WO2021023178A1 - Utilisation d'un composé hétérocyclique à six chaînons pyrrolo-fusionné dans la préparation d'un médicament pour le traitement d'une tumeur à mutation du gène fgfr2 - Google Patents

Utilisation d'un composé hétérocyclique à six chaînons pyrrolo-fusionné dans la préparation d'un médicament pour le traitement d'une tumeur à mutation du gène fgfr2 Download PDF

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WO2021023178A1
WO2021023178A1 PCT/CN2020/106766 CN2020106766W WO2021023178A1 WO 2021023178 A1 WO2021023178 A1 WO 2021023178A1 CN 2020106766 W CN2020106766 W CN 2020106766W WO 2021023178 A1 WO2021023178 A1 WO 2021023178A1
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seq
use according
antibody
cholangiocarcinoma
sequence
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PCT/CN2020/106766
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Chinese (zh)
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任文明
张蕾
唐蜜
王泉人
杨昌永
廖成
张连山
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江苏恒瑞医药股份有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to the field of medicinal chemistry.
  • the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating tumors with FGFR2 gene mutation.
  • Fibroblast growth factors play an important role in many physiological processes by acting on their receptors (fibroblast growth factor receptors, FGFRs), such as embryo formation, wound repair, angiogenesis, etc.
  • FGFRs fibroblast growth factor receptors
  • FGFRs are the driving genes of certain cancers, and maintain the malignant characteristics of tumor cells in a "cell autonomy" manner, by inducing mitogenic and survival signals, promoting tumor cell invasion and metastasis, and promoting epithelium Mesenchymal transition, promotion of angiogenesis, and participation in tumor recurrence and drug resistance are multiple steps of oncogenes participating in tumorigenesis and development.
  • RTKs receptor tyrosine kinases
  • FGFR2 is associated with many medical conditions, including abnormal bone development (such as craniosynostosis) and cancer.
  • Craniosynostosis syndrome such as Apert syndrome, Antley-Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson-Weiss syndrome, etc.
  • Cancers such as cholangiocarcinoma, breast cancer, endometrial cancer, melanoma, stomach cancer, cervical cancer, lung cancer, prostate cancer, bladder cancer, etc.
  • Cholangiocarcinoma is a malignant tumor originating from bile duct epithelial cells. According to its anatomical location, it can be divided into intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. In cholangiocarcinoma, hilar cholangiocarcinoma accounts for 50%, extrahepatic cholangiocarcinoma accounts for 40%, and intrahepatic cholangiocarcinoma accounts for less than 10%. Cholangiocarcinoma is the second most common liver tumor, second only to liver cancer, accounting for about 30% of liver cancers. Due to the insidious disease and difficult diagnosis, cholangiocarcinoma has missed the best treatment period when it is discovered, and is called the "invisible killer.”
  • intrahepatic cholangiocarcinoma occurs in the liver, if there is no pathology, it is mostly classified as primary liver cancer. In fact, intrahepatic cholangiocarcinoma is different from primary hepatocellular carcinoma in etiology, pathogenesis, pathology and biological behavior, clinical manifestations and treatment, but is similar to extrahepatic cholangiocarcinoma. Epidemiological studies have shown that the incidence and mortality of intrahepatic cholangiocarcinoma have increased year by year in the past 30 years, while extrahepatic cholangiocarcinoma has remained at a stable level or slightly decreased.
  • cholangiocarcinoma The etiology of cholangiocarcinoma is currently unclear, and it is related to bile duct stones and bile duct infections, liver flukes, and fatty meat diets. It has been gradually increasing in recent years. It has the characteristics of difficult early diagnosis, high degree of malignancy, limited treatment methods, and poor prognosis. The 5-year survival rate of patients is less than 5%.
  • Cholangiocarcinoma is a tumor that is not sensitive to radiotherapy.
  • Adjuvant radiotherapy can only improve the survival rate of patients.
  • radiotherapy After effective biliary drainage of unresectable and locally metastatic cholangiocarcinoma, radiotherapy can improve patients' symptoms and prolong life.
  • Cholangiocarcinoma is not sensitive to chemotherapy, but it may relieve symptoms and prolong survival.
  • CN101007815A discloses a compound of formula (I), and discloses that the compound has VEGF and EGFR inhibitory activity.
  • CN101007815A discloses that compounds of formula (I) can be used to treat pancreatic cancer.
  • CN106535896A discloses that compounds of formula (I) can be used to treat fibrotic diseases, such as pulmonary fibrosis, liver cirrhosis, scleroderma or renal fibrosis.
  • the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating tumors with FGFR2 gene mutation.
  • the FGFR2 gene variant tumors described in the present disclosure are selected from cholangiocarcinoma, endometrial cancer, urothelial cancer, breast cancer, gastric cancer, lung cancer, melanoma, prostate cancer, and bladder cancer.
  • the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating cholangiocarcinoma.
  • the cholangiocarcinoma has FGFR2 gene mutation.
  • the pharmaceutically acceptable salt described in the present disclosure is preferably malate.
  • the cholangiocarcinoma described in the present disclosure is selected from intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, or extrahepatic cholangiocarcinoma. In certain embodiments, the cholangiocarcinoma described in the present disclosure is intrahepatic cholangiocarcinoma.
  • the cholangiocarcinoma described in the present disclosure is a cholangiocarcinoma that has failed first-line treatment. In certain embodiments, the cholangiocarcinoma described in the present disclosure is intrahepatic cholangiocarcinoma that has failed first-line treatment. In certain embodiments, the cholangiocarcinoma described in the present disclosure is intrahepatic cholangiocarcinoma accompanied by FGFR2 gene mutation that has failed first-line treatment.
  • the FGFR2 gene variation described in the present disclosure is selected from the FGFR2 gene fusion/mutation/amplification/rearrangement type.
  • the FGFR2 gene fusion/mutation/amplification/rearrangement type described in the present disclosure is selected from FGFR2-BICC1, FGFR2-AHCYL1.
  • the intrahepatic cholangiocarcinoma is selected from the FGFR2 gene fusion/mutation/amplification/rearrangement type, preferably FGFR2-BICC1, FGFR2-AHCYL1.
  • the dosage of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.1-1000 mg, and the frequency of administration can be once a day, twice a day, or three times a day, preferably one day once.
  • the compound of formula (I) or its pharmaceutically acceptable salt is in a unit dosage form containing 0.1-1000 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the frequency of administration may be once a day, Two times a day, three times a day, preferably once a day.
  • the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.1-100 mg, specifically 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46m
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof contains 0.1-100 mg, specifically 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg , 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered according to body weight, and the dose is selected from 0.1-10.0 mg/kg.
  • the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg. kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/ kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/ kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg
  • the dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1-25 mg, specifically 15 mg, 20 mg, 25 mg, and the frequency of administration may be once a day, twice a day, Three times a day, preferably once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a unit dosage form containing 1-25 mg, specifically 15 mg, 20 mg, 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the frequency of medication may be once a day, twice a day, or three times a day, preferably once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with other anti-tumor agents.
  • the other anti-tumor agent described in the present disclosure is a tumor immunotherapeutic agent
  • the tumor immunotherapeutic agent comprises a PD-1 antibody or an antigen-binding fragment thereof, a PD-L1 antibody or an antigen-binding fragment thereof One or more of.
  • the present disclosure also relates to the combination of the compound of formula (I) or its pharmaceutically acceptable salt with PD-1 antibody or its antigen-binding fragment, or the combination of PD-L1 antibody or its antigen-binding fragment in the preparation and treatment of FGFR2 gene mutation The use of tumor medicine.
  • the PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is selected from Keytruda, Opdivo, AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Camrelizumab, LZM-009, AK-103.
  • the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises LCDR1, LCDR2 shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • LCDR3; the heavy chain variable region includes HCDR1, HCDR2, and HCDR3 shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
  • the PD-1 antibody is a humanized antibody.
  • the light chain variable region sequence of the humanized PD-1 antibody is the sequence shown in SEQ ID NO: 10 or a variant thereof, and the variant preferably has 0- 10 amino acid changes, more preferably A43S amino acid changes;
  • the humanized antibody heavy chain variable region sequence is the sequence shown in SEQ ID NO: 9 or a variant thereof, and the variant is preferably in the heavy chain
  • the variable region has 0-10 amino acid changes, more preferably G44R amino acid changes.
  • the light chain sequence of the PD-1 humanized antibody is the sequence shown in SEQ ID NO: 8 or a variant thereof; the variant preferably has 0-10 in the light chain variable region.
  • the amino acid change of A43S is more preferably the amino acid change of A43S;
  • the heavy chain sequence of the humanized PD-1 antibody is the sequence shown in SEQ ID NO: 7 or a variant thereof, and the variant is preferably a heavy chain variable
  • the region has 0-10 amino acid changes, more preferably G44R amino acid changes.
  • the light chain sequence of the PD-1 humanized antibody is the sequence shown in SEQ ID NO: 8
  • the heavy chain sequence is the sequence shown in SEQ ID NO: 7.
  • sequences of the heavy and light chains of the PD-1 humanized antibody are as follows:
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is 0.1-10.0 mg/kg, and may be 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg /kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg /kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg /kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg,
  • the dose of the PD-1 antibody or antigen-binding fragment thereof is 1 to 600 mg, which can be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2 mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg , 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9.0 mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15
  • the PD-1 antibody or antigen-binding fragment thereof contains 1 to 600 mg, which can be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2 mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg , 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9.0 mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15mg,
  • the frequency of administration of the anti-PD-1 antibody or its antigen-binding fragment is once a week, once every two weeks, once every three weeks, once every four weeks, or once a month; administration of the compound represented by formula I or a pharmaceutically acceptable salt thereof
  • the frequency is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.
  • the combined compound represented by formula (I) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof described in the present disclosure have a synergistic effect.
  • the PD-L1 antibody or antigen-binding fragment thereof described in the present disclosure is selected from tecentrip, Imfinzi, and Bavencio.
  • any one of the anti-PD-L1 antibody or antigen-binding fragment thereof is selected from the following CDR region sequence or its mutant sequence: antibody heavy chain variable region HCDR region sequence: SEQ ID NO: 11-13 ; And the sequence of the LCDR region of the antibody light chain variable region: SEQ ID NO: 14-16; details are as follows:
  • HCDR1 is selected from:
  • HCDR2 is selected from:
  • HCDR3 is selected from:
  • LCDR1 is selected from:
  • LCDR2 is selected from:
  • LCDR3 is selected from:
  • the PD-L1 antibody or antigen-binding fragment includes and amino acid sequence: SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of light chain variable region CDR sequences and amino acids Sequence: SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% , 95%, 96%, 97%, 98%, or 99% sequence identity of heavy chain variable region CDR sequences.
  • the PD-L1 antibody or antigen-binding fragment may be selected from murine antibodies, chimeric antibodies, humanized antibodies, human antibodies, and preferably humanized antibodies.
  • the PD-L1 antibody or antigen-binding fragment comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% of the amino acid sequence SEQ ID NO: 17 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of the heavy chain variable region sequence, and the amino acid sequence SEQ ID NO: 18 have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of the light chain variable region sequence.
  • the heavy chain variable region sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 17, and the light chain variable region sequence is SEQ ID NO: 18.
  • the PD-L1 antibody or antigen-binding fragment further comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 or a variant thereof, preferably comprising a human IgG2 or IgG4 heavy chain constant region More preferably, it comprises the constant region of an IgG4 heavy chain introduced with F234A and L235A mutations; the humanized antibody light chain further comprises a constant region of a human ⁇ , ⁇ chain or a variant thereof.
  • the PD-L1 antibody or antigen-binding fragment comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% of the amino acid sequence SEQ ID NO: 19 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of the heavy chain variable region sequence, and the amino acid sequence SEQ ID NO: 21 have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity of light chain sequences.
  • the heavy chain sequence of the PD-L1 antibody or antigen-binding fragment is SEQ ID NO: 19, and the light chain sequence is SEQ ID NO: 21.
  • the drug administration route in the present disclosure can be oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.
  • the PD-1 antibody or antigen-binding fragment thereof is administered by injection, such as subcutaneous or intravenous injection, and the PD-1 antibody or antigen-binding fragment thereof needs to be formulated into an injectable form before injection .
  • injectable forms of PD-1 antibodies or antigen-binding fragments thereof are injections or freeze-dried powders, for example, the injectable forms of PD-1 antibodies, which include PD-1 antibodies, buffers, stabilizers, and optional The ground also contains surfactants.
  • the buffer can be selected from one or more of acetate, citrate, succinate, and phosphate.
  • the stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, maltose.
  • the surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80 , Polysorbate 20 is most preferred.
  • the dose of the PD-L1 antibody or antigen-binding fragment described in the present disclosure is selected from 1-50 mg/kg, preferably from 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg.
  • the dose of the PD-L1 antibody or antigen-binding fragment is selected from 50-3000 mg, preferably from 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg , 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg , 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg,
  • the PD-L1 antibody or antigen-binding fragment contains 50-3000mg, preferably from 50mg, 60mg, 70mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg,
  • the frequency of administration of the PD-L1 antibody or its antigen-binding fragment in the present disclosure can be once a day, twice a day, three times a day, once a week, once two weeks, once three weeks, once a month, once every five weeks, Once every six weeks.
  • the frequency of administration of the PD-L1 antibody or antigen-binding fragment thereof is every 3 weeks as a dosing cycle, and the first day of each cycle is administered, preferably every 3 weeks as a dosing cycle (the first It is administered once every 28 days in a cycle), and the dose is 1200 mg per cycle.
  • the combination optionally further includes other components, and the other components include but are not limited to other anti-tumor drugs and the like.
  • the present disclosure also provides a method for treating tumor diseases, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, or PD-L1 antibody to a patient.
  • the frequency of administration of the PD-L1 antibody is every 3 weeks as a dosing cycle, and it is administered on the first day of each cycle, preferably every 3 weeks is a dosing cycle (the first cycle is administered once every 28 days).
  • the FGFR2 gene variation described in the present disclosure includes FGFR2 gene fusion/mutation/amplification/rearrangement, etc., which means that FGFR2 gene variation includes one or more of FGFR2 gene fusion, mutation, amplification, rearrangement and other types of mutations .
  • the gene mutations described in the present disclosure refer to gene abnormalities, and gene abnormalities such as deletions, translocations, shifts, inversions, insertions, and duplications are all covered by the term gene mutations in the present disclosure.
  • the present disclosure combines the compound of formula (I) or its pharmaceutically acceptable salt with PD-1 antibody, or combines the compound of formula (I) or its pharmaceutically acceptable salt with PD-L1 antibody, thereby enhancing Anti-tumor activity improves the therapeutic effect of tumor diseases.
  • the "combination" described in the present disclosure is a mode of administration, which means that at least one dose of the compound of formula (I) and other anti-tumor agents are administered within a certain period of time, wherein the given drugs all show pharmacological effects .
  • the time limit may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • the compound of formula (I) and other antitumor agents can be administered simultaneously or in no particular order. For example, such a period includes treatments in which the compound of formula (I) and the PD-L1 antibody or PD-L1 antibody are administered through the same route of administration or different routes of administration.
  • Effective amount includes an amount sufficient to improve or prevent the symptoms or conditions of a medical disease.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on the following factors: for example, the condition to be treated, the patient's general health, the method of administration and dosage, and the severity of side effects.
  • the effective amount can be the maximum dose or dosing schedule that avoids significant side effects or toxic effects.
  • First-line treatment failure refers to previous first-line systemic chemotherapy, treatment failure, and previous systemic treatment ⁇ 2 lines; patients with intrahepatic cholangiocarcinoma received neoadjuvant chemotherapy or adjuvant chemotherapy after R0 radical resection, if during chemotherapy or Disease progression within 6 months after stopping chemotherapy is counted as failure of first-line treatment.
  • Example 1 The compound of formula (I) is The therapeutic effect of drugs in a female BALB/c nude mouse model of CC6204 xenograft of cholangiocarcinoma
  • the BALB/c nude female mouse model CC6204 of subcutaneous xenograft of cholangiocarcinoma is a PDX model of FGFR2-BICC1 gene fusion.
  • Method subcutaneous inoculation of female BALB/c nude mice Cholangiocarcinoma CC6204 tumor mass, to establish a CC6204 xenograft tumor model.
  • the test is divided into Vehicle control group (BGJ398 solvent+CSW1 vehicle), BGJ398 15mg/kg+CSW1 vehicle, CSW1 10mg/kg+BGJ398 vehicle; and CSW1 20mg/kg+BGJ398 vehicle group.
  • Each group of 6 rats, BGJ398 and CSW1 were administered intragastrically, once a day.
  • the efficacy is evaluated based on the relative tumor inhibition rate (TGI), and the safety is evaluated based on the changes in animal weight and death.
  • TGI tumor inhibition rate
  • Dosing volume is 50 ⁇ l
  • mice BALB/c nude female mice of 9-10 weeks (mouse age at the start of administration), 18.5-23.7 g (weight of the mouse at the start of administration)
  • mice 48 female mice were inoculated subcutaneously on the right side Cholangiocarcinoma CC6204 xenotransplantation.
  • the average tumor volume was about 135mm 3
  • they were randomly divided into 4 experimental groups (see Table 2) according to the tumor size, with 6 in each group and 3 in each cage.
  • the day of grouping was defined as day 0.
  • the administration started on day 0 and was administered for 4 weeks.
  • Relative tumor proliferation rate is the percentage value of the treatment group and the control group relative to the tumor volume or tumor weight at a certain point in time. Calculated as follows:
  • T/C% T TW /C TW ⁇ 100% (T TW : average tumor weight at the end of the experiment in the treatment group; C TW : average tumor weight at the end of the experiment in the vehicle control group).
  • T and C are the relative tumor volume (RTV) or tumor weight (TW) at a specific time point in the treatment group and the control group, respectively).
  • mice in the control group were 1936.19 mm 3 .
  • the average tumor volume of) is 1046.52mm 3 , 962.33mm 3 and 549.11mm 3 respectively .
  • TGI % is 49.43%, 54.06% and 77.08%, respectively.
  • test drug CSW1 10mg/kg+BGJ398 vehicle treatment group has no statistically significant difference (p>0.05).
  • the results of tumor weight analysis basically coincided with the results of relative tumor volume analysis. See Table 3, Table 4, and Table 5 for tumor growth in each treatment group and control group.
  • Table 4 Analysis table of the efficacy of each group in the CC6204 animal model of cholangiocarcinoma
  • Example 2 A single-arm, open, multi-center phase II clinical trial of famitinib malate in the treatment of intrahepatic cholangiocarcinoma with FGFR2 gene abnormality that failed first-line treatment
  • Famitinib malate capsules once a day, continuous medication, 3 weeks as a cycle.
  • patients with intrahepatic cholangiocarcinoma enrolled in the study histopathologically confirmed intrahepatic cholangiocarcinoma (cannot be cured), who had previously undergone first-line system chemotherapy, and the treatment failed, and the previous systemic treatment was ⁇ 2 lines; patients with intrahepatic cholangiocarcinoma were preoperatively Adjuvant chemotherapy after neoadjuvant chemotherapy or R0 radical resection, if disease progression occurs during chemotherapy or within 6 months after stopping chemotherapy, it is counted as a failure of first-line treatment;
  • Biopsy can be performed during the screening period to obtain tumor tissue for genetic testing including but not limited to FGFR2; if the investigator judges that the biopsy cannot be accepted, the tumor tissue archived sample obtained within 12 months before signing the informed consent can be provided ( ⁇ Ermarin-fixed, paraffin-embedded [FFPE] tissue blocks or unstained FFPE glass slides) for FGFR2 detection; under special circumstances, if biopsy and archive tumor tissue samples are not available, peripheral blood ctDNA detection accompanied by FGFR2 gene fusion/ Those with rearrangements can be included in the study; if the tumor tissue samples and peripheral blood ctDNA provided cannot detect FGFR2, they cannot be included in the study;
  • FFPE paraffin-embedded

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Abstract

La présente invention concerne l'utilisation d'un composé hétérocyclique à six chaînons pyrrolo-fusionné dans la préparation d'un médicament pour le traitement de tumeurs à mutation du gène FGFR2. En particulier, la présente invention concerne l'utilisation d'un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci dans la préparation d'un médicament pour le traitement de tumeurs à mutation du gène FGFR2, en particulier, l'utilisation de celui-ci dans la préparation d'un médicament pour le traitement d'un cholangiocarcinome intrahépatique.
PCT/CN2020/106766 2019-08-05 2020-08-04 Utilisation d'un composé hétérocyclique à six chaînons pyrrolo-fusionné dans la préparation d'un médicament pour le traitement d'une tumeur à mutation du gène fgfr2 WO2021023178A1 (fr)

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WO2016173400A1 (fr) * 2015-04-27 2016-11-03 江苏恒瑞医药股份有限公司 Utilisation d'inhibiteur de protéine kinase dans la préparation d'un médicament pour le traitement de maladies fibrotiques
WO2018160841A1 (fr) * 2017-03-01 2018-09-07 Genentech, Inc. Procédés diagnostiques et thérapeutiques relatifs au cancer
WO2018220206A1 (fr) * 2017-06-02 2018-12-06 Janssen Pharmaceutica Nv Inhibiteurs de fgfr2 utilisés dans le traitement du cholangiocarcinome
WO2019096194A1 (fr) * 2017-11-16 2019-05-23 江苏恒瑞医药股份有限公司 Utilisation d'un anticorps anti-pd-1 combiné à un inhibiteur de vegfr dans le traitement du cancer du poumon à petites cellules
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