according to 9.
- Item 1 The antitumor agent according to any one of Items 1 to 10, wherein the tumor has an abnormality in the ⁇ pathway.
- Item 11 The antitumor agent according to Item 11, which is at least one selected from the group consisting of gene abnormalities and abnormal signal states.
- Item 13 The antitumor agent according to any one of Items 1 to 12, wherein the treatment with the antitumor agent brings about a sustained response in an individual after the treatment is stopped.
- Item 1 4. (3)-1-(3-(4-amino- 3- ((3, 5-dimethoxyphenyl) ethynyl)) 1 1 ⁇ 1—pyrazolo [3, 4—] pyrimidine-1 — Ill) Pyrrolidin-1-yl) proper-2-en-1-one or its salt used before the immune checkpoint inhibitor, used together with the immune checkpoint inhibitor, or used after the immune checkpoint inhibitor The antitumor agent according to any one of Items 1 to 13.
- An antitumor agent according to any one of Items 1 to 14, wherein pyrrolidin-1-yl) proper-2-en-1-one or a salt thereof is used continuously or intermittently.
- Item 1 (3)-1-(3-(4-amino- 3- ((3, 5-dimethoxyphenyl) ethynyl)) 1 1 ⁇ 1—pyrazolo [3, 4—] pyrimidine-1 — Ill) Pyrrolidin-1-yl) Proper-2-en-1-one or a salt thereof and an immune checkpoint inhibitor are administered in the treatment in the same therapeutic regimen, according to any one of paragraphs 1 to 15 Antitumor agent.
- Item 1 Targeting tumors resistant to immune checkpoint inhibitors
- Item 1 The antitumor agent according to any one of items 1 to 6 and 11 to 16.
- Item 17 The antitumor agent according to Item 17.
- Item 1 Targeting tumors resistant to immune checkpoint inhibitors
- Item 2 Immune checkpoint inhibitors (excluding bembrolizumab) and (
- Item 22 The pharmaceutical composition according to Item 21 for treating cancer having resistance to an immune checkpoint inhibitor.
- Item 23 Immune checkpoint inhibitors (excluding bembrolizumab) and (3)-1-(3 for producing antitumor agents for treating cancers resistant to immune checkpoint inhibitors -(4-amino-3-((3, 5- ⁇ 2020/175704 9 ⁇ (: 171-1? 2020/008527
- Item 24 (3) — 1 — (for the production of an antitumor agent to be co-administered with an immune checkpoint inhibitor (excluding vemubrolizumab) to patients with resistance to an immune checkpoint inhibitor 3— (4—Amino 3— ((3, 5—Dimethoxyphenyl)ethynyl) 1 1 1 to 1—Pyrazolo [3, 4—] Pyrimidin 1-yl) Pyrrolidin 1-yl) Proper 2 -En-! -Use of on or its salt.
- an immune checkpoint inhibitor excluding vemubrolizumab
- Item 25 In patients with resistance to immune checkpoint inhibitors, (3)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)) 11 1! —Pyrazolo [3,4—]pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or an immune checkpoint inhibitor (vembrolizuma) for the manufacture of an antitumor agent to be co-administered with (Excluding bu).
- Item 26 Immune checkpoint inhibitors (excluding bembrolizumab) and (3)-1-(3-(4-amino-3 for use in the treatment of cancers resistant to immune checkpoint inhibitors. -((3,5-Dimethoxyphenyl)ethynyl) 1 11 to 1—pyrazolo [3,4—]pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or a combination thereof.
- Item 27 (3)-1-(3-(for the use of combination therapy with immune checkpoint inhibitors (excluding vembolizumab) in the treatment of cancer resistant to immune checkpoint inhibitors) 4-Amino-3-((3,5-dimethoxyphenyl)ethynyl) 1 1 ⁇ 1—pyrazolo [3,4—]pyrimidin — 1 —yl) pyrrolidin 1 —yl) proper 2 —en 1 —one or Its salt.
- Item 29 Immune checkpoint inhibitors for treating cancers resistant to immune checkpoint inhibitors (excluding bembrolizumab) and (3)-1-(3-(4-amino-3_ ((3, Use of 5-dimethoxyphenyl)ethynyl) 1 1 to 1-pyrazolo [3,4d pyrimidin-1-yl)pyrrolidin_1-yl)prop-2-en-1-one or salts thereof.
- Item 30 (3) — 1 — (3-(4-amino-) for treating cancers resistant to immune checkpoint inhibitors by combination therapy with immune checkpoint inhibitors (excluding bembrolizumab) 3— ((3,5-dimethoxyphenyl)ethynyl) Use of pyrazolo [3, 4_] pyrimidin-1-yl) pyrrolidin-1-yl) proper-2-en-1-one or a salt thereof.
- Item 3 Cancers resistant to immune checkpoint inhibitors (3) —
- Item 32 A method for treating cancer resistant to immune checkpoint inhibitors, comprising a therapeutically effective amount of (3)-1-(3-(4-amino-3- ((3, 5 Toxylphenyl) Ethynyl) 1 1 to 1—pyrazolo [3, 4—] pyrimidin-1-yl) pyrrolidin-1-yl) proper-2-en-!-one or its salt and a therapeutically effective amount of immune checkpoint inhibition And administering the drug (excluding bembrolizumab) to a human in need thereof.
- Item 34 Immune checkpoint inhibitors (excluding bembrolizumab) and (
- Item 35 The pharmaceutical composition according to Item 34, for treating a cancer having resistance to an immune checkpoint inhibitor.
- Item 36 Immune checkpoint inhibitors (excluding bembrolizumab) and () for producing antitumor agents for treating cancer in cancer patients who have not been administered with immune checkpoint inhibitors. 3)-1-(3-(4 — amino 3 — ((3, 5 — dimethoxyphenyl) ethynyl) 1 1 ⁇ 1 — pyrazolo [3, 4 -] pyrimidin-1-yl) pyrrolidin-1-yl) proper Use of 2-en-1-one or a salt thereof.
- Item 37 (3) for producing an antitumor agent which is co-administered with an immune checkpoint inhibitor (excluding bembrolizumab) to a cancer patient who has not been administered with the immune checkpoint inhibitor.
- an immune checkpoint inhibitor excluding bembrolizumab
- 1 (3— (4— amino 3 — (( 3, 5 — dimethoxyphenyl) ethynyl) 1 1 1 to 1 — pyrazolo [3, 4—] pyrimidin-1-yl) pyrrolidin-1-yl) proper 2-en- 1-Use of salt or its salt.
- Item 38 (3)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)) 1 for cancer patients who have not been treated with immune checkpoint inhibitors.
- immune checkpoint inhibitors excluding bembrolizumab
- Item 39 Immune checkpoint inhibitors (excluding bembrolizumab) and (3)-1-(3 for use in the treatment of cancer in cancer patients who have not been administered with immune checkpoint inhibitors. -(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1 !—pyrazolo [3,4—]pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or its Combination with salt.
- Item 40 For use as a combination therapy with an immune checkpoint inhibitor (excluding bembrolizumab) in the treatment of cancer in a cancer patient who has never been administered with the immune checkpoint inhibitor (3)-1 -(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)) 1 1 ⁇ 1-pyrazolo [3, 4—] pyrimidin-1-yl) pyrrolidin-1-yl) proper-2-ene-1 -On or its salt.
- an immune checkpoint inhibitor excluding bembrolizumab
- Item 4 In the treatment of cancer in cancer patients who have not been administered with immune checkpoint inhibitors (3) — 1 — (3— ((3, 5 — Dimethoxyphenyl) ethynyl) 1 1 ⁇ 1 — Pyrazolo [3, 4—] Pyrimidin — 1 — yl) Pyrrolidin 1 — yl) Proper 2-en-1 — one or its salt Immune checkpoint inhibitors for use with therapy (except bembrolizumab).
- Immune checkpoint inhibitors (excluding bembrolizumab) for treating cancer in cancer patients who have not been administered with immune checkpoint inhibitors (3)-1-(3-( 4-amino-3-((3,5-dimethoxyphenyl)ethynyl) Use of pyrazolo [3, 4_] pyrimidin-1-yl) pyrrolidin-1-yl) proper-2-en-1-one or a salt thereof.
- Item 43 To treat cancer in a cancer patient who has never been administered with an immune checkpoint inhibitor by a combination therapy with an immune checkpoint inhibitor (excluding bembrolizumab) (3)-1- (3-(4-amino-3-((3, 5 ⁇ 2020/175704 13 ⁇ (: 171-1? 2020/008527
- Item 44 Cancer in cancer patients who have not been administered with immune checkpoint inhibitors (3) — 1 — (3— ((3, 5 - dimethyl Tokishife sulfonyl) ethynyl) Single 1 1 - 1 - pyrazolo [3, 4] pyrimidin-1 - yl) Pirorijin 1 - yl) proper 2 - En 1 - one or combination therapy with a salt thereof Use of immune checkpoint inhibitors (excluding bembrolizumab) for treatment by.
- immune checkpoint inhibitors excluding bembrolizumab
- Item 45 A method for treating cancer in a cancer patient who has never been administered with an immune checkpoint inhibitor, comprising a therapeutically effective amount of (3)-1-(3-(4-amino acid 3 — ((3,5-Dimethoxyphenyl)ethynyl)-1 !!—Pyrazolo [3,pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or its salt and a therapeutically effective amount of immunity check Administering a point inhibitor (excluding bembrolizumab) to a human in need thereof.
- a point inhibitor excluding bembrolizumab
- Item 46 The composition according to any one of Items 21 to 45, wherein the tumor has an abnormality in the ⁇ pathway, use, combination, (3)-1-(3-(4-amido) No 3—((3,5-dimethoxyphenyl)ethynyl) 1 1!!—Pyrazolo [3,pyrimidin 1-yl)pyrrolidin 1-yl)proper 2-en-1-one or salt thereof, immune checkpoint inhibitor , Or method.
- composition, use and combination according to Item 46 which is at least one selected from the group consisting of gene abnormalities and signal abnormal states, (3)-1-(3-(4-amino-3 — ((3,5-Dimethoxyphenyl)ethynyl) 1 1!!-Pyrazolo [3, Pyrimidin-1-yl) Pyrrolidin-1-yl) Proper-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.
- Item 48 (3)-1-(3-(4-amino- 3- ((3, 5-dimethoxyphenyl) ethynyl)) 1 1 ⁇ 1—pyrazolo [3, 4—] pyrimidine-1 — y Le) Pyrrolidin-1-yl) Proper-2-en-1-one or a salt thereof as an active ingredient, resistant to immune checkpoint inhibitors, and immune checkpoints against cancer patients who do not have abnormalities in the pathway Antitumor agent that is co-administered with inhibitors (excluding pembrolizumab).
- Item 49 Immune checkpoint inhibitors (excluding bembrolizumab) and (
- Item 50 The pharmaceutical composition according to Item 49, for treating cancer having resistance to an immune checkpoint inhibitor.
- Item 5 1. ⁇ Immune checkpoint inhibitors (excluding bembrolizumab) and (3)-1-(3) for producing antitumor agents for treating cancers without abnormal pathways -(4-amino-3-((3,5-dimethyoxyphenyl)ethynyl)-l 1 1 to 1-pyrazolo [3,4—]pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or Use of that salt.
- Item 52 ⁇ (3) — 1 — for the manufacture of an antitumor agent that is co-administered with an immune checkpoint inhibitor (excluding bembrolizumab) in cancer patients who do not have abnormality in the pathway.
- an immune checkpoint inhibitor excluding bembrolizumab
- an immune checkpoint inhibitor excluding bembrolizumab
- immune checkpoint inhibitors excluding peggar brolizumab
- Item 54 ⁇ Immune checkpoint inhibitors (except for bembrolizumab) and (3)-1-(3-(4—amino-3_ ((3 , 5-Dimethoxyphenyl)ethynyl) 1 1 to 1-pyrazolo [3,4-]pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or a salt thereof.
- Item 55 (3)-1-(3-(4-amino) for use in combination therapy with immune checkpoint inhibitors (excluding bembrolizumab) in the treatment of cancers that do not have abnormal pathways. 3- ((3,5-Dimethoxyphenyl)ethynyl) 1 1!!—Pyrazolo [3,4—]pyrimidin-1-yl) Pyrrolidin-1-yl) Proper-2-en-1-one or a salt thereof.
- Item 57 ⁇ Immune checkpoint inhibitors (excluding bembrolizumab) for treating cancers that do not have abnormal pathways and (3)-1-(3-(4-Amino 3— ((3, 5 —Dimethoxyphenyl)ethynyl) 1 1!!—Pyrazol mouth [3,4d pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or use of its salt.
- Item 58 (3)-1-(3-(4—amino-3— (to treat cancers that do not have abnormalities in the pathway by a combination therapy with an immune checkpoint inhibitor (excluding bembrolizumab)) Use of (3,5-dimethoxyphenyl)ethynyl)pyrazolo [3,4d pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof.
- Item 60 A method for treating cancer that does not have abnormalities in the pathway, which comprises a therapeutically effective amount of (3) — 1 — (3— (4-amino-3 — ((3, 5-dimethoxyphenyl). ) Ethinyl) Pyrazolo[3,4_]pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or a salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor (excluding bembrolizumab) are required. Administering to a human being.
- Item 6 An immune checkpoint inhibitor is an oral-1 pathway antagonist
- Item I A composition according to any one of Items 18 to 29, which is at least one member selected from the group consisting of 03 route agonists, 0! !- 81 number 4 channel antagonists, and 28 route agonists. , Combination, (3)-1-(3-(4—Amino 3 — ((3, 5 -Dimethoxyphenyl)ethynyl) 1 1 !!—Pyrazolo [3,4 d Pyrimidin 1 —yl) Pyrrolidin 1 — Il) proper 2-en-1-one or salt thereof, immune checkpoint inhibitor, or method ⁇
- Item 62 The composition according to any one of items 21 to 61, wherein the immune checkpoint inhibitor is an oral _ 1 pathway antagonist, use, combination, (3) — 1-(3- (4-amino-3_ ((3,5-dimethoxyphenyl)ethynyl)pyrazolo [3,4d pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en-1-one or a salt thereof, immunocheckpoint inhibitor, Or method.
- the immune checkpoint inhibitor is an oral _ 1 pathway antagonist
- Item 63 The Oral 1 Pathway Antagonist Antibodies, anti 0-!_ 1 antibodies and anti The composition according to Item 61 or 62, which is at least one kind selected from the group consisting of !_ 2 antibodies, the use, the combination, (3)-1-(3-(4 — amino 3-((3, 5—Dimethoxyphenyl)ethynyl) 1 1!!—Pyrazolo ⁇ 02020/175704 17 ⁇ (: 17 2020 /008527
- Item 64 The antagonist Item that is an antibody 61 ⁇
- composition according to any one of 63 uses, combinations, (3)-1-(3-(4-amino-3_((3,5-dimethoxyphenyl)ethynyl)-1 1 1 to 1_ pyrazolo [3, 4_] Pyrimidin-1-yl) Pyrrolidin-1-yl) Proper-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.
- Anti-oral _ 1 antibody is nivolumab, semi-primab, spartalizumab, taethrelizumab, 6 1 75409 1, dostalizumab, sasanlimab, 1 ⁇ /1 ⁇ 811 012, cetrelimab, 880 ⁇ 1 ⁇ 1— 2034, Jim berequimab, strength murelizumab, budigarimab or barstelimimab, preferably nivolumab, composition, use, combination, (3)-1-(3-(4-amino-3 — ((3,5-Dimethoxyphenyl)ethynyl) 1 1!!-Pyrazolo [3, Pyrimidin-1-yl) Pyrrolidin-1-yl) Proper-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.
- Item 66 The composition according to any one of Items 61 to 63, wherein the oral-1 pathway antagonist is an anti-0-!_1 antibody, the use, the combination, (3)-1-(3 -(4-amino-3_ ((3,5-dimethoxyphenyl)ethynyl) _ 1 1 ⁇ 1_ pyrazolo [3, 4_] pyrimidin-1-yl) pyrrolidin-1-yl) proper-2-ene-1-one or its salt , Immune checkpoint inhibitors, or methods.
- Item 67 Anti-zero 1
- Item 68 The composition, use, combination, (3)-1-(3- (4-amino-3--((3,5-dimethoxyphenyl)ethynyl)-1 1 ⁇ 1-pyrazolo [3,4 d pyrimidin-1-yl)pyrrolidin-1-yl)proper-2-en _ 1-one or its Salt, immune checkpoint inhibitor, or method.
- Item 69 The item in which the anti-Cha!_8_41 antibody is ipilimumab or tremelimumab
- Item 70 (3)-1-(3- (4-amino- 3- ((3, 5-dimethoxyphenyl) ethynyl)) 1 1 ⁇ 1—pyrazolo [3, 4—] pyrimidine-1 — Ill) Pyrrolidin-1-yl) Proper-2-en-1-one or its salt and treatment with an immune checkpoint inhibitor produces a persistent response in the individual after discontinuation of treatment, any of paragraphs 21-69 1 (3)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)) 1 1 1 to 1-pyrazolo [3, 4 —] Pyrimidin-1-yl) Pyrrolidin-1-yl) Proper-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.
- Item 7 (3)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)) 1 1 ⁇ 1—pyrazolo [3, 4—] pyrimidine-1 — Ill) Pyrrolidin-1-yl) Proper-2-en-1-one or its salt is used before the immune checkpoint inhibitor, simultaneously with the immune checkpoint inhibitor, or after the immune checkpoint inhibitor.
- Item 72 (3)-1-(3- (4-amino- 3- ((3, 5-dimethoxyphenyl) ethynyl)) 1 1 ⁇ 1—pyrazolo [3, 4—] pyrimidine-1 — y Le) Pyrrolidin-1-yl) Proper-2-en-1-one or a salt thereof is used continuously or intermittently, The composition or the use according to any one of Items 21 to 71 , Combination, (3)-1-(3-(4—Amino 3_ ((3, 5 — Dimethoxyphenyl) ethynyl) 1 1 1 ⁇ 1—Pyrazolo [3, 4—] Pyrimidin-1-yl) Pyrrolidine-1 —Il) proper-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.
- composition use, combination, (3) — 1-(3-(4-amino-3-((3, 5-dimethoxyphenyl) ethynyl) pyrazolo [3, 4 d pyrimidin-1-yl) pyrrolidin-1-yl) Proper 2-en-1-one or its salt, immune checkpoint inhibitor or method.
- Volumab is used according to the following method, wherein the composition according to any one of items 21 to 65 and 70 to 73, use, combination, (3)-1-(3-(4 -amino
- FIG. 1 Results of Example 1 (Bone marrow-derived immunosuppressive cells (Effect of Compound 1 on).
- the present disclosure provides: A combination of a compound having an inhibitory activity and an immune checkpoint inhibitor (excluding bembrolizumab), that is, Antitumor agents that are used in combination with immune checkpoint inhibitors (excluding bembrolizumab), including compounds that have inhibitory activity, ⁇ Antitumor effect enhancers that include compounds that have inhibitory activity, and ⁇ compounds that have inhibitory activity Providing the use of compounds with inhibitory activity, etc.
- an excellent antitumor effect is brought about by the combined use with an immune checkpoint inhibitor (3) — 1 — (3— (4-amino-3 — ((3, 5-dimethoxyphenyl) ethynyl) ) 1 1 !!—Pyrazolo [3, 4—] pyrimidin-1-yl) pyrrolidin-1-yl) proper-2-en-1-one is a disubstituted benzenealkynyl compound having the structure shown below.
- Compound 1 is described as Example Compound 2 in Patent Document 2 above.
- Compound 1 or a salt thereof has an excellent ⁇ inhibitory action, ⁇ [4] It has been reported to inhibit the phosphorylation ability of thyroidin to tyrosin in the substrate peptide sequence of its respective receptor protein tyrosine kinase (Patent Document 2).
- the above Compound 1 or a pharmaceutically acceptable salt thereof in the present disclosure is not particularly limited, but can be synthesized based on the production method described in Patent Document 2, for example.
- Compound 1 can be used as it is or in the form of a pharmaceutically acceptable salt.
- the pharmaceutically acceptable salt of Compound 1 is not particularly limited, and examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid, addition salts with organic acids such as acetic acid, citric acid, tartaric acid and maleic acid, potassium, Examples thereof include salts with alkali metals such as sodium, salts with alkaline earth metals such as calcium and magnesium, ammonium salts, salts with organic bases such as ethylamine salts and arginine salts.
- the immune checkpoint inhibitor according to the present disclosure has an action of acting on an immune checkpoint molecule, inducing an antitumor immune response in a living body of a subject, and controlling an immune escape of a tumor.
- Examples of such substances include a substance that promotes the function of a costimu atory molecule (stimulatory co-stimulatory molecule) or a function of a c ⁇ inhibit ⁇ ry molecule (inhibitory co-stimulatory molecule).
- Examples include substances that suppress.
- Examples of immune checkpoint molecules include B 7 f am ily (B 7-1, B ⁇ 2020/175704 24 ⁇ (: 171? 2020 /008527
- 0X40 a substance that targets the immune checkpoint molecule
- a substance that targets the immune checkpoint molecule can be used. Examples include 0-1 route antagonists, ⁇ ⁇ ⁇ 3 pathway agonists, ⁇ ⁇ !_ 81 route 4 antagonists, ⁇ 028 route agonists, Ming _ 8 route antagonists, 4-1 ⁇ route agonists, etc.
- 1-pathway antagonist preferably 1-pathway antagonist, ⁇ ⁇ 3-pathway agonist, ⁇ -Cho !_ 81 4 pathway antagonists and ⁇ ⁇ 28-pathway agonist, at least one or more selected, more preferably oral _ 1-path antagonist and ⁇ -Cho !_. It is at least one or more kinds selected from the Eighteenth Pathway Antagonist, and more preferably the Oral One Pathway Antagonist.
- 1 pathway antagonist is expressed on Ding cells 1 or its ligand, P DL ⁇ , or an inhibitor of the immunosuppressive signal by mouth! antibody,
- Anti-antibody 1 antibody preferably anti-
- Antibodies more preferably anti-_1 antibody
- the anti-orientation antibody is particularly preferable.
- _4!_8 pathway antagonist is expressed on _0 cells.
- These antibodies include immunoglobulins ( ⁇ 98, I 90 , I 9 and I 90 ,
- it is a humanized 9° monoclonal antibody or a human 9° monoclonal antibody.
- a preferred antibody-1 antibody is nivolumab (1 ⁇ !
- a preferred anti-! !1 antibody in the present disclosure is atezolizumab (8).
- the preferred anti-C! !8 antibody in the present disclosure is Ibilimumab (I
- Preferable _!__8_4__9 in the present disclosure includes abatacept and the like.
- agonists or antagonists can be produced by a generally known production method.
- anti-orbital 1 antibody was used as nivolumab
- Antibodies have already been sold as atezolizumab, durvalumab or avelumab, anti-Cho!_8i4 antibodies, Ibilimumab or tremelimumab, Octi__81-_9 and Avatasept, and are also planned for sale. Yes, it can also be used.
- the immune checkpoint inhibitor may be used singly or in combination of two or more kinds.
- immune checkpoint inhibitors when two or more immune checkpoint inhibitors are used, it is possible to use a combination of immune checkpoint inhibitors such as, for example, an anti-original antibody and anti-O TLA 4 antibody.
- bispecific antibodies that can bind to different immune checkpoint molecules can be used.
- a bispecific antibody One that can be combined with both 1 and (3!_8_4) is, for example, ⁇ 018 ⁇ 207 1 7 (? 0-1 0 _ 1_81 1 4).
- the treatment in the present disclosure includes treatment for the purpose of curing or ameliorating a disease, or for the purpose of suppressing the progression or relapse of a disease or alleviating the symptoms.
- Treatment includes administration of the agent before or after the surgical procedure, or administration of the agent during or before or after the radiation treatment.
- Antibodies and Compound 1 or salts thereof that block the interaction between a therapeutically effective amount of an immune checkpoint molecule may be associated with, without limitation, the stage and severity of the cancer, as well as the health of the patient. Depends on several factors, including some others. One of ordinary skill in the art would know how to determine a therapeutically effective amount.
- the present disclosure is used, in one embodiment, for tumors having abnormalities in the FGFR pathway.
- the FG FR is selected from the group consisting of FG FR 1, FG FR 2, FGFR 3 and FGFR 4.
- tumors having an abnormality in the FGFR pathway are preferable.
- Abnormalities in the FGFR pathway include overexpression of FGFR, abnormalities of the FGFR gene, and abnormal states of the FGFR signal.
- the present disclosure is, in one aspect, administered to a subject having or not having an abnormality in FGF/FGFR, but preferably having an abnormality in the FGFR pathway.
- Compound 1 can promote the antitumor effect of immune checkpoint inhibitors even in carcinomas without FGFR gene abnormality. It is known that the sensitivity of cancer to immune checkpoint inhibitors is also affected by the cancer microenvironment.
- the microenvironment includes, but is not limited to, cancer associated fibro b I ast (CAF) and other groups of cells that are regulated by FG F/FG FR pathway activation, and these groups of cells are sensitive to cancer immune checkpoint inhibitors. It is known to diminish. It is considered that administration of Compound 1 promotes the effects of cancer immune checkpoint inhibitors by causing changes in the microenvironment including inactivation of CAF.
- CAF cancer associated fibro b I ast
- Overexpression of FG FR includes, for example, gene expression and high expression of gene product protein.
- the presence or absence of FG FR expression can be detected by methods known to those skilled in the art. Detection of gene expression and high expression of gene product protein can be performed by known methods, for example, methods using antibodies (immunohistological staining, enzyme immunoassay (EL ⁇ SA), flow cytometry, immunoblotting, etc.). , Nuclear acid-based methods (in situ hybridization, PCR, Northern blotting, etc.) and methods based on common principles.
- the detection device may be a known device (Genechip, microarray, etc.). ⁇ 2020/175 704 28 ⁇ (:171? 2020 /008527
- the present disclosure in one embodiment, is used for a tumor having an abnormality in the gene.
- Gene abnormalities in the pathway include gene amplification, gene mutation, chromosomal translocation/insertion/inversion, gene fusion, and gene rearrangement. Some abnormalities in genes in tumors have already been reported in literature available to those skilled in the art (Non-patent Documents 7 and 8). Gene abnormalities can be determined by methods known to those of skill in the art, such as pyrosequencing, oral sequencing including 03 (next generation sequencing), 0-based methods involving allele-specific 0 chain reactions, and microarray-based comparative assays.
- the present disclosure is used, in one embodiment, for a tumor in which a ⁇ signal is activated.
- ⁇ By binding to form a dimer which is activated by phosphorylation, which induces the recruitment and activation of specific downstream signaling molecules, and exerts physiological functions.
- Activation of the signal can be detected by a method known to those skilled in the art.
- Signal activation can be detected, for example, by detecting ⁇ , which is a substrate for ⁇ , biological activity including the direct phosphorylation state or enzymatic activity of ⁇ , which is a phosphorylating enzyme, and ⁇ intracellular substrate located downstream of the signal cascade. And the phosphorylation state of intracellular proteins, the detection of biological activities including enzymatic activities, or the detection of gene products or gene transcripts.
- Tumors that do not have abnormal pathways are also included.
- a preferable daily dose of Compound 1 or a salt thereof is, for example, 4019 ⁇ 24019, 1
- the preferable number of administrations per day on the administration day, and the dose include once a day, 4019, 8019, 12019, 161119, 20 etc. another ⁇ 2020/175 704 29 ⁇ (:171? 2020 /008527
- the preferable number of administrations per day on the administration day and the dose include 8019, 12019, 16019, 20 and the like. In another embodiment, the preferable number of administrations per day on the administration day and the dose are 12, 1600, 19 and 201119.
- the stronger cancers desired effective (e.g. brain tumors) dose dose of Compound 1 or a salt thereof is greater than 1 times a day 2 0 9 When the Including that.
- the daily dose of Compound 1 or a salt thereof is intermittently administered, the dose is, for example, about 1 day of Compound 1 or a pharmaceutically acceptable salt thereof.
- the administration schedule of Compound 1 or a salt thereof includes daily administration and intermittent administration.
- “daily administration” includes, for example, an administration schedule in which a continuous administration schedule for 21 days is defined as one cycle, and a drug holiday may be provided at the end of each cycle. Good.
- intermittent administration is not particularly limited as long as it satisfies the condition that it is twice or more per week and the administration interval (the number of days between one administration day and the next administration day) is one or more days apart. ..
- the administration schedule is one cycle per week, and Compound 1 or a pharmaceutically acceptable salt thereof is administered every 1 to 3 days per cycle (the interval between one administration day and the next administration day is 1 to 3 days), and the administration cycle is repeated twice or more, and the cycle is repeated once or twice or more;
- Administration schedule 4 to 7 times every 3 days), and the cycle is repeated once or twice or more;
- the administration schedule is 1 cycle for 4 days, and during 1 4 days included in 1 cycle, Compound 1 or its salt is treated on the 1st, 4th, 8th and 11th days. Administration schedule on day;
- the administration schedule is 1 cycle for 4 days, and among 1 4 days included in 1 cycle, Compound 1 or its salt is treated on the 1st, 3rd, 5th, 7th day. Dosing schedule, administered on eyes, day 9, day 11 and day 13;
- the administration schedule is 1 cycle for 4 days, and within 1 4 days included in 1 cycle, Compound 1 or its salt is treated on the 1st, 3rd, 5th, 8th day.
- the administration schedule and the like are administered on the 1st day, the 10th day and the 12th day.
- the administration schedule is to administer 1609 once a day on the 1st, 3rd, 5th, 8th, 10th and 12th days.
- the amount of compound 1 or a salt thereof can be reduced to 1 200!, 8019, 5619, 3619, 2419, 169, 8019.
- the daily dose of the immune checkpoint inhibitor on the day of administration is, from the viewpoint of enhancing the antitumor effect of the immune checkpoint inhibitor with Compound 1 or a salt thereof, 30 to 100% of the recommended dose when the checkpoint inhibitor is administered alone is preferred, more preferably 50 to 100%, more preferably 70 to 100%, more preferably Is 80 to 100%, more preferably 90 to 100%, and further preferably 100%.
- a preferred dose of an immune checkpoint inhibitor administered alone depends on the type of drug, but is, for example, 1 to 4 9 /1 ⁇ 9 (body weight) once,
- the preferred dose of nivolumab alone is 1 to 30,000 19/1 ⁇ 9 (body weight) or 80 to 240019 once, or 2 to 30 19/1 ⁇ once.
- the preferred dose of nivolumab administered alone is 80 to 480 ⁇ !, 80 000 19, 1 2401 119, 1 dose, or 1 dose. Etc.
- the preferred dose of semi-primab administered alone is 359, etc. once.
- the preferred dose of atezolizumab administered alone is 84 ⁇ to 1 680 ⁇ 19 , once 840, 1200, Etc.
- the preferred dose of ibilimumab administered alone is 1.0 to 1 0019 / 1 ⁇ 9 (body weight) once, 10 or 3.0 once, or 1 0019 / 1 ⁇ 9 (body Heavy) etc.
- Preferable doses of durabalumab administered alone include 5.0 to 1 0019/1 ⁇ 9 (body weight) once, 10019/1 ⁇ 9 (body weight) once, and the like. Preferred dosages when administered to Aberumabu alone, 1 0 9 / (body weight) once, 80_Rei 9, etc. once.
- Preferred dosages per day in administration day of nivolumab in this disclosure once 40 480_Rei_1 9, once 80, 240, or 480_Rei_1 9, and the like.
- the administration interval of nivolumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and further preferably 2 weeks.
- the dose and interval of administration of nivolumab are: nivolumab Dosage once, and from the 5th dose, administer nivolumab 2400! 9 at 2-week intervals.
- the administration interval of semiprimab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and further preferably 2 weeks.
- the preferred daily dose of atezolizumab in the present disclosure is as follows:
- the administration interval of atezolizumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and further preferably 3 weeks.
- the preferred daily dose of ipilimumab in the present disclosure is one dose per day. (Weight) once! . 0, 3.0, or 1 ⁇ 9/1 ⁇ 9 (body weight), and the like.
- the administration interval of ibilimumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and further preferably 3 weeks.
- the preferred daily dose of duravalumab in the present disclosure is once 5. (Weight), once 1 001 9/9 (Weight
- the administration interval of duravalumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and further preferably 2 weeks.
- the preferred daily dose of avelumab in the present disclosure is one dose of 5.0 to 10 9 /1 ⁇ 9 (body weight), (Weight) and the like. In another embodiment, the preferred daily dose of avelumab is 400-800 per dose. Once 800 And so on.
- the administration interval of avelumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and further preferably 2 weeks.
- the daily dose of Compound 1 or a salt thereof in the present disclosure on the day of administration, and the daily dose of nivolumab, or a preferable combination of the usage and the dose includes the following:
- nivolumab Administered 4 doses every 3 weeks and then administered nivolumab from the 5th dose. And nivolumab
- Compound 1 or a salt thereof in the present disclosure is 4 mg to 24 mg and nivolumab is 80 to 480 mg once.
- Compound 1 or salt thereof in the present disclosure 4 mg to 24 mg and nivolumab once 1 60 to 480 mg
- Compound 1 or a salt thereof in the present disclosure 4 mg to 24 mg and nivolumab once 80 mg
- Compound 1 or a salt thereof in the present disclosure 4 mg to 24 mg and nivolumab once 240 mg
- Compound 1 or salt thereof in the present disclosure 4 mg to 24 mg and nivolumab once 480 mg ⁇
- Compound 1 or a salt thereof in the present disclosure at 4 mg to 24 mg and nivolumab at 1 mg/kg 2 weeks apart.
- Compound 1 or a salt thereof in the present disclosure at 4 mg to 24 mg and nivolumab at 2 mg/kg 2 weeks apart.
- Compound 1 or a salt thereof in the present disclosure is 4 mg to 24 mg and nivolumab is 3 mg/kg every 2 weeks.
- Compound 1 or a salt thereof in the present disclosure is 4 mg to 24 mg and nivolumab is 1 mg/kg at 3 week intervals.
- Compound 1 or a salt thereof in the present disclosure at 4 mg to 24 mg and nivolumab at 2 mg/kg every 3 weeks.
- Compound 1 or a salt thereof in the present disclosure at 4 mg to 24 mg and nivolumab at 3 mg/kg at 3 week intervals.
- Compound 1 or a salt thereof in the present disclosure at 4 mg to 24 mg and nivolumab at 1 mg/kg 4 week intervals.
- Compound 1 or a salt thereof in the present disclosure at 4 mg to 24 mg and nivolumab at 2 mg/kg 4 week intervals.
- Compound 1 or salt thereof in the present disclosure is 4 mg to 24 mg and nivolumab is 3 mg. 20/175704 37 ⁇ (: 171? 2020 /008527 And nivolumab 8
- Compound 1 or a salt thereof in the present disclosure is 12 to 2 4 019 and nivolumab is 2 01
- Compound 1 or salt thereof in the present disclosure is 12 to 2 4 019 and nivolumab is 3 01
- Compound 1 or a salt thereof in the present disclosure is 1 to 2 4 019 and nivolumab is 1 1 1
- Compound 1 or a salt thereof in the present disclosure is 12 to 2 4 019 and nivolumab is 2 01
- Compound 1 or salt thereof in the present disclosure is 12 to 2 4 019 and nivolumab is 3 01
- Compound 1 or a salt thereof in the present disclosure is 1 to 2 4 019 and nivolumab is 1 1 1
- Compound 1 or a salt thereof in the present disclosure is 12 to 2 4 019 and nivolumab is 2 01
- Compound 1 or salt thereof in the present disclosure is 12 to 2 4 019 and nivolumab is 3 01
- nivolumab Compounds in the present disclosure And nivolumab were given four times at an interval of 80 3 weeks, and then from the fifth onward, nivolumab
- Compound 1 or a salt thereof according to the present disclosure is 16 to 24! 9 and nivolumab is 20!
- Compound 1 or a salt thereof in the present disclosure is 16 to 24! 9 and nivolumab is 30!
- Compound 1 or a salt thereof in the present disclosure is 16 to 24! 9 and nivolumab is 10!
- Compound 1 or a salt thereof according to the present disclosure is 16 to 24! 9 and nivolumab is 20!
- Compound 1 or a salt thereof in the present disclosure is 16 to 24! 9 and nivolumab is 30!
- Compound 1 or a salt thereof in the present disclosure is 16 to 24! 9 and nivolumab is 10! 20/175704 42 ⁇ (: 171? 2020 /008527
- the number of administrations per day, the dose, and the daily dose of nivolumab of Compound 1 or a salt thereof according to the present disclosure, or the combination of the usage and the dose includes the following:
- nivolumab once 1 60 to 480 ⁇ 19 ⁇ Compound 1 or a salt thereof in the present disclosure 4 mg once daily and nivolumab 80 mg once daily
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab once at 240 mg
- Compound 1 or a salt thereof according to the present disclosure is administered at a daily dose of 4 mg and nivolumab at a dose of 480 mg ⁇
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 1 mg/kg 2 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 2 mg/kg 2 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 3 mg/kg 2 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 1 mg/kg 3 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 2 mg/kg 3 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure once daily at 4 mg and nivolumab at 3 mg/kg 3 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 1 mg/kg 4 week intervals.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 2 mg/kg 4 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 3 mg/kg at 4 week intervals.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 4 mg and nivolumab at 80 mg 2 weeks apart.
- Compound 1 or a salt thereof in the present disclosure is administered at a daily dose of 4 mg and nivolumab 2
- Compound 1 or a salt thereof according to the present disclosure is administered once a day at 4019 and nivolumab at 480!
- Compound 1 or a salt thereof according to the present disclosure can be administered once a day with 409 and nivolumab.
- Compound 1 or a salt thereof according to the present disclosure can be administered once a day with 409 and nivolumab.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 8 mg and nivolumab once at 160 to 480 mg ⁇
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 8 mg and nivolumab at 1 mg/kg 2 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 8 mg and nivolumab at 2 mg/kg 2 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once daily at 8 mg and nivolumab at 3 mg/kg every 2 weeks. 8019 of Compound 1 or a salt thereof in the present disclosure once daily and nivolumab 1 mg/kg every 3 weeks.
- nivolumab 1 mg/kg every 4 weeks.
- Compound 1 or a salt thereof in the present disclosure can be administered once daily to 8019 and nivolumab.
- Compound 1 or a salt thereof in the present disclosure can be administered once daily to 8019 and nivolumab to
- Compound 1 or a salt thereof in the present disclosure can be administered once daily with 8019 and nivolumab
- Compound 1 or a salt thereof in the present disclosure is administered once a day at 1 210 9 and nivolumab at 8 00! 9 2 week intervals.
- nivolumab 2 4 0 0 1 9 3 weeks, 4 doses, then 5th dose of nivolumab And nivolumab
- nivolumab 480 019 4 weeks apart 5th dose of nivolumab 480 019 4 weeks apart.
- Compound 1 or salt thereof in the present disclosure 1 6019 once a day and nivolumab once 80-480 ⁇ 19 ⁇
- Compound 1 or salt thereof in the present disclosure 1 6019 once daily and nivolumab 1 60-480019.
- Compound 1 or a salt thereof according to the present disclosure can be administered once daily to 6019 and nivolumab.
- Compound 1 or a salt thereof according to the present disclosure can be administered once daily to 6019 and nivolumab. Every two weeks. 20/175704 52 (:171? 2020/008527) Compound 1 or a salt thereof according to the present disclosure was treated with 1 6 01 9 and nivolumab once a day.
- Compound 1 or a salt thereof in the present disclosure is administered once a day for 1 6019 and nivolumab at 800 ! 94 week intervals.
- nivolumab Compounds in the present disclosure And nivolumab were administered 4 times at 240 ⁇ 19 3 week intervals, and then nivolumab And nivolumab
- nivolumab Compounds in the present disclosure And nivolumab were administered 4 times at 240 ⁇ 19 3 week intervals, and then nivolumab
- Compound 1 or a salt thereof according to the present disclosure is administered once daily to 20019 and nivolumab. And nivolumab
- Compound 1 or a salt thereof according to the present disclosure can be administered once a day with 20 01 9 and nivolumab.
- Compound 1 or a salt thereof according to the present disclosure can be administered once a day with 20 01 9 and nivolumab.
- nivolumab were administered 4 times at 2 400 1 3 week intervals, and then nivolumab was administered from the 5th dose onward.
- the daily dose of Compound 1 or a salt thereof in the present disclosure on the day of administration, and the daily dose of atezolizumab, or a preferable combination of the usage and the dose, includes the following:
- Atezorizuma Breakfast 1 2 0 0 9 2-week intervals.
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab 20/175704 58 ⁇ (: 171? 2020 /008527
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab Every two weeks.
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab Every two weeks.
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab Every 3 weeks.
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab Every 3 weeks.
- Compound 1 or a salt thereof according to the present disclosure 16 to 24019 and atezolizumab ⁇ 2020/175 704 59 ⁇ (:171? 2020 /008527
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and atezolizumab
- the number of administrations per day, the dose, and the daily dose of atezolizumab of Compound 1 or a salt thereof according to the present disclosure, or the combination of the usage and the dose includes the following. :
- Compound 1 or a salt thereof in the present disclosure is administered once daily to 4019 and atezolizumab.
- Compound 1 or a salt thereof according to the present disclosure may be administered once daily to 8019 and atezolizumab.
- Atezolizuma 20/175704 62 ⁇ (: 171? 2020 /008527
- Compound 1 or a salt thereof according to the present disclosure can be administered once daily to 6019 and atezolizumab.
- Atezolizuma 2020/175 704 63 ⁇ (:171? 2020 /008527
- the daily dose of Compound 1 or a salt thereof in the present disclosure on the day of administration, and the daily dose of ibilimumab, or a preferable combination of the usage and the dose include the following:
- Compound 1 or a salt thereof according to the present disclosure is 12 to 2 4 019 and ipilimumab is 1.0 ⁇ ! 9/1 ⁇ 9 (body weight) every 3 weeks.
- Compound 1 or a salt thereof according to the present disclosure 12 to 2 4 019 and ipilimumab 3.00! 9/1 ⁇ 9 (body weight) every two weeks.
- Compound 1 or a salt thereof according to the present disclosure is 12 to 2 4 019 and ipilimumab is 3.00! 9/1 ⁇ 9 (body weight) every 3 weeks.
- Compound 1 or a salt thereof in the present disclosure is 12 to 2 4 019 and ipilimumab is 1 And ipilimumab 1 And ipilimumab 1 ⁇ 2020/175 704 66 ⁇ (:171? 2020/008527
- Compound 1 or a salt thereof according to the present disclosure 16 to 2 4 019 and ipilimumab 1.00! 9/1 ⁇ 9 (body weight) every 3 weeks.
- Compound 1 or a salt thereof according to the present disclosure 16 to 2 4 019 and ipilimumab 3.00! 9/1 ⁇ 9 (body weight) every 2 weeks.
- Compound 1 or a salt thereof according to the present disclosure 16 to 2 4 019 and ipilimumab 3.00! 9/1 ⁇ 9 (body weight) every 3 weeks.
- Compound 1 or a salt thereof in the present disclosure is 1-6 to 2 4 019 and ipilimumab is 1 And ipilimumab 1 (Weight) 3 weeks apart.
- the number of administrations per day, the dose, and the daily dose of ibilimumab on the administration day of Compound 1 or a salt thereof in the present disclosure, or the combination of the usage and the dose includes the following. :
- Compound 1 or a salt thereof according to the present disclosure once daily, 8019 and ibilimumab 1.0019/1 ⁇ 9 (body weight) every two weeks.
- Compound 1 or a salt thereof in the present disclosure once a day 1 2019 and ipilimumab 3. (Weight) 3 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is administered once a day with 20019 and ibilimumab is administered once (body weight)
- the daily dose of Compound 1 or a salt thereof in the present disclosure on the day of administration, and the daily dose of duravalumab, or a preferable combination of the usage and the dose includes the following:
- Compound 1 or a salt thereof according to the present disclosure is 9 and Durabalumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and Durabalumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and Durabalumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and Durabalumab (Weight) 3 weeks apart.
- Compound 1 or a salt thereof according to the present disclosure is 9 and Durabalumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and Durabalumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and Durabalumab
- Compound 1 or a salt thereof according to the present disclosure is 9 and Durabalumab ⁇ 2020/175 704 72 ⁇ (: 171? 2020 /008527
- the number of administrations per day, the dose, and the daily dose of duravalumab on the administration day of Compound 1 or a salt thereof in the present disclosure, or the combination of the usage and the dose includes the following. :
- the daily dose of Compound 1 or a salt thereof in the present disclosure on the day of administration, and the daily dose of avelumab, or the preferred combination of the usage and the dose, includes the following:
- Compound 1 or a salt thereof according to the present disclosure is 12 to 24 ⁇ !9 and avelumab is 80
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AU2020228514A AU2020228514A1 (en) | 2019-02-28 | 2020-02-28 | Cancer therapy using 3,5-disubstituted benzene alkynyl compound and immune checkpoint inhibitor |
JP2021502667A JPWO2020175704A1 (ja) | 2019-02-28 | 2020-02-28 | |
US17/434,573 US20220125793A1 (en) | 2019-02-28 | 2020-02-28 | Cancer therapy using 3,5-disubstituted benzene alkynyl compound and immune checkpoint inhibitor |
KR1020217030409A KR20210130774A (ko) | 2019-02-28 | 2020-02-28 | 3,5-2치환 벤젠알키닐 화합물과 면역 체크포인트 저해약을 사용한 암 치료법 |
EP20763207.6A EP3932425A4 (en) | 2019-02-28 | 2020-02-28 | CANCER THERAPY USING A 3,5-DISUBSTITUTED ALKYNYL BENZENE COMPOUND AND AN IMMUNE CHECKPOINT INHIBITOR |
JP2023102852A JP2023112136A (ja) | 2019-02-28 | 2023-06-22 | 3,5-二置換ベンゼンアルキニル化合物と免疫チェックポイント阻害薬とを用いた癌治療法 |
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PCT/JP2020/008509 WO2020175697A1 (ja) | 2019-02-28 | 2020-02-28 | 3,5-二置換ベンゼンアルキニル化合物とペムブロリズマブとを用いた癌治療法 |
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EP (2) | EP3932427A4 (ja) |
JP (4) | JPWO2020175697A1 (ja) |
KR (2) | KR20210130774A (ja) |
AU (2) | AU2020229714A1 (ja) |
MA (2) | MA55091A (ja) |
TW (2) | TW202045182A (ja) |
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Cited By (3)
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---|---|---|---|---|
US11833151B2 (en) | 2018-03-19 | 2023-12-05 | Taiho Pharmaceutical Co., Ltd. | Pharmaceutical composition including sodium alkyl sulfate |
US11883404B2 (en) | 2016-03-04 | 2024-01-30 | Taiho Pharmaceuticals Co., Ltd. | Preparation and composition for treatment of malignant tumors |
US11975002B2 (en) | 2016-03-04 | 2024-05-07 | Taiho Pharmaceutical Co., Ltd. | Preparation and composition for treatment of malignant tumors |
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- 2020-02-28 JP JP2021502662A patent/JPWO2020175697A1/ja active Pending
- 2020-02-28 EP EP20763687.9A patent/EP3932427A4/en active Pending
- 2020-02-28 MA MA055091A patent/MA55091A/fr unknown
- 2020-02-28 EP EP20763207.6A patent/EP3932425A4/en active Pending
- 2020-02-28 US US17/434,655 patent/US20220184082A1/en active Pending
- 2020-02-28 WO PCT/JP2020/008527 patent/WO2020175704A1/ja unknown
- 2020-02-28 KR KR1020217030410A patent/KR20210131387A/ko not_active Application Discontinuation
- 2020-02-28 AU AU2020229714A patent/AU2020229714A1/en active Pending
- 2020-02-28 US US17/434,573 patent/US20220125793A1/en active Pending
- 2020-02-28 WO PCT/JP2020/008509 patent/WO2020175697A1/ja unknown
- 2020-02-28 AU AU2020228514A patent/AU2020228514A1/en active Pending
- 2020-02-28 MA MA055088A patent/MA55088A/fr unknown
- 2020-02-28 JP JP2021502667A patent/JPWO2020175704A1/ja active Pending
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Cited By (3)
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Also Published As
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JP2023112136A (ja) | 2023-08-10 |
JPWO2020175697A1 (ja) | 2020-09-03 |
KR20210130774A (ko) | 2021-11-01 |
AU2020228514A1 (en) | 2021-10-07 |
MA55088A (fr) | 2022-01-05 |
EP3932427A1 (en) | 2022-01-05 |
WO2020175697A1 (ja) | 2020-09-03 |
AU2020229714A1 (en) | 2021-10-07 |
JPWO2020175704A1 (ja) | 2020-09-03 |
EP3932425A4 (en) | 2022-12-07 |
EP3932425A1 (en) | 2022-01-05 |
US20220184082A1 (en) | 2022-06-16 |
MA55091A (fr) | 2022-01-05 |
JP2023096156A (ja) | 2023-07-06 |
US20220125793A1 (en) | 2022-04-28 |
TW202039507A (zh) | 2020-11-01 |
EP3932427A4 (en) | 2022-12-07 |
KR20210131387A (ko) | 2021-11-02 |
TW202045182A (zh) | 2020-12-16 |
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