WO2020119757A1 - Utilisation d'un inhibiteur de cdk4/6 en combinaison avec une immunothérapie dans la préparation d'un médicament pour le traitement d'un lymphome - Google Patents

Utilisation d'un inhibiteur de cdk4/6 en combinaison avec une immunothérapie dans la préparation d'un médicament pour le traitement d'un lymphome Download PDF

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WO2020119757A1
WO2020119757A1 PCT/CN2019/124831 CN2019124831W WO2020119757A1 WO 2020119757 A1 WO2020119757 A1 WO 2020119757A1 CN 2019124831 W CN2019124831 W CN 2019124831W WO 2020119757 A1 WO2020119757 A1 WO 2020119757A1
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antibody
antigen
binding fragment
pharmaceutically acceptable
acceptable salt
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PCT/CN2019/124831
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English (en)
Chinese (zh)
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江瑶
王泉人
李华军
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江苏恒瑞医药股份有限公司
苏州盛迪亚生物医药有限公司
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Priority to CN201980072280.8A priority Critical patent/CN112955148B/zh
Publication of WO2020119757A1 publication Critical patent/WO2020119757A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present disclosure belongs to the field of pharmacy, and relates to the use of a CDK4/6 inhibitor combined immunotherapy in the preparation of a medicament for treating lymphoma.
  • tumor immunotherapy represented by anti-PD-1/PD-L1 monoclonal antibodies represents the research direction of tumor therapy.
  • the immune checkpoint inhibitory receptors of programmed cell death protein-1 (PD-1) are mainly expressed in activated T cells.
  • the PD-1 signal cascade negatively regulates T cell receptor activation and also reduces T cell proliferation and function.
  • the final result is T cell depletion.
  • PD-1 expression was significantly up-regulated.
  • cytokines such as IFN- ⁇ and IFN- ⁇ appear in the tumor microenvironment
  • the expression of PD-1 ligand (PD-L1) in tumor cells and tumor-related immune cells also increases significantly.
  • PD-1 monoclonal antibodies such as nivolumab and pembrolizumab, have the ability to bind to PD-1, thereby disrupting the interaction between PD-1 protein and its ligands (PD-L1 and PD-L2) and preventing T Inhibitory signal in the cell microenvironment.
  • PD-1 monoclonal antibodies are now approved for the treatment of various cancers, including squamous cell carcinoma of the bladder, lung, head and neck, and are approved for the treatment of melanoma in the United States, Europe and other regions.
  • anti-PD-1 monoclonal antibodies to achieve PD-1 blockade has proved to be effective for relapsed/refractory classic Hodgkin lymphoma, and also shows certain efficacy for non-Hodgkin lymphoma.
  • In a phase 1 study with anti-PD-1 antibodies to treat relapsed T-cell lymphoma clinical remission was also observed. Previous studies have shown that EBV infection may enhance the expression of PD-L1 in tumor cells.
  • EBV-related non-Hodgkin lymphomas such as mature T cells and NK cell lymphomas express high levels of PD-L1, indicating that EBV-related mature T Cell and NK cell lymphomas may be more susceptible to PD-1 blockade.
  • many patients with non-Hodgkin's lymphoma have not obtained good results with anti-PD-l/PD-Ll monoclonal antibody alone, so it is still necessary to continue to find a combination drug that enhances the anti-PD-l/PD-Ll monoclonal antibody.
  • CDK4/6 inhibitors are abemaciclib, ribociclib or palbociclib.
  • W02014183520 provides a potent CDK4/6 inhibitor with the structure shown in formula I.
  • WO2016124067 discloses the hydroxyethyl group of CDK4/6 inhibitor formula I compounds Sulfonate,
  • the present disclosure provides the use of a compound represented by formula I or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating gold lymphoma,
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is selected from 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, Pembrolizumab, LZM-009, AK-103 and Nivolumab.
  • the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof includes LCDR1 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • LCDR2 and LCDR3; the heavy chain variable region contains HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
  • each CDR sequence of the PD-1 antibody or antigen-binding fragment thereof is shown in the following table:
  • the anti-PD-1 antibody or antigen-binding fragment thereof is selected from humanized antibodies or fragments thereof.
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') 2 fragments.
  • immunoglobulin can be derived from any commonly known isotype, including but not limited to IgA, secreted IgA, IgG and IgM.
  • IgG subclasses are also well known to those skilled in the art, including but not limited to IgG1, IgG2, IgG3 and IgG4.
  • immunotype refers to the Ab species or subclass (eg, IgM or IgG1) encoded by the heavy chain constant region gene.
  • the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably comprising IgG1 or IgG4 isotype Of the heavy chain constant region.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region of a light chain constant region of ⁇ or ⁇ .
  • the humanized antibody comprises the light chain variable region shown in SEQ ID NO: 10 or a variant thereof, and the variant preferably has 0- in the light chain variable region shown in SEQ ID NO: 10 10 amino acid changes, more preferably A43S amino acid changes; the humanized antibody comprises the heavy chain variable region shown in SEQ ID NO: 9 or a variant thereof, the variant is preferably shown in SEQ ID NO: 9
  • the heavy chain variable region has 0-10 amino acid changes, more preferably G44R amino acid changes.
  • the humanized antibody comprises the light chain shown in SEQ ID NO: 8 or a variant thereof, the variant preferably has 0-10 amino acid changes in the light chain variable region, More preferably, the amino acid change of A43S; the humanized antibody comprises the heavy chain shown in SEQ ID NO: 7 or a variant thereof, and the variant preferably has a 0-10 amino acid change in the variable region of the heavy chain, more preferably Amino acid changes of G44R.
  • the humanized antibody contains a light chain as shown in SEQ ID NO: 8, and a heavy chain as shown in SEQ ID NO: 7.
  • sequences of the heavy and light chains of the humanized antibody are as follows:
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof described in the present disclosure in a human subject is 0.1 to 10.0 mg/kg, and may be 0.1 mg/kg, 0.2 mg/kg , 0.3mg/kg, 0.4mg/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,
  • the PD-1 antibody or antigen-binding fragment thereof is administered in a human subject at a dosage of 1-600 mg, which may be 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0mg, 2.2mg, 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, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.6mg, 9.9
  • the frequency of administration of the anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure is selected from once a week, once every two weeks, once every three weeks, once every four weeks, or once a month;
  • the administration frequency of the salt is once a day, twice a day, three times a day, once a day, once a day or once a week.
  • the compound represented by the formula I or its pharmaceutically acceptable salt is continuously administered for three times Withdrawal for 1 week.
  • the anti-PD-1 antibody or antigen-binding fragment thereof in combination with the compound represented by Formula I or a pharmaceutically acceptable salt thereof has a cycle of every 4 weeks.
  • the compound of formula I described in the present disclosure or a pharmaceutically acceptable salt thereof has a synergistic effect in combination with an anti-PD-1 antibody or antigen-binding fragment thereof.
  • the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof described in the present disclosure in a human subject is selected from 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg or any value between any two values, preferably 100mg or 150mg.
  • the dosage of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 1 to 600 mg, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered in humans
  • the dosage of the test subject is selected from 20 to 500 mg.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 1 to 600 mg, once every 1 to 4 weeks, the compound of formula I or The dosage of pharmaceutically acceptable salts in human subjects is selected from 20 to 500 mg once a day.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, once every 2 weeks, the compound of formula I or a pharmaceutically acceptable salt thereof
  • the administered dose in human subjects is selected from 150 mg once a day.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, once every 2 weeks, intravenous injection, the compound of formula I or its
  • the dosage of the pharmaceutically acceptable salt in human subjects is selected from 150 mg, once a day, orally.
  • the dose of the anti-PD-1 antibody or antigen-binding fragment thereof in a human subject is selected from 200 mg, once every 2 weeks, intravenous injection, the compound of formula I or its
  • the dosage of the pharmaceutically acceptable salt in human subjects is selected from 150 mg, once a day, orally, and the drug is discontinued for three consecutive weeks.
  • the patient prior to the administration of the anti-PD-1 antibody or antigen-binding fragment thereof in combination with the compound of Formula I or a pharmaceutically acceptable salt thereof, the patient is first treated with the compound of Formula I or a pharmaceutically acceptable salt thereof
  • the induction protocol loading
  • the induction protocol refers to the initial stage of treatment with the compound of formula I or a pharmaceutically acceptable salt monotherapy.
  • the period of the induction regimen may be 1 week (or 7 days), 2 weeks (or 14 days), 3 weeks or longer, preferably 3 weeks (or 21 days); the compound of formula I or
  • the dosage of the pharmaceutically acceptable salt in human subjects is selected from 50 mg, 100 mg or 150 mg, and the frequency of administration is selected from once a day, once every two days or once every three days.
  • the administration route in the present disclosure may 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 needs to be formulated into an injectable form before injection .
  • a particularly preferred injectable form of the PD-1 antibody or antigen-binding fragment thereof is an injection solution or a lyophilized powder injection, for example, the injectable form of the PD-1 antibody, which contains the PD-1 antibody, buffer, stabilizer, optionally The ground also contains surfactants.
  • the buffer may 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 , Most preferably polysorbate 20.
  • the pharmaceutically acceptable salts of the drugs described in this disclosure may be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate Salt, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate .
  • the pharmaceutically acceptable salt of the compound of Formula I is selected from isethionates.
  • the isethionate of the compound of formula I is administered in combination with the PD-1 antibody or antigen-binding fragment thereof, thereby enhancing anti-lymphoma activity and improving lymphoma disease Treatment effect.
  • the lymphoma in the present disclosure is non-Hodgkin's lymphoma, preferably relapsed and/or refractory.
  • the recurrence refers to a patient who develops new lesions at the primary site or other sites after sufficient treatment to achieve complete or partial remission.
  • the refractory condition is any one of the following situations: the currently commonly used combination chemotherapy regimen in clinical use, the efficacy evaluation after 2 cycles is disease progression (PD), or the efficacy evaluation after 4 cycles Partial remission (PR) was not reached, or after 6 cycles, the efficacy evaluation was not completed (CR).
  • PD disease progression
  • PR Partial remission
  • the lymphoma patient described in this disclosure has received lymphoma treatment, and the tumor treatment is selected from one or more of chemotherapy, immunotherapy, surgery, or vaccines, preferably self-chemotherapy.
  • the patients with lymphoma described in the present disclosure receive at least 1 line therapy (excluding radiotherapy) after relapse.
  • the lymphoma patient has previously received combined chemotherapy with CHOP, R-CHOP, IMVP-I6, EPOCH, DHAP, or similar regimens.
  • CHOP regimen cyclophosphamide, 750 mg/m 2 , intravenous injection, first day; adriamycin, 50 mg/m 2 , intravenous injection, first day; vincristine, 1.4 mg/m 2 , intravenous injection, first Days; prednisone, 100 mg/m 2 , orally every day for the first to fifth days; the administration period is 21 days.
  • R-CHOP regimen Rituxan, 375 mg/m 2 , intravenous injection, first day * 6 cycles; cyclophosphamide, 750 mg/m 2 , intravenous injection, first day; doxorubicin, 50 mg/m 2 , intravenous injection, The first day; vincristine, 1.4 mg/m 2 , intravenously, the first day; prednisone, 100 mg/m 2 , daily oral, the first to fifth days; the administration period is 21 days.
  • E-CHOP regimen etoposide, 50 mg/m 2 , intravenous injection, day one to four days; vincristine, 1.4 mg/m 2 , intravenous injection, day one to four days; doxorubicin, 50 mg/ m 2 , intravenous injection, day one to four days; prednisone, 60 mg/m 2 , taken orally daily, day one to six days; cyclophosphamide, 750 mg/m 2 , intravenous injection, day six; administration 21 days cycle.
  • DHAP regimen cisplatin, 1000 mg/m 2 , intravenously, on the first day; cytarabine, 2 mg/m 2 , intravenously, twice a day; dexamethasone, 40 mg/d, oral or intravenous, first One day to four days; dosing cycle 21 days.
  • IMVP-I6 regimen ifosfamide, 1000 mg/m 2 , intravenous injection, day one to five days; mesna, 60% of the total amount of ifosfamide, intravenous injection 4h, 8h, day one to five Day, intravenous injection; methotrexate, 30 mg/m 2 , on days 3 and 10, etoposide, 100 mg/m 2 , intravenous injection, first day to three days; dosing cycle 21 days to 28 days .
  • the lymphoma patient has previously received L-asparaginase-based treatment.
  • the lymphoma patient has previously received a regimen containing rituximab or its analogs (single or combined chemotherapy drugs).
  • the combination optionally further includes other components, including but not limited to other drugs for treating lymphoma.
  • the present disclosure also provides a method for treating lymphoma, comprising: administering an effective dose of an anti-PD-1 antibody or antigen-binding fragment thereof and a compound represented by Formula I or a pharmaceutically acceptable salt thereof to a lymphoma patient.
  • the method of lymphoma according to the present disclosure includes administering 1 to 600 mg of an anti-PD-1 antibody or antigen-binding fragment thereof and 20 to 500 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient.
  • the method of lymphoma described in the present disclosure includes administering 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof to a patient once every 2 weeks and 150 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, one Once a day.
  • the method of lymphoma according to the present disclosure includes: before administering an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a compound of Formula I or a pharmaceutically acceptable salt thereof, the patient is given Formula I
  • the indicated compound or its pharmaceutically acceptable salt induces a loading regimen, which refers to the monotherapy of the compound of formula I or its pharmaceutically acceptable salt administered at the initial stage of treatment.
  • the induction regimen period may be 1 week (or 7 days), 2 weeks (or 14 days), 3 weeks or longer, preferably 3 weeks (or 21 days); the compound of formula I Or a pharmaceutically acceptable salt thereof is administered in a human subject at a dosage selected from 50 mg, 100 mg, or 150 mg, and the frequency of administration is selected from once a day, once every two days, or once every three days.
  • the present disclosure also provides a method for reducing adverse reactions caused by an anti-PD-1 antibody or antigen-binding fragment thereof, a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, including the simultaneous administration of an effective dose of anti-PD to patients with lymphoma -1 antibody or antigen-binding fragment thereof and a compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a method for reducing the dose of a PD-1 antibody or antigen-binding fragment thereof, a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, including simultaneous administration of an effective dose of anti-PD-1 to a lymphoma patient Antibodies or antigen-binding fragments thereof and compounds of formula I or pharmaceutically acceptable salts thereof.
  • Another aspect of the present disclosure also provides a pharmaceutical combination comprising a pharmaceutical composition containing the PD-1 antibody or antigen-binding fragment thereof and a pharmaceutical composition containing the compound represented by Formula I or a pharmaceutically acceptable salt thereof.
  • the PD-1 antibody or antigen-binding fragment thereof comprises a light chain as shown in SEQ ID NO: 8, and a heavy chain as shown in SEQ ID NO: 7.
  • the "humanized antibody” in the present disclosure also known as CDR-grafted antibody, refers to grafting the mouse CDR sequence into the framework of human antibody variable region, that is, different types Antibodies produced in the framework sequence of human germline antibodies. It can overcome the strong antibody variable antibody reaction induced by the chimeric antibody due to carrying a large amount of mouse protein components.
  • Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc. People, 1991 Sequences of Proteins of Immunological Interest, found in the 5th edition.
  • the CDR sequence of the PD-1 humanized antibody is selected from SEQ ID NO: 1, 2, 3, 4, 5, 6.
  • the "antigen-binding fragment” in the present disclosure refers to a Fab fragment having an antigen-binding activity, a Fab' fragment, an F(ab') 2 fragment, and an Fv fragment sFv fragment that binds to human PD-1; One or more CDR regions of the antibody selected from SEQ ID NO: 1 to SEQ ID NO: 6.
  • the Fv fragment contains the antibody heavy chain variable region and light chain variable region, but has no constant region, and has the smallest antibody fragment with all antigen binding sites.
  • Fv antibodies also contain a polypeptide linker between the VH and VL domains, and are capable of forming the structure required for antigen binding.
  • Different linkers can also be used to connect the variable regions of two antibodies into a single polypeptide chain, called single chain antibody (single chain antibody) or single chain Fv (sFv).
  • binding with PD-1 in this disclosure refers to being able to interact with human PD-1.
  • antigen binding site in the present disclosure refers to a discrete three-dimensional site on the antigen recognized by the antibody or antigen binding fragment in the present disclosure.
  • immunotherapy in this disclosure refers to the use of the immune system to treat diseases. In this disclosure, it mainly refers to the stimulation and enhancement of the body’s anti-tumor by increasing the immunogenicity of tumor cells and sensitivity to effector cell killing Immune response, and infusion of immune cells and effector molecules into the host body to cooperate with the body's immune system to kill tumors and inhibit tumor growth.
  • “Combination or combination” in this disclosure refers to a mode of administration, which means that at least one dose of the compound of formula I or a pharmaceutically acceptable salt thereof and at least one dose of PD-1 antibody or Antigen-binding fragments, both of which show pharmacological effects.
  • the time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment can be administered simultaneously or sequentially. This period includes treatments in which the compound of formula I or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment are administered by the same route of administration or different routes of administration.
  • the combined administration method of the present invention is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.
  • the "effective amount or effective dose” described in the present disclosure includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition.
  • An effective amount or effective dose also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of the method of administration, and the severity of side effects.
  • the effective amount or effective dose may be the maximum dose or dosage regimen to avoid significant side effects or toxic effects.
  • treatment failure in the present disclosure means that the subject is accompanied by measurable tumor lesions at baseline, and is classified as disease progression (PD) or intolerable according to the RECIST 1.1 efficacy evaluation standard.
  • the overall survival period refers to the period from random period to death from any cause. For subjects who were still alive at the last follow-up, the OS was deleted based on the time of the last follow-up. For the lost follow-up, the OS is calculated as data deletion based on the last confirmed survival time before the follow-up.
  • the OS for data censoring is defined as the time from random grouping to censoring.
  • Objective response rate refers to the proportion of patients whose tumor shrinkage reaches a certain level and remains for a certain period of time, including cases of CR and PR.
  • the tumor response assessment standard (RECIST 1.1 standard) was used to evaluate the objective tumor response. Subjects must be accompanied by measurable tumor lesions at baseline. The evaluation criteria for efficacy are divided into complete response (CR), partial response (PR), stability (SD), and progression (PD) according to the RECIST 1.1 standard.
  • DCR Disease Control Rate
  • CR Complete remission
  • Partial remission The sum of target lesion diameters is reduced by at least 30% from the baseline level.
  • PD Disease progression: the minimum value of the sum of the diameters of all the measured target lesions in the entire experimental study is taken as a reference, and the diameter and the relative increase are at least 20% (if the baseline measurement value is the smallest, the baseline value is used as a reference); otherwise
  • the absolute value of the sum of diameters must be increased by at least 5 mm (the appearance of one or more new lesions is also regarded as disease progression).
  • SD Disease stabilization
  • the isethionate of the compound represented by formula I in the present disclosure can be prepared according to the method described in WO2016124067, and other equipment or reagents used can be obtained commercially.
  • Relapse is defined as a patient who develops a new lesion at the primary site or elsewhere after sufficient treatment to achieve complete or partial remission. After relapse of B-cell lymphoma, at least receive ⁇ 1 line of treatment (excluding radiotherapy).
  • Refractory is defined as any of the following conditions: the currently commonly used combination chemotherapy in clinical use, the efficacy evaluation after 2 cycles is disease progression (PD), or the efficacy evaluation after 4 cycles does not reach partial response (PR), or After 6 cycles, the efficacy evaluation did not reach complete remission (CR)
  • T-NHL Previously received combined chemotherapy such as CHOP, EPOCH or similar regimens.
  • NKTL Previous treatment based on L-asparaginase.
  • B-NHL For CD20-positive B-NHL, it is necessary to receive treatment with rituximab or its analogs (single or combined chemotherapy drugs).
  • Drug A (PD-1, prepared according to the method in patent application WO2017054646A): dose 200 mg, intravenous injection, 30 min per infusion (not less than 20 min, not more than 60 min), once every 2 weeks, every 4 weeks 1 cycle;
  • Drug B (a isethionate tablet of the compound represented by formula I, prepared according to the method disclosed in WO2017133542): 125 mg/tablet or 150 mg, taken orally, once a day, once a time, continuously for 3 weeks Withdrawal for 1 week, 4 weeks as a cycle.

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Abstract

L'invention concerne l'utilisation d'un inhibiteur de CDK4/6 en combinaison avec une immunothérapie dans la préparation d'un médicament pour le traitement d'un lymphome. L'invention concerne notamment l'utilisation d'un composé représenté par La formule I ou d'un sel pharmaceutiquement acceptable de celui-ci en combinaison avec un anticorps anti-PD-1 ou un fragment de liaison à l'antigène de celui-ci dans la préparation d'un médicament pour le traitement d'un lymphome. Le procédé présente une bonne tolérance, une toxicité contrôlable et un effet antitumoral amélioré.
PCT/CN2019/124831 2018-12-13 2019-12-12 Utilisation d'un inhibiteur de cdk4/6 en combinaison avec une immunothérapie dans la préparation d'un médicament pour le traitement d'un lymphome WO2020119757A1 (fr)

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WO2023173170A1 (fr) * 2022-03-17 2023-09-21 Aucentra Therapeutics Pty Ltd Utilisation de dérivés de 4-thiazol-n-(pyridin-2-yl)pyrimidin-2-amine dans des polythérapies pour le cancer
WO2023173172A1 (fr) * 2022-03-17 2023-09-21 Aucentra Therapeutics Pty Ltd Utilisation de 5-(2-((5-(4-(diméthylamino)pipéridin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-n,4-diméthylthiazol-2-amine dans des polythérapies pour le cancer

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023173170A1 (fr) * 2022-03-17 2023-09-21 Aucentra Therapeutics Pty Ltd Utilisation de dérivés de 4-thiazol-n-(pyridin-2-yl)pyrimidin-2-amine dans des polythérapies pour le cancer
WO2023173172A1 (fr) * 2022-03-17 2023-09-21 Aucentra Therapeutics Pty Ltd Utilisation de 5-(2-((5-(4-(diméthylamino)pipéridin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-n,4-diméthylthiazol-2-amine dans des polythérapies pour le cancer

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