WO2021129616A1 - Pharmaceutical combination of anti-pd-1 antibody and histone deaceylase inhibitor, use thereof, and usage method therefor - Google Patents

Pharmaceutical combination of anti-pd-1 antibody and histone deaceylase inhibitor, use thereof, and usage method therefor Download PDF

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WO2021129616A1
WO2021129616A1 PCT/CN2020/138343 CN2020138343W WO2021129616A1 WO 2021129616 A1 WO2021129616 A1 WO 2021129616A1 CN 2020138343 W CN2020138343 W CN 2020138343W WO 2021129616 A1 WO2021129616 A1 WO 2021129616A1
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carbon atoms
group
antibody
cancer
hdac inhibitor
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PCT/CN2020/138343
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French (fr)
Chinese (zh)
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黄慧强
高岩
唐晓义
鲁先平
付鑫
俞德超
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信达生物制药(苏州)有限公司
深圳微芯生物科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical combination of an anti-PD-1 antibody or an antigen binding fragment thereof and a histone deacetylase inhibitor, which is used for the prevention or treatment of cancer, especially extranodal NK/T cell lymphoma.
  • the present invention also relates to the use of the drug combination in the preparation of a drug for preventing or treating cancer, especially extranodal NK/T cell lymphoma, and a method for applying the drug combination to prevent or treat cancer, especially extranodal NK/T cell lymphoma .
  • Extranodal NK/T-cell lymphoma, nasal type is a rare subtype of non-Hodgkin’s lymphoma, in all non-Hodgkin’s lymphoma subtypes in my country Among them, it accounts for up to 6%. It is highly invasive, and the prognosis of patients with newly-treated late stage and refractory relapsed patients is poor. ENKTL mainly occurs in the nasal cavity, followed by the skin and gastrointestinal tract. The main pathological manifestations of this disease are vascular invasion and tissue destruction. Specific markers and specific genetic changes on the surface of ENKTL cells can also help diagnose the disease.
  • ENKTL is closely related to Epstein-Barr virus (EBV) infection, and the level of EBV-DNA has important significance for its prognosis and auxiliary diagnosis.
  • EBV Epstein-Barr virus
  • the treatment of ENKTL lacks prospective, randomized, controlled clinical research, and there is no standard treatment method.
  • Its main treatment methods include radiotherapy, chemotherapy and hematopoietic stem cell transplantation.
  • radiotherapy ⁇ L-asparaginase-based chemotherapy combined treatment mode is adopted, and the 5-year overall survival (OS) of the patient can exceed 80%.
  • NCCN National Comprehensive Cancer Network
  • the ORR and CRR were 81% and 66%, respectively, the 5-year OS rate was 50%, and the 4-year progression-free survival (PFS) rate was 64%; 57 patients had grade 3/4 neutropenia , 36 patients had grade 3/4 thrombocytopenia, and 15 patients had nephrotoxicity. Among them, 5 patients died of treatment-related sepsis; 1 patient died of acute renal failure caused by high-dose methotrexate [2].
  • the GELA and GOELAMS collaborative group reported the results of AspaMetDex (L-asparaginase, high-dose methotrexate, and dexamethasone) in the treatment of 19 patients with refractory and relapsed ENKTL.
  • the ORR and CRR were 78% and 61%, respectively.
  • the median OS was 1 year, and the median duration of response was 12 months.
  • the main adverse events were hepatitis, cytopenias and allergies, but there were still 5 patients with high-dose methotrexate-related transient renal insufficiency, and grade 3/4 agranular fever [3].
  • the P-Gemox regimen is safer than SMILE and AspaMetDex regimens, and the survival of newly-treated stage I/II patients is satisfactory, but the survival of newly-treated stage III/IV and refractory relapsed patients is still poor [4].
  • domestic and foreign researchers have tried to further improve the prognosis of ENKTL in the late stage and refractory relapsed ENKTL through different cytotoxic drug combinations, but they have not achieved a breakthrough, and traditional cytotoxic drug treatment has encountered a bottleneck in curative effect. Therefore, how to improve the survival of newly treated stage III/IV and refractory relapsed patients is the direction of the next treatment.
  • Histone deacytelase is involved in the biological processes of a variety of tumors. When tumors occur, their activity is significantly increased, which makes the histones in the nucleosomes in a state of hypoacetylation, leading to tumor suppressor genes. Transcription activity is inhibited, and the abnormal expression of a variety of genes that regulate cell proliferation and cell cycle causes malignant transformation of cells [5].
  • HDAC inhibitors are a new type of small-molecule targeted drugs that play an anti-tumor effect by regulating epigenetics. By blocking the deacetylation of HDAC, DNA maintains transcriptional activity and causes changes in multiple downstream signaling pathways. , Can cause tumor cell apoptosis, induce cell differentiation and inhibit angiogenesis [5-7].
  • Chidamide is a subtype-selective oral HDAC inhibitor. Its main target is type I and type II HDAC. It has been approved for the treatment of refractory and relapsed peripheral T-cell lymphoma in my country. In the pivotal phase II clinical trial (registered clinical trial), a total of 83 patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) were enrolled, and all received 30 mg/time, twice/week of chidamide Treatment until the disease progresses or untolerable adverse reactions occur.
  • PTCL peripheral T-cell lymphoma
  • ORR The main efficacy index is ORR.
  • the ORR of chidamide was only 25%, and the CRR was 6% [8].
  • DCR disease control rate
  • Chidamide may be an effective drug for potential treatment of ENKTL, its efficacy still has great limitations.
  • Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis is a powerful signaling pathway to inhibit immune activation, and it is also a tumor to achieve immune escape One of the important mechanisms [10,11].
  • Tumor infiltrating lymphocytes highly express PD-1. These PD-1 combine with PD-L1 on the surface of tumor cells or immune cells to inhibit the initial activation of T cells, and inhibit the production and function of effector T cells (including cytokine production and Cytotoxicity) [12,13].
  • Cinda Biopharmaceuticals (Suzhou) Co., Ltd. a well-known national medical center in the United Nations, carried out a multi-center, single-arm Phase II clinical study (ORIENT-4) of Sintilimab as a single agent in refractory and relapsed ENKTL in 2017. , The patient received Sintilizumab (200mg IV Q3W) monotherapy until the disease progressed, died, the toxicity was intolerable or the study was withdrawn. In the study, PET-CT and enhanced CT/MRI were used to evaluate tumor response. The main study endpoint is ORR based on the LUGANO 2014 efficacy evaluation criteria for malignant lymphoma.
  • AE adverse events
  • the present invention provides a pharmaceutical combination comprising a PD-1 antibody or an antigen-binding fragment thereof and an HDAC inhibitor,
  • the anti-PD-1 antibody contains 6 CDRs, and LCDR1, LCDR2, and LCDR3 are composed of the amino acid sequences RASQGISSWLA (SEQ ID NO: 9), SAASSLQS (SEQ ID NO: 10) and QQANHLPFT (SEQ ID NO: 11), respectively, and Wherein HCDR1, HCDR2 and HCDR3 are respectively composed of amino acid sequences KASGGTFSSYAIS (SEQ ID NO: 2), LIIPMFDTAGYAQKFQG (SEQ ID NO: 5) and ARAEHSSTGTFDY (SEQ ID NO: 8); or
  • the anti-PD-1 antibody is selected from Sintilimab, Pembrolizumab, Nivolumab, Teriplizumab and Carrelizumab;
  • HDAC inhibitor is selected from the following compounds of formula I or pharmaceutically acceptable salts thereof:
  • A is a benzene ring or heterocyclic ring, which can contain 1 to 4 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, 1 to 4 Carbon atom alkoxy group, 1 to 4 carbon atom aminoalkyl group, 1 to 4 carbon atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acyl group, 1 to 4 A thioalkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a perfluoroalkoxy group of 1 to 4 carbon atoms, a carboxyl group of 1 to 4 carbon atoms, and a perfluoroalkyl group of 1 to 4 carbon atoms Alkoxycarbonyl, phenyl or heterocyclic substituents;
  • B is a benzene ring or heterocyclic ring, which can contain 1 to 3 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, and 1 to 4 carbon atoms Alkoxy, aminoalkyl of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, acyl of 2 to 4 carbon atoms, acylamino of 2 to 4 carbon atoms, 1 to 4 carbons Atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 carbon atom perfluoroalkoxy group, 1 to 4 carbon atom carboxyl group, 1 to 4 carbon atom alkoxy group Carbonyl, phenyl or heterocyclic substituents:
  • Z is a covalent bond, an alkylene of 1 to 4 carbon atoms, or a linear structure or a ring containing -O-, -S-, -NH, -CO-, -CS-, -SO-, -SO 2- Structure or a combination of linear structure and cyclic structure;
  • Y is a linear structure, a cyclic structure or a combination of a linear structure and a cyclic structure containing -CO-, -CS-, -SO-, -SO 2 -, wherein the center point (W1) of ring A and the center of ring B
  • the distance between the point (W2) and the O atom or S atom (W3) contained in Y as the hydrogen bond acceptor satisfies the following conditions: The better distance between them is
  • R 1 and R 2 are respectively hydrogen or an alkyl group containing 1 to 4 carbon atoms, and R 1 and R 2 can also form a covalent bond together;
  • R 3 is hydrogen or an alkyl group containing 1 to 4 carbon atoms
  • R 4 is hydrogen, halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 Alkylamino of to 4 carbon atoms, acyl of 2 to 4 carbon atoms, amido of 2 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, perfluoroalkane of 1 to 4 carbon atoms Group, perfluoroalkoxy group of 1 to 4 carbon atoms, carboxyl group of 1 to 4 carbon atoms, alkoxycarbonyl group of 1 to 4 carbon atoms;
  • One of X 1 , X 2 , X 3 , and X 4 is halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, 1 to Aminoalkyl groups of 4 carbon atoms, alkylamino groups of 1 to 4 carbon atoms, acyl groups of 2 to 4 carbon atoms, acylamino groups of 2 to 4 carbon atoms, thioalkyl groups of 1 to 4 carbon atoms, Perfluoroalkyl groups of 1 to 4 carbon atoms, perfluoroalkoxy groups of 1 to 4 carbon atoms, carboxyl groups of 1 to 4 carbon atoms, alkoxycarbonyl groups of 1 to 4 carbon atoms; the rest are hydrogen , Halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to
  • HDAC inhibitor is selected from Vorinostat, Romidepsin, Belinostat, Panobinostat, Chidamide, Entinol Special (Entinostat) and Mocetinostat (MGCD0103).
  • the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 13 or has at least 90% of the sequence of SEQ ID NO: 13 , 95%, 98%, or 99% identical sequences, and/or the light chain variable region comprising the sequence of SEQ ID NO: 15 or a sequence having at least 90%, 95%, 98% or 99% identity therewith;
  • the anti-PD-1 antibody comprises SEQ ID NO: 17 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and/or SEQ ID NO: 22 or has A light chain sequence that is at least 90%, 95%, 98%, or 99% identical.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is selected from Sintilimab, Pembrolizumab, Nivolumab, and Trepre Lizumab and Carrelizumab; preferably, the anti-PD-1 antibody is Sintilizumab.
  • the HDAC inhibitor is selected from the group consisting of Vorinostat, Romidepsin, Belinostat, Panobinostat, and Panobinostat. Chidamide, Entinostat and Mocetinostat (MGCD0103) or a pharmaceutically acceptable salt thereof, more preferably, the HDAC inhibitor is Chidamide.
  • the drug combination is used to prevent or treat cancer, preferably non-Hodgkin's lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably late or refractory extranodal NK/T Cell lymphoma.
  • the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is in the form of a dosage unit of 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, more preferably 200 mg, Preferably it is a parenteral, more preferably an intravenous administration form; and/or
  • the HDAC inhibitor is in the form of a dosage unit of 10 to 50 mg, preferably 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, preferably in a dosage form for oral administration.
  • the single administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from 100-300 mg, such as 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, preferably once every two to four weeks, preferably It is administered by intravenous infusion.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is intravenously infused once every three weeks, and the single infusion dose is 200 mg.
  • the single administration dose of the HDAC inhibitor is selected from 10mg-50mg, preferably 1-4 times per week, preferably by oral administration;
  • the oral dose of the HDAC inhibitor is selected from 20 mg, 25 mg and 30 mg.
  • the HDAC inhibitor is taken orally twice a week, and each oral dose is 30 mg.
  • the anti-PD-1 antibody or antigen-binding fragment thereof and the HDAC inhibitor are administered separately, simultaneously or sequentially.
  • the anti-PD-1 antibody or its binding fragment can be continuously administered for treatment.
  • the present invention provides the use of the drug combination of the anti-PD-1 antibody or its antigen-binding fragment and HDAC inhibitor as defined in the first aspect in the preparation of a drug for the prevention or treatment of cancer, and the cancer is preferably selected From non-Hodgkin's lymphoma, extranodal NK/T cell lymphoma is more preferred, and extranodal NK/T cell lymphoma that is advanced or refractory to relapse is most preferred.
  • the present invention provides a method for preventing or treating cancer, the method comprising administering to a patient in need a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof defined in the first aspect and HDAC inhibition
  • the cancer is preferably selected from non-Hodgkin’s lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably advanced or refractory and relapsed extranodal NK/T cell lymphoma.
  • the present invention also provides a single drug dosage unit, which includes a therapeutically effective amount of the drug combination of the anti-PD-1 antibody or antigen-binding fragment thereof as defined in the first aspect and an HDAC inhibitor.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof as defined in the first aspect and a pharmaceutical combination of an HDAC inhibitor and pharmaceutically acceptable excipients Agent.
  • the present invention also provides a kit of medicines comprising a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof defined in the first aspect and a drug combination of an HDAC inhibitor.
  • the present invention also provides the use of the above-mentioned single drug dosage unit, pharmaceutical composition or kit in the preparation of a drug for preventing or treating cancer.
  • the cancer is preferably selected from non-Hodgkin’s lymphoma, more preferably nodal. Extranodal NK/T cell lymphoma, most preferably advanced or refractory and relapsed extranodal NK/T cell lymphoma.
  • the term “comprising” or “including” means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps.
  • the term “comprises” or “includes” when used, unless otherwise specified, it also encompasses the situation consisting of the stated elements, integers or steps.
  • an antibody variable region that "comprises” a specific sequence when referring to an antibody variable region that "comprises” a specific sequence, it is also intended to encompass the antibody variable region composed of the specific sequence.
  • antibody refers to a polypeptide comprising at least a light chain or heavy chain immunoglobulin variable region, which specifically recognizes and binds to an antigen.
  • the term encompasses various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, single-chain or multi-chain antibodies, monospecific or multispecific antibodies (such as bispecific antibodies), fully human antibodies, or Chimeric antibodies or humanized antibodies, full-length antibodies, and antibody fragments, as long as they exhibit the desired antigen-binding activity.
  • antigen-binding fragment of an antibody (which can be used interchangeably with “antibody fragment” and “antigen-binding portion” herein) refers to a molecule that is not an intact antibody, which includes the intact antibody used to bind the intact antibody. Part of the antigen. As understood by those skilled in the art, the antigen-binding portion of an antibody usually contains amino acid residues from the "complementarity determining region" or "CDR".
  • the antigen-binding fragment can be prepared by recombinant DNA technology, or by enzymatic or chemical cleavage of the intact antibody.
  • Antigen-binding fragments include but are not limited to Fab, scFab, Fab', F(ab')2, Fab'-SH, Fv, single-chain Fv, double-chain antibody (diabody), triabody (triabody), four-chain antibody ( tetrabody), minibody (minibody), single domain antibody (sdAb).
  • prevention includes the suppression or delay of the occurrence or frequency of the occurrence or occurrence of a disease or disorder or its symptoms, and it generally refers to the administration of drugs before the occurrence or occurrence of the symptoms or symptoms, especially before the occurrence of the symptoms or symptoms in individuals at risk.
  • treatment refers to the slowing, prevention or reversal of the progression of a subject's cancer (for example, extranodal NK/T cell lymphoma) as evidenced by the reduction or elimination of clinical or diagnostic symptoms of the disease. Treatment may include, for example, reducing the severity of symptoms, the number of symptoms, or the frequency of recurrence, for example, tumor growth inhibition, tumor growth arrest, or regression of existing tumors.
  • single drug dosage unit refers to a single drug dosage form administered to a patient at the time of the dosing schedule, including injections, tablets, and freeze-dried powders.
  • drug combination refers to a non-fixed combination product or a fixed combination product, such as a kit.
  • non-fixed combination means that the active ingredients (for example, (i) anti-PD-1 antibodies or antigen-binding fragments thereof, and (ii) HDAC inhibitors as separate entities are simultaneously, without a specific time limit, or in the same or different
  • the two agents are administered to the patient sequentially at intervals of time, wherein such administration provides prophylactic or therapeutically effective levels of the two active agents in the patient.
  • the anti-PD-1 antibody molecule and HDAC used in the drug combination The two molecules of the inhibitor are administered at a level not exceeding the level when they are used alone.
  • the term "fixed combination" means that the two active agents are administered to the patient simultaneously in the form of a single entity.
  • the dosage and/or of the two active agents are preferred.
  • the time interval is selected so that the combined use of each part can produce an effect greater than that achieved by using any single component in the treatment of diseases or conditions.
  • Each component can be in the form of a separate preparation, and the preparation form can be the same or different.
  • the term “therapeutically effective amount” as used herein refers to the combined effect that triggers the desired biological or medical response when administered in combination, that is, one or more cancers that are inhibited or improved include extranodal NK/T cell lymph
  • the combined dose for the clinical or diagnostic symptoms of tumors when referring to combination therapy, the term “therapeutically effective amount” as used herein refers to antibodies that produce a therapeutically effective and/or synergistic combination when administered together (sequentially or simultaneously) on the same day or on different days in the treatment cycle. Dosage and dosage of chemotherapy drugs.
  • the amount of individual antibodies and/or chemicals may or may not be therapeutically effective.
  • each treatment cycle refers to a specific period of time expressed in days or weeks that repeats on a regular schedule.
  • each treatment cycle is 15 to 30 days, such as 15 to 24 days, and preferably each treatment cycle is three weeks (ie, 21 days). In one embodiment, one treatment cycle is four weeks (ie, 28 days).
  • administration refers to the physical introduction of each active ingredient of the pharmaceutical composition of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art.
  • the route of administration of each active ingredient in the pharmaceutical combination of the present invention includes oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other parenteral routes of administration .
  • parenteral administration refers to methods of administration other than gastrointestinal and topical administration, usually via intravenous, and without limitation includes intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrasaccular , Intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injection and infusion, and in vivo electroporation.
  • each active ingredient in the pharmaceutical combination of the present invention can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, etc.
  • dose is the amount of a drug that induces a therapeutic effect. Unless otherwise stated, the dosage is related to the amount of the free form of the drug. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased in proportion to the amount of the drug in the free form. For example, the dosage will be stated on the product packaging or product information sheet.
  • HADC inhibitors including compounds of formula (I) formed with inorganic acids, such as hydrochloride, hydrogen Bromate, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.
  • acid addition salts formed by HADC inhibitors including compounds of formula (I)
  • organic acids such as methyl Acid salt, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxy Ethyl sulfonate, benzoate, salicylate, stearate, and salt formed with alkane dicarboxylic acid of the formula HOOC-(CH 2 ) n -COOH (wherein n is 0-4), etc.
  • “Pharmaceutically acceptable salts” also include base
  • pharmaceutically acceptable refers to those compounds and materials that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and commensurate with a reasonable benefit/risk ratio , Composition and/or dosage form.
  • AE adverse event
  • an adverse event may be related to the activation of the immune system in response to treatment or the expansion of immune system cells (e.g., T cells) in response to treatment.
  • Medical treatments can have one or more related AEs, and each AE can have the same or different levels of severity.
  • anti-PD-1 antibody used herein includes the anti-PD-1 antibodies described in WO2017025016, CN108473977B and WO2017133540, the entire contents of which are incorporated herein by reference.
  • the anti-PD-1 antibody is preferably the anti-PD-1 antibody D-S228P IgG4 disclosed in WO2017025016A1, which is also referred to as sintilimab in this application.
  • the numbering of the sequence used herein directly corresponds to the numbering in WO2017025016A1, and has not been renumbered.
  • HDAC inhibitor as used herein includes the compound described in Chinese application 03139760.3 (publication number CN1513839A), the entire content of which is incorporated herein by reference.
  • the HDAC inhibitor is preferably Chidamide
  • the present invention provides the aforementioned pharmaceutical combination of the present invention for preventing and/or treating the severity of at least one symptom or indication of cancer in an individual or inhibiting the growth of cancer cells.
  • the present invention provides a method of preventing or treating cancer, which comprises administering an effective amount of the pharmaceutical combination of the present invention to an individual in need.
  • the effective amount includes a preventive effective amount and a therapeutically effective amount.
  • the present invention provides the use of the aforementioned pharmaceutical combination of the present invention in the preparation of drugs for the prevention or treatment of cancer.
  • the cancer of the present invention includes solid tumors and hematological malignancies, such as non-Hodgkin’s lymphoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, lung cancer, such as non-small cell lung cancer, thymic cancer, kidney cancer, melanoma Tumors, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors, such as stomach cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma, brain cancer, and bone cancer.
  • non-Hodgkin’s lymphoma hepatocellular carcinoma, ovarian cancer
  • lung cancer such as non-small cell lung cancer, thymic cancer, kidney cancer, melanoma Tumors, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors, such as stomach cancer, gastric adenocarcinoma, gastro
  • the cancer is preferably advanced cancer, refractory cancer and/or cancer resistant to chemotherapy, more preferably advanced solid tumor, unresectable or metastatic advanced solid tumor (confirmed by histology or cytology).
  • the cancer is preferably extranodal NK/T cell lymphoma, bowel cancer (including colorectal cancer), lung cancer (including non-small cell lung cancer).
  • the cancer is preferably late-stage recurrent or metastatic cancer (advanced malignant tumor), preferably late-stage or refractory extranodal NK/T cell lymphoma.
  • the drug combination of the present invention can be administered to individuals who have been treated with one or more previous therapies but subsequently relapsed or metastasized.
  • the drug combination of the present invention is administered to display one or more cancer-related biomarkers [e.g., programmed death ligand 1 (PD-L1), CA125, CA19-9, prostate specific antigen (PSA), lactate Individuals with elevated levels of hydrogenase, KIT, carcinoembryonic antigen, vascular endothelial growth factor (VEGF)].
  • PD-L1 programmed death ligand 1
  • PSA prostate specific antigen
  • lactate Individuals with elevated levels of hydrogenase KIT
  • carcinoembryonic antigen vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • the anti-PD-1 antibody in the pharmaceutical combination of the present invention can be administered to an individual in need in one or more doses, where in the case of administering multiple doses, after the previous dose 1, 2, 3, 4, 5, The next dose is administered at 6, 7, 8, 9 or 10 weeks.
  • a dose of anti-PD-1 antibody may be selected from 0.1-10 mg/kg of the individual's body weight (for example, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg).
  • each dose contains 50-500 mg of anti-PD-1 antibody, such as 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of anti-PD-1 antibody.
  • the HDAC inhibitor (for example, chidamide or its pharmaceutically acceptable salt) in the pharmaceutical combination of the present invention is administered approximately once a day, once every two days, once every three days, once every four days, twice a week, and weekly One time, once every two weeks for continuous administration, or two times a week for three weeks and one week off every three weeks, two times a week for two weeks and two weeks off for one week.
  • the dosage of the HDAC inhibitor is 10 to 50 mg/time, for example, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 45 mg/time, or 50 mg/time.
  • the pharmaceutical combination of the present invention can be administered for at least one cycle, for example 2-12 or more treatment cycles, preferably wherein the one cycle is administered 1-2 doses of anti-PD-1 antibody, and at least The HDAC inhibitor is administered on days 1 to 10 of each cycle, preferably on days 1 to 14 or on days 1 to 21, preferably twice a week, and preferably at least 15 per cycle To 30 days, more preferably 21 days or 28 days.
  • the HDAC inhibitor in the pharmaceutical combination of the present invention is at a dose of 10 to 50 mg/time, for example, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 45 mg
  • a dose of 50 mg/time or 50 mg/time is taken orally twice a week, continuously administered for 2, 3 or 4 weeks and stopped for 1 week or continuously administered during the use cycle, and the anti-PD-1 antibody is administered intravenously at 100-300 mg, such as 200 mg, Once every 3, 4, or 5 weeks, every 3, 4, or 5 weeks is a cycle.
  • the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally at a dose of 20 mg twice a week for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks.
  • the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally at a dose of 25 mg twice a week for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks.
  • the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally twice a week at a dose of 30 mg for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks, once every 3 weeks.
  • the anti-PD-1 antibody in the pharmaceutical combination of the present invention may be administered before, at the same time, or after the start of administration of the HDAC inhibitor.
  • the anti-PD-1 antibody may be greater than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours before the start of the HDAC inhibitor. , About 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes, about 15 minutes or Approximately 10 minutes to apply.
  • the anti-PD-1 antibody When administered after the HDAC inhibitor starts to be administered, the anti-PD-1 antibody may be about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 minutes after the start of administration of the HDAC inhibitor. Hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours. Administration "simultaneously" with the start of administration of the HDAC inhibitor means that the anti-PD-1 antibody is administered to the individual within less than 10 minutes (before, after, or simultaneously) of the start of administration of the HDAC inhibitor.
  • the anti-PD-1 antibody in the pharmaceutical combination of the present invention is administered after the HDAC inhibitor starts to be administered, for example, the anti-PD-1 antibody is administered about 1 hour, about 3 hours, about 6 hours after the start of the HDAC inhibitor administration. About 12 hours, about 15 hours administration.
  • the anti-PD-1 antibody in the pharmaceutical combination of the present invention is an injection, and if it is administered by intravenous infusion, the administration time may be about 15-60 minutes.
  • the administration of at least one cycle of the drug combination of the present invention results in an increased, preferably synergistically increased, ORR of the patient compared to a patient administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy ( Objective response rate), CRR (complete response rate), progression-free survival (PFS) or overall survival (OS).
  • the administration of at least one cycle of the drug combination of the present invention results in an increase in the patient's PFS by at least about 1 month, compared to a patient administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy.
  • the administration of at least one cycle of the drug combination of the present invention results in an increase in the patient's OS by at least about 1 month, compared to patients who are administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy.
  • the drug combination of the present invention results in an improved, preferably synergistically improved, therapeutic effect on cancer.
  • the drug combination of the present invention results in a patient's ORR (objective response rate) increased by about 10%, about 20%, About 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150 %, about 200%, or about 300%.
  • the drug combination of the present invention results in a patient's CRR (complete remission rate) increased by about 10%, about 20%, About 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150 %, about 200%, or about 300%.
  • the drug combination of the present invention results in an increase, preferably a synergistic increase in the inhibitory effect on tumor growth.
  • the drug combination of the present invention results in tumor growth being inhibited by at least about 10%, about 20%, about 30%, compared with the administration of anti-PD-1 antibody monotherapy or the administration of HDAC inhibitor monotherapy.
  • administration of the drug combination of the invention results in increased tumor regression, tumor shrinkage and/or disappearance.
  • the drug combination of the present invention prevents tumor recurrence and/or increases the duration of survival in an individual compared with an untreated individual or with a monotherapy with an anti-PD-1 antibody or a monotherapy with an HDAC inhibitor For example, increase the duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more Within 36 months, or more than 48 months.
  • the drug combination of the present invention can increase progression-free survival or overall survival.
  • administration of the drug combination of the invention to an individual suffering from cancer results in the complete disappearance of the tumor ("complete response"). In some embodiments, administration of the drug combination of the invention to an individual suffering from cancer results in a reduction in tumor cells or tumor size by at least 30% or more (“partial response").
  • the tumor reduction can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computer tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetics analysis.
  • the pharmaceutical combination of the present invention can reduce adverse events caused by the administration of anti-PD-1 antibodies and/or HDAC inhibitors, such as hematological toxic reactions, non-hematological toxic reactions or other toxic reactions, such as pneumonia, Diarrhea, enterocolitis, renal insufficiency, skin rash, hepatitis, endocrine disease and peripheral or central neuritis, liver function abnormalities, etc.
  • hematological toxic reactions such as pneumonia, Diarrhea, enterocolitis, renal insufficiency, skin rash, hepatitis, endocrine disease and peripheral or central neuritis, liver function abnormalities, etc.
  • Another object of the present invention is to provide a kit of medicines comprising the drug combination of the present invention, preferably the kit is in the form of a single drug dosage unit.
  • kit of the present invention contains in the same package:
  • -A second container containing a pharmaceutical composition for oral administration, said pharmaceutical composition containing the HDAC inhibitor described above.
  • Sintilimab Injection Specification 10ml:100mg, Xinda Biopharmaceutical (Suzhou) Co., Ltd.
  • the age at the time of signing the ICF is ⁇ 18 years old and ⁇ 75 years old.
  • the ECOG score is 0 to 1.
  • Expected survival is greater than 3 months.
  • Coagulation function International Normalized Ratio (INR) ⁇ 1.5 times ULN; Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) ⁇ 1.5 times ULN ( Unless the subject is receiving anticoagulant therapy, and PT and APTT are within the expected range of anticoagulant therapy at the time of screening).
  • INR International Normalized Ratio
  • PT Prothrombin Time
  • APTT Activated Partial Thromboplastin Time
  • Thyroid-stimulating hormone Thyroid-stimulating hormone (TSH) or free thyroxine (FT4) or free triiodothyronine (FT3) are all within ⁇ 10% of the normal value.
  • Subjects must pass pulmonary function tests (PFT) to confirm that forced expiratory volume (FEV1)/forced vital capacity (FVC)> 60% in the first second, unless it is caused by a large mediastinal mass caused by Hodgkin’s lymphoma This standard cannot be met; the diffusion of carbon monoxide (DLCO), FEV1 and FVC are more than 50% above the predicted value; all PFT results must be obtained within 4 weeks before the first administration of Sintilimab.
  • PFT pulmonary function tests
  • Subjects who have received anti-tumor therapy in the past should return to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grade score ⁇ level 1 or baseline level after the toxicity of the previous treatment has returned to the evaluation criteria for common adverse events (CTCAE) Entry into the group; Grade 2 toxicity (such as thrombocytopenia, anemia, neurotoxicity, alopecia, and hearing loss) caused by previous anti-tumor therapy that is irreversible and is not expected to worsen during the study treatment period, with the consent of the investigator, you can Join the group.
  • CCAE Common Terminology Criteria for Adverse Events
  • CCAE common adverse events
  • WOBCP Women of Childbearing Potential
  • phase Ib/II clinical study This study is a phase Ib/II clinical study, divided into two parts.
  • phase Ib subjects received chidamide and sintilizumab, and the dose of chidamide was explored in this phase.
  • the initial dose of chidamide 3 dose groups (20mg, 25mg, 30mg) are set up, with 3-6 subjects in each group. Starting dose: 20 mg/time, 2 times/week, for continuous oral administration. If DLT (Dose-Limiting Toxicities) does not appear, follow the established dose escalation plan to continue the next dose level test. If there is 1 case of DLT, add 3 subjects to this dose level. When no new DLT appears, continue to the next dose level test. If there are ⁇ 2 cases of DLT, the previous dose level of this dose level is defined as MTD (Maximum Tolerated Dose).
  • Sintilimab dose 200mg/time (fixed dose), 1 time/3 weeks, intravenous infusion.
  • the administration method of the phase II study is RP2D dose (Recommended Phase II Dose, the recommended phase II clinical study dose), 2 times a week, continuous oral; Sintilizumab dose: 200 mg/time (fixed Dose), 1 time/3 weeks, intravenous infusion.
  • grade IV blood Toxicity including but not limited to the following: febrile neutropenia (ANC ⁇ 1.0 ⁇ 10 9 /L with a single body temperature >38.3°C, or continuous body temperature ⁇ 38°C for more than 1h); non-hematology of grade III or above Toxicity (excluding hair loss and electrolyte imbalance that can be corrected within 3 days); despite symptomatic treatment, nausea, vomiting or diarrhea of grade ⁇ III still occurs.
  • febrile neutropenia ANC ⁇ 1.0 ⁇ 10 9 /L with a single body temperature >38.3°C, or continuous body temperature ⁇ 38°C for more than 1h
  • non-hematology of grade III or above Toxicity excluding hair loss and electrolyte imbalance that can be corrected within 3 days
  • nausea, vomiting or diarrhea of grade ⁇ III still occurs.
  • the Sun Yat-sen University Cancer Center enrolled a total of 9 subjects.
  • the 9 subjects were divided into 3 groups, and 3 patients in each group were subjected to a study of chidamide dose climbing.
  • the three dosage levels are 20mg, 25mg, 30mg, biw (twice a week). Except for subjects 0106 and 0107 who failed to complete 6 courses of treatment due to disease progression (received 5 and 3 courses of treatment respectively) among the 9 subjects, the remaining 7 subjects all completed more than 6 courses of combined treatment. Subjects in the three dose groups did not have MTD or DLT, so the recommended dose of RP2D is 30 mg biw.
  • stage Ib 9 subjects in stage Ib can be evaluated for efficacy, of which 7 subjects (0101, 0102, 0103, 0104, 0105, 0108, 0109) obtained CR (Complete Response), and 1 subject ( 0106) After obtaining PR (Partial Response), it progressed again, and 1 subject (0107) had the effect of PD (Progressive Disease, disease progression).
  • ORR Objective Response Rate, objective response rate
  • CRR Complete Response Rate, complete response rate
  • the phase II study adopted the simon two-phase optimal design method.
  • 7 patients were enrolled. If only 4 or fewer patients are effective, the trial will be terminated. Otherwise, enter the second phase, and 21 patients will be enrolled in the second phase, that is, a total of 28 patients will be enrolled in the phase II study.
  • a Phase II clinical study was conducted. As of November 4, 2019, 11 subjects have been enrolled in the Phase II study. Subject 0117-0120 received only one course of treatment, and the efficacy has not been evaluated yet. Among them, 5 of the 0110-0116 subjects can be evaluated for efficacy, 2 cases of CR, 2 cases of SD (stable disease), and 1 case of PD.
  • NK/T cell lymphoma recurred in the right lung more than 2 years after radiotherapy and chemotherapy.
  • NK/T cell lymphoma complicated with hematopoietic syndrome, recurrence after chemotherapy and maintenance of anti-PD-1 antibody injection.
  • the patient was diagnosed with NK/T-cell lymphoma with hemophagocytic syndrome in March 2018. After treatment with HLH2004 regimen, the bloodthirsty phenomenon was corrected, and then the P-Gemox regimen was given 3 cycles of chemotherapy, and the curative effect was PR. From 2018.6-2018.8, Pembrolizumab was treated for 4 courses, and the effect was CR. Later, the treatment was stopped due to economic reasons. In April 2019, the patient went to the doctor due to "continuous high fever". On April 28, 2019, PET/CT in our hospital showed: right supraclavicular, bilateral subclavian, mediastinum, right hilum, hepatic hilum, portal space, right kidney posterior Multiple enlarged lymph nodes.
  • HDACIs Histone deacetylase inhibitors

Abstract

The present invention relates to a pharmaceutical combination of an anti-PD-1 antibody targeting programmed death protein-1 (PD-1) and a HDAC inhibitor, which combination is used for treating cancers, especially extranodal NK/T cell lymphoma. The present invention also relates to a use of and method for using the combination to prevent or treat cancers, especially extranodal NK/T cell lymphoma.

Description

抗PD-1抗体和组蛋白去乙酰化酶抑制剂的药物组合及其用途、使用方法Drug combination of anti-PD-1 antibody and histone deacetylase inhibitor and its use and use method 技术领域Technical field
本发明涉及抗PD-1抗体或其抗原结合片段和组蛋白去乙酰化酶抑制剂的药物组合，其用于预防或治疗癌症尤其是结外NK/T细胞淋巴瘤。本发明还涉及所述药物组合在制备预防或治疗癌症尤其结外NK/T细胞淋巴瘤的药物中的用途，以及应用所述药物组合预防或治疗癌症尤其结外NK/T细胞淋巴瘤的方法。The present invention relates to a pharmaceutical combination of an anti-PD-1 antibody or an antigen binding fragment thereof and a histone deacetylase inhibitor, which is used for the prevention or treatment of cancer, especially extranodal NK/T cell lymphoma. The present invention also relates to the use of the drug combination in the preparation of a drug for preventing or treating cancer, especially extranodal NK/T cell lymphoma, and a method for applying the drug combination to prevent or treat cancer, especially extranodal NK/T cell lymphoma .
背景技术Background technique
结外NK/T细胞淋巴瘤，鼻型(extranodal natural killer/T-cell lymphoma，nasal type，ENKTL)是非霍奇金淋巴瘤的一种少见亚型，在我国所有非霍奇金淋巴瘤亚型中，所占比例可达6％，其侵袭性强，初治晚期和难治复发患者预后较差。ENKTL主要发生于鼻腔，其次是皮肤、胃肠道等。该病以血管侵犯和组织破坏为主要病理学表现。ENKTL细胞表面的特异性标志物和特异性遗传学改变也可以帮助诊断该病。ENKTL与EB病毒(EBV)的感染密切相关，EBV-DNA水平对其预后以及辅助诊断有重要的意义。目前，ENKTL的治疗，缺乏前瞻、随机、对照临床研究，尚无标准的治疗方法，其主要治疗方式包括放疗、化疗和造血干细胞移植。初治早期患者采用放疗±左旋门冬酰胺酶为基础的化疗联合治疗模式，患者5年总生存(OS)可超过80％。但是初治晚期及难治复发患者采用以左旋门冬酰胺酶为基础的化疗和/或造血干细胞移植治疗，患者5年OS仅30-50％。目前，美国国立综合癌症网络(National Comprehensive Cancer Network，NCCN)推荐SMILE(日本)，AspaMetDe(法国)和P-Gemox(中山大学肿瘤医院)方案做为联合化疗方案。2011年，日本学者首次采用SMILE方案(***、大剂量甲氨喋呤、异环磷酰胺、左旋门冬酰胺酶、依托泊苷)治疗38例初治Ⅳ期、复发或难治ENKTL患者，客观缓解率(ORR)和完全缓解率(CRR)分别为79％和45％，1年OS率为55％。但是，92％患者发生4级中性粒细胞减少，61％患者出现3/4级感染[1]。香港玛丽医院后续报道了SMILE方案扩大样本量的结果，包括43例初治晚期和44例难治复发患者。治疗完成后，ORR和CRR分别为81％和66％，5年OS率为50％，4年无进展生存(PFS)率为64％；57例患者出现了3/4级中性粒细胞减少，36例患者出现3/4级血小板减少，15例患者出现肾毒性。其中5例患者因治疗相关脓毒血症死亡；1例患者因大剂量甲氨蝶呤导致的急性肾功能衰竭死亡[2]。此外，GELA和GOELAMS协作组报道了AspaMetDex(左旋门冬酰胺酶、大剂量甲氨喋呤、***)治疗19例难治复发ENKTL患者的结果，ORR和CRR分别为78％和61％，中位OS为1年，中位反应持续时间为12个月。主要不良事件为肝炎、血细胞减少和过敏，但是仍然有5例患者出现大剂量甲氨蝶呤相关的一过性肾功能不全，以及3/4级粒缺性发热[3]。2018年，中山大学肿瘤防治中心黄慧强教授等研究者在美国血液学年会报道了P-Gemox方案(培门冬酶、吉西他滨、奥沙利铂)治疗267例初治和难治复发ENKTL患者真实世界的结果，P-Gemox方案安全性优于SMILE和AspaMetDex方案，且初治I/II期患者的生存令人满意，但初治III/IV 期和难治复发患者生存依旧不佳[4]。近年来国内外学者试图通过不同细胞毒药物组合进一步改善初治晚期和难治复发ENKTL预后，但始终未能获得突破，传统细胞毒药物治疗遭遇疗效瓶颈。因此，如何提高初治III/IV期和难治复发患者生存是下一步治疗的方向。Extranodal NK/T-cell lymphoma, nasal type (extranodal natural killer/T-cell lymphoma, nasal type, ENKTL) is a rare subtype of non-Hodgkin’s lymphoma, in all non-Hodgkin’s lymphoma subtypes in my country Among them, it accounts for up to 6%. It is highly invasive, and the prognosis of patients with newly-treated late stage and refractory relapsed patients is poor. ENKTL mainly occurs in the nasal cavity, followed by the skin and gastrointestinal tract. The main pathological manifestations of this disease are vascular invasion and tissue destruction. Specific markers and specific genetic changes on the surface of ENKTL cells can also help diagnose the disease. ENKTL is closely related to Epstein-Barr virus (EBV) infection, and the level of EBV-DNA has important significance for its prognosis and auxiliary diagnosis. At present, the treatment of ENKTL lacks prospective, randomized, controlled clinical research, and there is no standard treatment method. Its main treatment methods include radiotherapy, chemotherapy and hematopoietic stem cell transplantation. In the early stage of initial treatment, radiotherapy ± L-asparaginase-based chemotherapy combined treatment mode is adopted, and the 5-year overall survival (OS) of the patient can exceed 80%. However, patients with newly diagnosed advanced and refractory relapses who are treated with L-asparaginase-based chemotherapy and/or hematopoietic stem cell transplantation, the 5-year OS of the patients is only 30-50%. At present, the National Comprehensive Cancer Network (NCCN) recommends SMILE (Japan), AspaMetDe (France) and P-Gemox (Sun Yat-sen University Cancer Hospital) as a combination chemotherapy regimen. In 2011, Japanese scholars first used SMILE regimen (dexamethasone, high-dose methotrexate, ifosfamide, L-asparaginase, etoposide) to treat 38 patients with newly-treated stage IV, relapsed or refractory ENKTL The objective response rate (ORR) and complete response rate (CRR) were 79% and 45%, respectively, and the 1-year OS rate was 55%. However, 92% of patients had grade 4 neutropenia, and 61% of patients had grade 3/4 infection [1]. The Hong Kong Queen Mary Hospital subsequently reported the results of the SMILE program to expand the sample size, including 43 cases of newly diagnosed late stage and 44 cases of refractory relapsed patients. After treatment, the ORR and CRR were 81% and 66%, respectively, the 5-year OS rate was 50%, and the 4-year progression-free survival (PFS) rate was 64%; 57 patients had grade 3/4 neutropenia , 36 patients had grade 3/4 thrombocytopenia, and 15 patients had nephrotoxicity. Among them, 5 patients died of treatment-related sepsis; 1 patient died of acute renal failure caused by high-dose methotrexate [2]. In addition, the GELA and GOELAMS collaborative group reported the results of AspaMetDex (L-asparaginase, high-dose methotrexate, and dexamethasone) in the treatment of 19 patients with refractory and relapsed ENKTL. The ORR and CRR were 78% and 61%, respectively. The median OS was 1 year, and the median duration of response was 12 months. The main adverse events were hepatitis, cytopenias and allergies, but there were still 5 patients with high-dose methotrexate-related transient renal insufficiency, and grade 3/4 agranular fever [3]. In 2018, Professor Huang Huiqiang from the Cancer Center of Sun Yat-sen University and other researchers reported on the P-Gemox regimen (peaspartase, gemcitabine, oxaliplatin) in the treatment of 267 patients with newly treated and refractory relapsed ENKTL at the American Hematology Annual Meeting. As a result, the P-Gemox regimen is safer than SMILE and AspaMetDex regimens, and the survival of newly-treated stage I/II patients is satisfactory, but the survival of newly-treated stage III/IV and refractory relapsed patients is still poor [4]. In recent years, domestic and foreign scholars have tried to further improve the prognosis of ENKTL in the late stage and refractory relapsed ENKTL through different cytotoxic drug combinations, but they have not achieved a breakthrough, and traditional cytotoxic drug treatment has encountered a bottleneck in curative effect. Therefore, how to improve the survival of newly treated stage III/IV and refractory relapsed patients is the direction of the next treatment.
组蛋白去乙酰化酶(histone deacytelase，HDAC)参与了多种肿瘤的生物学过程，当肿瘤发生时，其活性明显增高，使得核小体中组蛋白处于低乙酰化状态，导致抑癌基因的转录活性被抑制，而调控细胞增殖及细胞周期的多种基因的异常表达，致使细胞发生恶性转化[5]。HDAC抑制剂是一类通过调控表观遗传学而发挥抗肿瘤作用的新型小分子靶向药物，它通过阻断HDAC的去乙酰化作用，使DNA保持转录活性并引起下游多条信号通路的变化，可引起肿瘤细胞凋亡、诱导细胞分化以及抑制血管生成等[5-7]。同时它还对机体的免疫细胞也具有调节作用，可诱导和增强NK细胞及细胞毒性T淋巴细胞(CTL)介导的肿瘤杀伤作用。西达本胺是一种亚型选择性的口服HDAC抑制剂，主要作用靶点为Ⅰ型和Ⅱ型HDAC，目前已经获批用于我国难治复发外周T细胞淋巴瘤的治疗。在关键性临床Ⅱ期试验(注册性临床试验)中，共入组83例复发或难治性外周T细胞淋巴瘤(PTCL)患者，全部接受30mg/次、2次/周的西达本胺治疗，直至疾病进展或出现不可耐受的不良反应为止。主要疗效指标为ORR。79例患者进行疗效评估，结果显示：ORR为28％，中位PFS和中位OS分别为2.1个月和21.4个月；最常见的3/4级不良反应为血小板减少(22％)，白细胞减少(13％)和中性粒细胞减少(10％)。研究中包括16例难治复发ENKTL患者，西达本胺的ORR仅为25％，其中CRR为6％[8]。在我国真实世界研究的报道中，西达本胺单药治疗难治复发ENKTL患者的ORR、CRR和疾病控制率(DCR)分别为15％、6％和42％[9]。西达本胺在真实世界的疗效并不理想。中山大学肿瘤医院黄慧强教授团队也进行了一项西达本胺单药治疗22例难治复发ENKTL的研究，研究结果显示ORR达到50％，CR率31.3％，能获得CR的患者生存超过了2年。虽然西达本胺可能是潜在治疗ENKTL的有效药物，但是其疗效仍有很大局限性。Histone deacytelase (HDAC) is involved in the biological processes of a variety of tumors. When tumors occur, their activity is significantly increased, which makes the histones in the nucleosomes in a state of hypoacetylation, leading to tumor suppressor genes. Transcription activity is inhibited, and the abnormal expression of a variety of genes that regulate cell proliferation and cell cycle causes malignant transformation of cells [5]. HDAC inhibitors are a new type of small-molecule targeted drugs that play an anti-tumor effect by regulating epigenetics. By blocking the deacetylation of HDAC, DNA maintains transcriptional activity and causes changes in multiple downstream signaling pathways. , Can cause tumor cell apoptosis, induce cell differentiation and inhibit angiogenesis [5-7]. At the same time, it also has a regulatory effect on the body's immune cells, and can induce and enhance the tumor killing effect mediated by NK cells and cytotoxic T lymphocytes (CTL). Chidamide is a subtype-selective oral HDAC inhibitor. Its main target is type I and type II HDAC. It has been approved for the treatment of refractory and relapsed peripheral T-cell lymphoma in my country. In the pivotal phase II clinical trial (registered clinical trial), a total of 83 patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) were enrolled, and all received 30 mg/time, twice/week of chidamide Treatment until the disease progresses or untolerable adverse reactions occur. The main efficacy index is ORR. The efficacy of 79 patients was evaluated, and the results showed that: ORR was 28%, median PFS and median OS were 2.1 months and 21.4 months, respectively; the most common grade 3/4 adverse reactions were thrombocytopenia (22%), white blood cells Decrease (13%) and neutropenia (10%). The study included 16 patients with refractory and relapsed ENKTL. The ORR of chidamide was only 25%, and the CRR was 6% [8]. In the reports of real-world studies in my country, the ORR, CRR and disease control rate (DCR) of chidamide monotherapy in patients with refractory and relapsed ENKTL were 15%, 6% and 42%, respectively [9]. The efficacy of Chidamide in the real world is not ideal. The team of Professor Huang Huiqiang from Sun Yat-sen University Cancer Hospital also conducted a study of chidamine monotherapy in 22 patients with refractory relapsed ENKTL. The results of the study showed that the ORR reached 50%, the CR rate was 31.3%, and the survival of patients who could obtain CR exceeded 2 year. Although Chidamide may be an effective drug for potential treatment of ENKTL, its efficacy still has great limitations.
程序性死亡蛋白1(Programmed death-1，PD-1)/程序性死亡配体1(Programmed death ligand-1，PD-L1)轴是抑制免疫激活的强有力的信号途径，也是肿瘤实现免疫逃逸的重要机制之一[10,11]。肿瘤浸润淋巴细胞高表达PD-1，这些PD-1与肿瘤细胞或免疫细胞表面的PD-L1相结合抑制起始活化的T细胞，并抑制效应T细胞的产生和功能(包括细胞因子生成和细胞毒性)[12,13]。包括霍奇金淋巴瘤[14]、弥漫大B细胞淋巴瘤[15]、ENKTL[16]等在内的多种类型肿瘤会表达PD-L1，并通过PD-L1抑制抗肿瘤T细胞反应[17]。阻断PD-L1/PD-1轴能恢复T细胞杀伤肿瘤功能并能获得持久的临床反应[10,11,18]。国内外已经有多项研究证实PD-1单抗在难治复发ENKTL患者中的疗效。郑州大学第一附院曾在Journal of Hematology&Oncology杂志上报道了Pembrolizumab单药治疗7例难治复发ENKTL患者的结果，中位治疗4(2-18)个疗程后，ORR为57％，CR率28.6％(2例CR、2例PR)，不良反应轻微。该研究再次证实了PD-1抑制剂在难治复发ENKTL的潜在治疗价值[19]。信达生物制药(苏州)有限公司***内国家知名医疗中心在2017年开展了信迪利单抗单药在难治复发ENKTL的一项多中心，单臂的II期临床研究(ORIENT-4)，患者接受信迪利单抗(200mg IV Q3W)单药治疗，直至疾病进展、死亡、毒性无法耐受或退出研究。研究中，通过PET-CT和增强CT/MRI评 估肿瘤反应。主要研究终点为基于LUGANO 2014恶性淋巴瘤疗效评价标准的ORR。截止到2019年2月2日，共纳入28例患者，60.7％为男性，中位年龄为37岁。68％患者为IV期，89.3％为ECOG评分≥1。所有患者均接受含门冬酰胺酶方案治疗失败，既往治疗方案的中位线数为3，78.6％患者接受过放疗，7.1％患者接受过造血干细胞移植。初步结果显示，中位治疗持续时间为14个月，19例患者仍在接受信迪利单抗治疗中。ORR为68％，CR率为7.1％。中位随访15.4个月，1年OS率为82.1％，中位OS尚未达到。ORR的亚组分析显示，EBV阴性、无B症状、LDH水平正常和骨髓未受累患者有效率更高[20]。虽然信迪利单抗对ENKTL有效，然而如何提高肿瘤治疗的有效性仍是目前肿瘤治疗领域迫切需要解决的一个难题。Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis is a powerful signaling pathway to inhibit immune activation, and it is also a tumor to achieve immune escape One of the important mechanisms [10,11]. Tumor infiltrating lymphocytes highly express PD-1. These PD-1 combine with PD-L1 on the surface of tumor cells or immune cells to inhibit the initial activation of T cells, and inhibit the production and function of effector T cells (including cytokine production and Cytotoxicity) [12,13]. Many types of tumors, including Hodgkin’s lymphoma [14], diffuse large B-cell lymphoma [15], ENKTL [16], etc., express PD-L1 and inhibit anti-tumor T cell responses through PD-L1 [ 17]. Blocking the PD-L1/PD-1 axis can restore the function of T cells to kill tumors and obtain a lasting clinical response [10,11,18]. There have been many studies at home and abroad that have confirmed the efficacy of PD-1 monoclonal antibody in patients with refractory and relapsed ENKTL. The First Affiliated Hospital of Zhengzhou University reported in the Journal of Hematology&Oncology the results of Pembrolizumab monotherapy in 7 patients with refractory and relapsed ENKTL. After a median of 4 (2-18) courses of treatment, the ORR was 57% and the CR rate was 28.6. % (2 cases of CR, 2 cases of PR), the side effects were mild. This study once again confirmed the potential therapeutic value of PD-1 inhibitors in refractory and relapsed ENKTL [19]. Cinda Biopharmaceuticals (Suzhou) Co., Ltd., a well-known national medical center in the United Nations, carried out a multi-center, single-arm Phase II clinical study (ORIENT-4) of Sintilimab as a single agent in refractory and relapsed ENKTL in 2017. , The patient received Sintilizumab (200mg IV Q3W) monotherapy until the disease progressed, died, the toxicity was intolerable or the study was withdrawn. In the study, PET-CT and enhanced CT/MRI were used to evaluate tumor response. The main study endpoint is ORR based on the LUGANO 2014 efficacy evaluation criteria for malignant lymphoma. As of February 2, 2019, a total of 28 patients were enrolled, 60.7% of them were male, and the median age was 37 years. 68% of patients had stage IV, and 89.3% had ECOG score ≥1. All patients received asparaginase-containing regimens that failed. The median number of previous treatment regimens was 3, 78.6% of patients had received radiotherapy, and 7.1% of patients had received hematopoietic stem cell transplantation. Preliminary results showed that the median duration of treatment was 14 months, and 19 patients were still receiving sintilizumab. The ORR was 68%, and the CR rate was 7.1%. With a median follow-up of 15.4 months, the 1-year OS rate was 82.1%, and the median OS has not yet been reached. ORR subgroup analysis showed that patients with EBV negative, no B symptoms, normal LDH levels, and bone marrow unaffected patients were more effective [20]. Although Sintilimab is effective against ENKTL, how to improve the effectiveness of tumor treatment is still an urgent problem that needs to be solved in the current tumor treatment field.
大部分肿瘤的生物学行为并非由单一信号传导通路所支配，而是多个信号传导通路共同起作用。在某些情况下，具有不同作用机制的药物可以联合使用。但是，具有不同作用机制但在类似领域起作用的药物的任何联合形式，并不必然能够产生具有有益效果的联合形式。因此，虽然现有技术中针对不同信号转导通路的联合用药方案和产品的确存在需求，但是鉴于肿瘤发生机制的复杂性、不同药物之间相互作用的不可预见性等因素，发现可行且能够带来相比单药而言具有更优异效果(减少单药剂量、改善治疗中的不良事件(AE)发生率和/或严重程度，和/或以协同作用的方式起作用等)的联合用药的方案和产品，仍然是医药领域的一大挑战。The biological behavior of most tumors is not dominated by a single signal transduction pathway, but multiple signal transduction pathways work together. In some cases, drugs with different mechanisms of action can be used in combination. However, any combination form of drugs that have different mechanisms of action but work in similar fields does not necessarily produce a combination form with beneficial effects. Therefore, although there is indeed a demand for combination medication schemes and products for different signal transduction pathways in the prior art, in view of the complexity of tumorigenesis and the unpredictability of interactions between different drugs, it has been found to be feasible and capable of bringing about Compared with a single drug, a combination drug that has a better effect (reduce the dose of a single drug, improve the incidence and/or severity of adverse events (AE) during treatment, and/or act in a synergistic manner, etc.) Solutions and products are still a major challenge in the field of medicine.
发明内容Summary of the invention
本发明人令人惊讶地发现，本申请的药物组合能够以协同作用和/或改善治疗中的不良事件(AE)发生率和/或严重程度的方式对癌症、尤其是结外NK/T细胞淋巴瘤起到预防和/或治疗的效果。The inventors surprisingly found that the drug combination of the present application can treat cancer, especially extranodal NK/T cells in a way that synergistically acts and/or improves the incidence and/or severity of adverse events (AE) during treatment. Lymphoma plays a preventive and/or therapeutic effect.
第一方面，本发明提供了一种药物组合，其包含PD-1抗体或其抗原结合片段和HDAC抑制剂，In the first aspect, the present invention provides a pharmaceutical combination comprising a PD-1 antibody or an antigen-binding fragment thereof and an HDAC inhibitor,
其中抗PD-1抗体包含6个CDR，其中LCDR1、LCDR2和LCDR3分别由氨基酸序列RASQGISSWLA(SEQ ID NO:9)、SAASSLQS(SEQ ID NO:10)和QQANHLPFT(SEQ ID NO:11)组成，且其中HCDR1、HCDR2和HCDR3分别由氨基酸序列KASGGTFSSYAIS(SEQ ID NO:2)、LIIPMFDTAGYAQKFQG(SEQ ID NO:5)和ARAEHSSTGTFDY(SEQ ID NO:8)组成；或The anti-PD-1 antibody contains 6 CDRs, and LCDR1, LCDR2, and LCDR3 are composed of the amino acid sequences RASQGISSWLA (SEQ ID NO: 9), SAASSLQS (SEQ ID NO: 10) and QQANHLPFT (SEQ ID NO: 11), respectively, and Wherein HCDR1, HCDR2 and HCDR3 are respectively composed of amino acid sequences KASGGTFSSYAIS (SEQ ID NO: 2), LIIPMFDTAGYAQKFQG (SEQ ID NO: 5) and ARAEHSSTGTFDY (SEQ ID NO: 8); or
其中抗PD-1抗体选自信迪利单抗(Sintilimab)、帕博利珠单抗(Pembrolizumab)、纳武利尤单抗(Nivolumab)、特瑞普利单抗和卡瑞利珠单抗；The anti-PD-1 antibody is selected from Sintilimab, Pembrolizumab, Nivolumab, Teriplizumab and Carrelizumab;
其中HDAC抑制剂选自下述式I化合物或其可药用盐：Wherein the HDAC inhibitor is selected from the following compounds of formula I or pharmaceutically acceptable salts thereof:
Figure PCTCN2020138343-appb-000001
Figure PCTCN2020138343-appb-000001
其中，A为苯环或杂环，可以含有1至4个取代基，其取代基可以是卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酰氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基、苯基或杂环取代基；Among them, A is a benzene ring or heterocyclic ring, which can contain 1 to 4 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, 1 to 4 Carbon atom alkoxy group, 1 to 4 carbon atom aminoalkyl group, 1 to 4 carbon atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acyl group, 1 to 4 A thioalkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a perfluoroalkoxy group of 1 to 4 carbon atoms, a carboxyl group of 1 to 4 carbon atoms, and a perfluoroalkyl group of 1 to 4 carbon atoms Alkoxycarbonyl, phenyl or heterocyclic substituents;
B为苯环或杂环，可以含有1至3个取代基，其取代基可以是卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酰氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基、苯基或杂环取代基:B is a benzene ring or heterocyclic ring, which can contain 1 to 3 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, and 1 to 4 carbon atoms Alkoxy, aminoalkyl of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, acyl of 2 to 4 carbon atoms, acylamino of 2 to 4 carbon atoms, 1 to 4 carbons Atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 carbon atom perfluoroalkoxy group, 1 to 4 carbon atom carboxyl group, 1 to 4 carbon atom alkoxy group Carbonyl, phenyl or heterocyclic substituents:
Z为共价键、1至4个碳原子的烷撑或含有-O-、-S-、-NH、-CO-、-CS-、-SO-、-SO 2-的线性结构、环状结构或线性结构与环状结构的组合； Z is a covalent bond, an alkylene of 1 to 4 carbon atoms, or a linear structure or a ring containing -O-, -S-, -NH, -CO-, -CS-, -SO-, -SO 2- Structure or a combination of linear structure and cyclic structure;
Y为含有-CO-、-CS-、-SO-、-SO 2-的线性结构、环状结构或线性结构与环状结构的组合，其中环A的中心点(W1)、环B的中心点(W2)与Y中所含的作为氢键受体的O原子或S原子(W3)之间的距离满足下列条件：
Figure PCTCN2020138343-appb-000002
Figure PCTCN2020138343-appb-000003
它们之间较佳的距离为
Figure PCTCN2020138343-appb-000004
Y is a linear structure, a cyclic structure or a combination of a linear structure and a cyclic structure containing -CO-, -CS-, -SO-, -SO 2 -, wherein the center point (W1) of ring A and the center of ring B The distance between the point (W2) and the O atom or S atom (W3) contained in Y as the hydrogen bond acceptor satisfies the following conditions:
Figure PCTCN2020138343-appb-000002
Figure PCTCN2020138343-appb-000003
The better distance between them is
Figure PCTCN2020138343-appb-000004
R 1、R 2分别为氢或含有1至4个碳原子的烷基，R 1、R 2还可以一起构成一个共价键； R 1 and R 2 are respectively hydrogen or an alkyl group containing 1 to 4 carbon atoms, and R 1 and R 2 can also form a covalent bond together;
R 3为氢或含有1至4个碳原子的烷基； R 3 is hydrogen or an alkyl group containing 1 to 4 carbon atoms;
R 4为氢、卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酰氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基； R 4 is hydrogen, halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 Alkylamino of to 4 carbon atoms, acyl of 2 to 4 carbon atoms, amido of 2 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, perfluoroalkane of 1 to 4 carbon atoms Group, perfluoroalkoxy group of 1 to 4 carbon atoms, carboxyl group of 1 to 4 carbon atoms, alkoxycarbonyl group of 1 to 4 carbon atoms;
X 1、X 2、X 3、X 4其中之一为卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酰氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基；其余分别为氢、卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酸氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基； One of X 1 , X 2 , X 3 , and X 4 is halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, 1 to Aminoalkyl groups of 4 carbon atoms, alkylamino groups of 1 to 4 carbon atoms, acyl groups of 2 to 4 carbon atoms, acylamino groups of 2 to 4 carbon atoms, thioalkyl groups of 1 to 4 carbon atoms, Perfluoroalkyl groups of 1 to 4 carbon atoms, perfluoroalkoxy groups of 1 to 4 carbon atoms, carboxyl groups of 1 to 4 carbon atoms, alkoxycarbonyl groups of 1 to 4 carbon atoms; the rest are hydrogen , Halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 to 4 carbons Atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acid amino group, 1 to 4 carbon atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 Perfluoroalkoxy with 4 carbon atoms, carboxyl with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms;
或其中HDAC抑制剂选自伏立诺他(Vorinostat)、罗米地辛(Romidepsin)、贝利司他(Belinostat)、帕比司他(Panobinostat)、西达本胺(Chidamide)、恩替诺特(Entinostat)和Mocetinostat(MGCD0103)。Or wherein the HDAC inhibitor is selected from Vorinostat, Romidepsin, Belinostat, Panobinostat, Chidamide, Entinol Special (Entinostat) and Mocetinostat (MGCD0103).
在一个优选实施方案中，优选地，抗PD-1抗体包含重链可变区VH和轻链可变区VL，其中重链可变区包含SEQ ID NO:13的序列或与其具有至少90％,95％,98％或99％同一性的序列，和/或轻链可变区包含SEQ ID NO:15的序列或与其具有至少90％,95％,98％或99％同一性的序列；In a preferred embodiment, preferably, the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 13 or has at least 90% of the sequence of SEQ ID NO: 13 , 95%, 98%, or 99% identical sequences, and/or the light chain variable region comprising the sequence of SEQ ID NO: 15 or a sequence having at least 90%, 95%, 98% or 99% identity therewith;
优选地，所述抗PD-1抗体包含SEQ ID NO:17或与之具有至少90％,95％,98％或99％同一性的重链序列和/或SEQ ID NO：22或与之具有至少90％,95％,98％或99％同一性的轻链序列。Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 17 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and/or SEQ ID NO: 22 or has A light chain sequence that is at least 90%, 95%, 98%, or 99% identical.
在一个优选实施方案中，所述抗PD-1抗体或其抗原结合片段选自信迪利单抗(Sintilimab)、帕博利珠单抗(Pembrolizumab)、纳武利尤单抗(Nivolumab)、特瑞普利单抗和卡瑞利珠单抗；优选地，所述抗PD-1抗体为信迪利单抗。In a preferred embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from Sintilimab, Pembrolizumab, Nivolumab, and Trepre Lizumab and Carrelizumab; preferably, the anti-PD-1 antibody is Sintilizumab.
在本发明的一个优选实施方案中，所述HDAC抑制剂选自伏立诺他(Vorinostat)、罗米地辛(Romidepsin)、贝利司他(Belinostat)、帕比司他(Panobinostat)、西达本胺(Chidamide)、恩替诺特(Entinostat)和Mocetinostat(MGCD0103)或其可药用盐，更优选地，所述HDAC抑制剂为西达本胺。In a preferred embodiment of the present invention, the HDAC inhibitor is selected from the group consisting of Vorinostat, Romidepsin, Belinostat, Panobinostat, and Panobinostat. Chidamide, Entinostat and Mocetinostat (MGCD0103) or a pharmaceutically acceptable salt thereof, more preferably, the HDAC inhibitor is Chidamide.
在一个优选实施方案中，所述药物组合用于预防或治疗癌症，优选非霍奇金淋巴瘤，更优选结外NK/T细胞淋巴瘤，最优选晚期或难治复发的结外NK/T细胞淋巴瘤。In a preferred embodiment, the drug combination is used to prevent or treat cancer, preferably non-Hodgkin's lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably late or refractory extranodal NK/T Cell lymphoma.
在一个优选实施方案中，所述药物组合中抗PD-1抗体或其抗原结合片段为100-300mg、优选为100mg、150mg、200mg、250mg或300mg、更优选地为200mg的剂量单元的形式，优选为胃肠外、更优选静脉内施用剂型；和/或In a preferred embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is in the form of a dosage unit of 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, more preferably 200 mg, Preferably it is a parenteral, more preferably an intravenous administration form; and/or
HDAC抑制剂为10至50mg、优选为10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg的剂量单元的形式，优选为口服施用剂型。The HDAC inhibitor is in the form of a dosage unit of 10 to 50 mg, preferably 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, preferably in a dosage form for oral administration.
在一个优选实施方案中，所述抗PD-1抗体或其抗原结合片段的单次施用剂量选自100-300mg，例如100mg、150mg、200mg、250mg或300mg，优选每二至四周施用一次，优选通过静脉输注施用。In a preferred embodiment, the single administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from 100-300 mg, such as 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, preferably once every two to four weeks, preferably It is administered by intravenous infusion.
在一个优选实施方案中，所述抗PD-1抗体或其抗原结合片段每三周静脉输注一次，单次输注剂量为200mg。In a preferred embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is intravenously infused once every three weeks, and the single infusion dose is 200 mg.
在一个优选实施方案中，所述HDAC抑制剂的单次施用剂量选自10mg-50mg，优选每周施用1-4次，优选通过口服施用；In a preferred embodiment, the single administration dose of the HDAC inhibitor is selected from 10mg-50mg, preferably 1-4 times per week, preferably by oral administration;
在一个优选实施方案中，所述HDAC抑制剂的口服剂量选自20mg、25mg和30mg。In a preferred embodiment, the oral dose of the HDAC inhibitor is selected from 20 mg, 25 mg and 30 mg.
在一个优选实施方案中，所述HDAC抑制剂每周口服2次，每次口服剂量为30mg。In a preferred embodiment, the HDAC inhibitor is taken orally twice a week, and each oral dose is 30 mg.
在一个优选实施方案中，其中所述抗PD-1抗体或其抗原结合片段和HDAC抑制剂分开、同时或依次施用。In a preferred embodiment, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the HDAC inhibitor are administered separately, simultaneously or sequentially.
在一个优选实施方案中，所述抗PD-1抗体和所述HDAC抑制剂联合治疗周期结束后，可继续给予抗PD-1抗体或其结合片段给予治疗。In a preferred embodiment, after the anti-PD-1 antibody and the HDAC inhibitor combined treatment cycle is over, the anti-PD-1 antibody or its binding fragment can be continuously administered for treatment.
第二方面，本发明提供第一方面中所定义的抗PD-1抗体或其抗原结合片段和HDAC抑制剂的药物组合在制备用于预防或治疗癌症的药物中的用途，所述癌症优选选自非霍奇金淋巴瘤，更优选结外NK/T细胞淋巴瘤，最优选晚期或难治复发的结外NK/T细胞淋巴瘤。In the second aspect, the present invention provides the use of the drug combination of the anti-PD-1 antibody or its antigen-binding fragment and HDAC inhibitor as defined in the first aspect in the preparation of a drug for the prevention or treatment of cancer, and the cancer is preferably selected From non-Hodgkin's lymphoma, extranodal NK/T cell lymphoma is more preferred, and extranodal NK/T cell lymphoma that is advanced or refractory to relapse is most preferred.
第三方面，本发明提供用于预防或治疗癌症的方法，所述方法包括向有需要的患者施用治疗有效量的第一方面中所定义的抗PD-1抗体或其抗原结合片段和HDAC抑制剂的药物组合，所述癌症优选选自非霍奇金淋巴瘤，更优选结外NK/T细胞淋巴瘤，最优选晚期或难治复发的结外NK/T细胞淋巴瘤。In the third aspect, the present invention provides a method for preventing or treating cancer, the method comprising administering to a patient in need a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof defined in the first aspect and HDAC inhibition The cancer is preferably selected from non-Hodgkin’s lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably advanced or refractory and relapsed extranodal NK/T cell lymphoma.
第四方面，本发明还提供一种单次药物剂量单元，其包括治疗有效量的第一方面中所定义的抗PD-1抗体或其抗原结合片段和HDAC抑制剂的药物组合。In the fourth aspect, the present invention also provides a single drug dosage unit, which includes a therapeutically effective amount of the drug combination of the anti-PD-1 antibody or antigen-binding fragment thereof as defined in the first aspect and an HDAC inhibitor.
第五方面，本发明还提供一种药物组合物，包含治疗有效量的第一方面中所定义的抗PD-1抗体或其抗原结合片段和HDAC抑制剂的药物组合和可药用的赋形剂。In the fifth aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof as defined in the first aspect and a pharmaceutical combination of an HDAC inhibitor and pharmaceutically acceptable excipients Agent.
第六方面，本发明还提供一种成套药盒，其包含治疗有效量的第一方面中所定义的抗PD-1抗体或其抗原结合片段和HDAC抑制剂的药物组合。In the sixth aspect, the present invention also provides a kit of medicines comprising a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof defined in the first aspect and a drug combination of an HDAC inhibitor.
第七方面，本发明还提供上述单次药物剂量单元、药物组合物或成套药盒在制备预防或治疗癌症的药物中的用途，所述癌症优选选自非霍奇金淋巴瘤，更优选结外NK/T细胞淋巴瘤，最优选晚期或难治复发的结外NK/T细胞淋巴瘤。In a seventh aspect, the present invention also provides the use of the above-mentioned single drug dosage unit, pharmaceutical composition or kit in the preparation of a drug for preventing or treating cancer. The cancer is preferably selected from non-Hodgkin’s lymphoma, more preferably nodal. Extranodal NK/T cell lymphoma, most preferably advanced or refractory and relapsed extranodal NK/T cell lymphoma.
定义definition
除非另有定义，否则本文中使用的所有技术和科学术语均具有与本领域一般技术人员通常所理解的含义相同的含义。为了本发明的目的，下文定义了以下术语。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. For the purpose of the present invention, the following terms are defined below.
术语“约”在与数字数值联合使用时意为涵盖具有比指定数字数值小5％的下限和比指定数字数值大5％的上限的范围内的数字数值。The term "about" when used in conjunction with a numerical value means to encompass a numerical value within a range having a lower limit that is 5% smaller than the specified numerical value and an upper limit that is 5% larger than the specified numerical value.
术语“和/或”应理解为意指可选项中的任一项或可选项中的任意两项或多项的组合。The term "and/or" should be understood to mean any one of the alternatives or a combination of any two or more of the alternatives.
如本文中所用，术语“包含”或“包括”意指包括所述的要素、整数或步骤，但是不排除任意其他要素、整数或步骤。在本文中，当使用术语“包含”或“包括”时，除非另有指明，否则也涵盖由所述及的要素、整数或步骤组成的情形。例如，当提及“包含”某个具体序列的抗体可变区时，也旨在涵盖由该具体序列组成的抗体可变区。As used herein, the term "comprising" or "including" means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps. In this document, when the term "comprises" or "includes" is used, unless otherwise specified, it also encompasses the situation consisting of the stated elements, integers or steps. For example, when referring to an antibody variable region that "comprises" a specific sequence, it is also intended to encompass the antibody variable region composed of the specific sequence.
在本文中，术语“抗体”是指至少包含轻链或重链免疫球蛋白可变区的多肽，所述免疫球蛋白可变区特异性识别并结合抗原。该术语涵盖各种抗体结构，包括、但不限于单克隆抗体、多克隆抗体、单链抗体或多链抗体、单特异性或多特异性抗体(例如双特异性抗体)、全人源抗体或嵌合抗体或人源化抗体、全长抗体和抗体片段，只要它们呈现期望的抗原结合活 性即可。As used herein, the term "antibody" refers to a polypeptide comprising at least a light chain or heavy chain immunoglobulin variable region, which specifically recognizes and binds to an antigen. The term encompasses various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, single-chain or multi-chain antibodies, monospecific or multispecific antibodies (such as bispecific antibodies), fully human antibodies, or Chimeric antibodies or humanized antibodies, full-length antibodies, and antibody fragments, as long as they exhibit the desired antigen-binding activity.
术语抗体的“抗原结合片段”(在本文中可与“抗体片段”和“抗原结合部分”互换使用)，是指并非完整抗体的分子，其包含完整抗体中用于结合该完整抗体所结合的抗原的部分。如本领域技术人员理解的，抗体的抗原结合部分通常包含来自“互补决定区”或“CDR”的氨基酸残基。可以通过重组DNA技术、或通过酶或化学切割完整的抗体制备抗原结合片段。抗原结合片段包括但不限于Fab、scFab、Fab’、F(ab’)2、Fab’-SH、Fv、单链Fv、双链抗体(diabody)、三链抗体(triabody)、四链抗体(tetrabody)、微抗体(minibody)、单结构域抗体(sdAb)。关于抗体片段的更详细的描述，可以参见：基础免疫学(Fundamental Immunology),W.E.Paul编辑,Raven Press,N.Y.(1993)；邵荣光等人(编辑)，抗体药物研究与应用，人民卫生出版社(2013)；Hollinger等人，PNAS USA 90:6444-6448(1993)；Hudson等人，Nat.Med.9:129-134(2003)。The term "antigen-binding fragment" of an antibody (which can be used interchangeably with "antibody fragment" and "antigen-binding portion" herein) refers to a molecule that is not an intact antibody, which includes the intact antibody used to bind the intact antibody. Part of the antigen. As understood by those skilled in the art, the antigen-binding portion of an antibody usually contains amino acid residues from the "complementarity determining region" or "CDR". The antigen-binding fragment can be prepared by recombinant DNA technology, or by enzymatic or chemical cleavage of the intact antibody. Antigen-binding fragments include but are not limited to Fab, scFab, Fab', F(ab')2, Fab'-SH, Fv, single-chain Fv, double-chain antibody (diabody), triabody (triabody), four-chain antibody ( tetrabody), minibody (minibody), single domain antibody (sdAb). For a more detailed description of antibody fragments, please refer to: Fundamental Immunology, edited by WEPaul, Raven Press, NY (1993); Shao Rongguang et al. (ed.), Research and Application of Antibody Drugs, People's Medical Publishing House (2013); Hollinger et al., PNAS USA 90:6444-6448 (1993); Hudson et al., Nat. Med. 9:129-134 (2003).
术语“预防”包括对疾病或病症或其症状的发生或发生频率的抑制或推迟，其通常是指在病征或症状发生前，特别是在具有风险个体的病征或症状发生前的药物施用。The term "prevention" includes the suppression or delay of the occurrence or frequency of the occurrence or occurrence of a disease or disorder or its symptoms, and it generally refers to the administration of drugs before the occurrence or occurrence of the symptoms or symptoms, especially before the occurrence of the symptoms or symptoms in individuals at risk.
本文所用术语“治疗”指通过疾病的临床或诊断症状的减轻或消除来证明的对象癌症(例如结外NK/T细胞淋巴瘤)进展的减缓、阻止或逆转。治疗可包括例如，降低症状严重程度、症状数量或复发频率，例如，肿瘤生长抑制、肿瘤生长阻滞或已有肿瘤的消退。The term "treatment" as used herein refers to the slowing, prevention or reversal of the progression of a subject's cancer (for example, extranodal NK/T cell lymphoma) as evidenced by the reduction or elimination of clinical or diagnostic symptoms of the disease. Treatment may include, for example, reducing the severity of symptoms, the number of symptoms, or the frequency of recurrence, for example, tumor growth inhibition, tumor growth arrest, or regression of existing tumors.
本文所用术语“单次药物剂量单元”表示在给药方案的时刻给予病人的单次药物剂型，包括注射液、药片以及冻干粉等。The term "single drug dosage unit" as used herein refers to a single drug dosage form administered to a patient at the time of the dosing schedule, including injections, tablets, and freeze-dried powders.
术语“药物组合”是指非固定组合产品或固定组合产品，例如药盒。术语“非固定组合”意指活性成分(例如，(i)抗PD-1抗体或其抗原结合片段、和(ii)HDAC抑制剂以分开的实体被同时、无特定时间限制或以相同或不同的时间间隔、依次地施用于患者，其中这类施用在患者体内提供预防或治疗有效水平的所述两种活性剂。在一些实施方案中，药物组合中使用的抗PD-1抗体分子和HDAC抑制剂这两种分子以不超过它们单独使用时的水平施用。术语“固定组合”意指两种活性剂以单个实体的形式被同时施用于患者。优选对两种活性剂的剂量和/或时间间隔进行选择，从而使各部分的联合使用能够在治疗疾病或病症时产生大于单独使用任何一种成分所能达到的效果。各成分可以各自呈单独的制剂形式，其制剂形式可以相同也可以不同。The term "drug combination" refers to a non-fixed combination product or a fixed combination product, such as a kit. The term "non-fixed combination" means that the active ingredients (for example, (i) anti-PD-1 antibodies or antigen-binding fragments thereof, and (ii) HDAC inhibitors as separate entities are simultaneously, without a specific time limit, or in the same or different The two agents are administered to the patient sequentially at intervals of time, wherein such administration provides prophylactic or therapeutically effective levels of the two active agents in the patient. In some embodiments, the anti-PD-1 antibody molecule and HDAC used in the drug combination The two molecules of the inhibitor are administered at a level not exceeding the level when they are used alone. The term "fixed combination" means that the two active agents are administered to the patient simultaneously in the form of a single entity. The dosage and/or of the two active agents are preferred. The time interval is selected so that the combined use of each part can produce an effect greater than that achieved by using any single component in the treatment of diseases or conditions. Each component can be in the form of a separate preparation, and the preparation form can be the same or different.
涉及联合治疗时，本文所用术语“治疗有效量”指联合给药时联合作用引发所需的生物学或医学反应，即，抑制或改善的一种或多种癌症包括结外NK/T细胞淋巴瘤临床或诊断症状的联合给药量。例如，提到联合治疗时，本文所用术语“治疗有效量”是在治疗周期中的同一天或不同天一起给药(依次或同时)时，产生治疗有效和/或协同性的联合作用的抗体用量和化疗药物用量。而且，本领域技术人员应认识到，在用治疗有效量联合治疗的情况下(如上述实例)，单独的抗体和/或化学药用量可能是或不是治疗有效的。When it comes to combination therapy, the term "therapeutically effective amount" as used herein refers to the combined effect that triggers the desired biological or medical response when administered in combination, that is, one or more cancers that are inhibited or improved include extranodal NK/T cell lymph The combined dose for the clinical or diagnostic symptoms of tumors. For example, when referring to combination therapy, the term "therapeutically effective amount" as used herein refers to antibodies that produce a therapeutically effective and/or synergistic combination when administered together (sequentially or simultaneously) on the same day or on different days in the treatment cycle. Dosage and dosage of chemotherapy drugs. Moreover, those skilled in the art should recognize that in the case of combined treatment with a therapeutically effective amount (as in the above example), the amount of individual antibodies and/or chemicals may or may not be therapeutically effective.
术语“周期”是指以常规时间表重复的以天或周表示的特定时间段。例如，每个治疗周期为15至30天、例如15至24天，优选每个治疗周期为三周(即，21天)。在一个实施方案中，一个治疗周期是四周(即，28天)。The term "period" refers to a specific period of time expressed in days or weeks that repeats on a regular schedule. For example, each treatment cycle is 15 to 30 days, such as 15 to 24 days, and preferably each treatment cycle is three weeks (ie, 21 days). In one embodiment, one treatment cycle is four weeks (ie, 28 days).
术语“施用”指用本领域技术人员已知的多种方法和递送***中的任一种将本发明的药 物组合中的各活性成分物理导入至个体。本发明的药物组合中的各活性成分的施用途径包括口服、静脉内(例如输注(又称滴注)或注射)、肌内、皮下、腹膜内、脊髓、局部或其他胃肠外施用途径。本文所用的短语“胃肠外施用”指胃肠和局部施用之外的施用方式，通常通过静脉内，且非限制性地包括肌内、动脉内、鞘内、淋巴内、病灶内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注，以及体内电穿孔。相应地，本发明的药物组合中的各活性成分可以被配制成胶囊剂、片剂、注射剂(包括输液或注射液)、糖浆、喷雾剂、锭剂、脂质体或栓剂等。The term "administration" refers to the physical introduction of each active ingredient of the pharmaceutical composition of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art. The route of administration of each active ingredient in the pharmaceutical combination of the present invention includes oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other parenteral routes of administration . As used herein, the phrase "parenteral administration" refers to methods of administration other than gastrointestinal and topical administration, usually via intravenous, and without limitation includes intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrasaccular , Intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injection and infusion, and in vivo electroporation. Correspondingly, each active ingredient in the pharmaceutical combination of the present invention can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, etc.
术语“剂量”是引发治疗效果的药物的量。除非另有说明，否则剂量与游离形式的药物的量有关。如果药物是可药用盐形式，药物的量与游离形式的药物的量相比成比例地增加。例如，剂量将在产品包装或产品信息单中声明。The term "dose" is the amount of a drug that induces a therapeutic effect. Unless otherwise stated, the dosage is related to the amount of the free form of the drug. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased in proportion to the amount of the drug in the free form. For example, the dosage will be stated on the product packaging or product information sheet.
术语“可药用盐”包括但不限于酸加成盐或碱加成盐，例如：HADC抑制剂(包括式(I)化合物)与无机酸形成的酸加成盐，例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等；以及HADC抑制剂(包括式(I)化合物)与有机酸形成的酸加成盐，例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH 2) n-COOH(其中n是0-4)的链烷二羧酸形成的盐等。“药学上可接受的盐”也包括带有酸性基团的式(I)化合物与药学上可接受的阳离子如钠、钾、钙、铝、锂和铵形成的碱加成盐。 The term "pharmaceutically acceptable salt" includes but is not limited to acid addition salts or base addition salts, for example: HADC inhibitors (including compounds of formula (I)) formed with inorganic acids, such as hydrochloride, hydrogen Bromate, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts formed by HADC inhibitors (including compounds of formula (I)) and organic acids, such as methyl Acid salt, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxy Ethyl sulfonate, benzoate, salicylate, stearate, and salt formed with alkane dicarboxylic acid of the formula HOOC-(CH 2 ) n -COOH (wherein n is 0-4), etc. "Pharmaceutically acceptable salts" also include base addition salts of compounds of formula (I) with acidic groups and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium.
术语“可药用的”是指那些适合用于与人类和动物组织接触使用而没有过多的毒性、刺激、过敏反应或其他问题或并发症，与合理的益处/风险比相称的化合物、材料、组合物和/或剂型。The term "pharmaceutically acceptable" refers to those compounds and materials that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and commensurate with a reasonable benefit/risk ratio , Composition and/or dosage form.
术语“不良事件”(AE)是与医学治疗的使用相关的任何不利且通常非预期或不想要的病征(包括异常实验室发现)、症状或疾病。例如，不良事件可以与免疫***响应治疗而激活或免疫***细胞(例如T细胞)响应治疗而扩增相关。医学治疗可以具有一种或多种相关AE，且各AE可以具有相同或不同水平的严重度。The term "adverse event" (AE) is any unfavorable and often unexpected or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of medical treatment. For example, an adverse event may be related to the activation of the immune system in response to treatment or the expansion of immune system cells (e.g., T cells) in response to treatment. Medical treatments can have one or more related AEs, and each AE can have the same or different levels of severity.
本文所用的“抗PD-1抗体”包括描述于WO2017025016、CN108473977B和WO2017133540中的抗PD-1抗体，其全部内容被引入本文作为参考。其中，所述抗PD-1抗体优选是WO2017025016A1中公开的抗PD-1抗体D-S228P IgG4，在本申请中也称为信迪利单抗。本文中所用的序列的编号直接对应于WO2017025016A1中的编号，未重新编号。The "anti-PD-1 antibody" used herein includes the anti-PD-1 antibodies described in WO2017025016, CN108473977B and WO2017133540, the entire contents of which are incorporated herein by reference. Wherein, the anti-PD-1 antibody is preferably the anti-PD-1 antibody D-S228P IgG4 disclosed in WO2017025016A1, which is also referred to as sintilimab in this application. The numbering of the sequence used herein directly corresponds to the numbering in WO2017025016A1, and has not been renumbered.
本文所用的“HDAC抑制剂”包括描述于中国申请03139760.3(公开号CN1513839A)中的化合物，其全部内容被引入本文作为参考。上文式I化合物中的术语定义参见中国申请03139760.3(公开号CN1513839A)。HDAC抑制剂优选为西达本胺"HDAC inhibitor" as used herein includes the compound described in Chinese application 03139760.3 (publication number CN1513839A), the entire content of which is incorporated herein by reference. For the definition of the terms in the compound of formula I above, please refer to Chinese Application 03139760.3 (Publication No. CN1513839A). The HDAC inhibitor is preferably Chidamide
Figure PCTCN2020138343-appb-000005
Figure PCTCN2020138343-appb-000005
或其可药用盐。Or its pharmaceutically acceptable salt.
本发明的药物组合的用途和使用本发明的药物组合治疗方法Use of the drug combination of the present invention and treatment method using the drug combination of the present invention
本发明提供了前述本发明的药物组合，其用于预防和/或治疗个体中癌症的至少一种症状或指征的严重性或抑制癌细胞生长。The present invention provides the aforementioned pharmaceutical combination of the present invention for preventing and/or treating the severity of at least one symptom or indication of cancer in an individual or inhibiting the growth of cancer cells.
本发明提供了预防或治疗癌症的方法，其包括向有需要的个体施用有效量的本发明的药物组合。所述有效量包括预防有效量和治疗有效量。The present invention provides a method of preventing or treating cancer, which comprises administering an effective amount of the pharmaceutical combination of the present invention to an individual in need. The effective amount includes a preventive effective amount and a therapeutically effective amount.
本发明提供了前述本发明的药物组合在制备用于预防或治疗癌症的药物中的用途。The present invention provides the use of the aforementioned pharmaceutical combination of the present invention in the preparation of drugs for the prevention or treatment of cancer.
本发明所述癌症包括实体瘤和血液***恶性肿瘤，例如非霍奇金淋巴瘤、肝细胞癌、卵巢癌、子宫内膜癌、肺癌、例如非小细胞肺癌、胸腺癌、肾癌、黑素瘤、头颈癌、膀胱癌、***癌、乳腺癌、胃肠道肿瘤、例如胃癌、胃腺癌、胃食管结合部腺癌、结肠癌、结肠直肠癌、结直肠腺癌、脑癌和骨癌。所述癌症优选是晚期癌症、顽固性癌症和/或对化疗产生耐药性的癌症，更优选晚期实体瘤、(经组织学或细胞学确诊的)不能手术切除或转移性晚期实体瘤。所述癌症优选是结外NK/T细胞淋巴瘤、肠癌(包括结肠直肠癌)、肺癌(包括非小细胞肺癌)。所述癌症优选是晚期复发性或转移性癌症(晚期恶性肿瘤)，优选晚期或难治复发的结外NK/T细胞淋巴瘤。The cancer of the present invention includes solid tumors and hematological malignancies, such as non-Hodgkin’s lymphoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, lung cancer, such as non-small cell lung cancer, thymic cancer, kidney cancer, melanoma Tumors, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors, such as stomach cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma, brain cancer, and bone cancer. The cancer is preferably advanced cancer, refractory cancer and/or cancer resistant to chemotherapy, more preferably advanced solid tumor, unresectable or metastatic advanced solid tumor (confirmed by histology or cytology). The cancer is preferably extranodal NK/T cell lymphoma, bowel cancer (including colorectal cancer), lung cancer (including non-small cell lung cancer). The cancer is preferably late-stage recurrent or metastatic cancer (advanced malignant tumor), preferably late-stage or refractory extranodal NK/T cell lymphoma.
本发明的药物组合可以施用于已经用一种或多种先前疗法治疗但随后复发或转移的个体。The drug combination of the present invention can be administered to individuals who have been treated with one or more previous therapies but subsequently relapsed or metastasized.
本发明的药物组合被施用于显示一种或多种癌症相关生物标志物[例如，程序性死亡配体1(PD-L1)、CA125、CA19-9、***特异性抗原(PSA)、乳酸脱氢酶、KIT、癌胚抗原、血管内皮生长因子(VEGF)]水平升高的个体。例如，向PD-L1水平升高和/或VEGF水平升高的个体施用预防有效量或治疗有效量的本发明的药物组合。The drug combination of the present invention is administered to display one or more cancer-related biomarkers [e.g., programmed death ligand 1 (PD-L1), CA125, CA19-9, prostate specific antigen (PSA), lactate Individuals with elevated levels of hydrogenase, KIT, carcinoembryonic antigen, vascular endothelial growth factor (VEGF)]. For example, a prophylactically effective amount or a therapeutically effective amount of the pharmaceutical combination of the present invention is administered to an individual with an elevated PD-L1 level and/or an elevated VEGF level.
本发明药物组合中的抗PD-1抗体可以以一个或多个剂量施用于有需要的个体，其中在施用多个剂量的情况下，在前一剂量之后1、2、3、4、5、6、7、8、9或10周施用下一个剂量。抗PD-1抗体的一个剂量可以选自0.1-10mg/kg个体体重(例如，0.3mg/kg、1mg/kg、3mg/kg或10mg/kg)。在一些其他实施方案中，每个剂量包含50-500mg的抗PD-1抗体，例如50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg或500mg抗PD-1抗体。The anti-PD-1 antibody in the pharmaceutical combination of the present invention can be administered to an individual in need in one or more doses, where in the case of administering multiple doses, after the previous dose 1, 2, 3, 4, 5, The next dose is administered at 6, 7, 8, 9 or 10 weeks. A dose of anti-PD-1 antibody may be selected from 0.1-10 mg/kg of the individual's body weight (for example, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg). In some other embodiments, each dose contains 50-500 mg of anti-PD-1 antibody, such as 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of anti-PD-1 antibody.
本发明药物组合中的HDAC抑制剂(例如，西达本胺或其可药用盐)以约一天一次、每两天一次、每三天一次、每四天一次、每周两次、每周一次、每两周一次连续施用，或以每周两次施用三周且每三周停一周、每周两次施用两周且每两周停一周的方案使用。HDAC抑制 剂的剂量为10至50mg/次，例如10mg/次、15mg/次、20mg/次、25mg/次、30mg/次、35mg/次、40mg/次、45mg/次或50mg/次。The HDAC inhibitor (for example, chidamide or its pharmaceutically acceptable salt) in the pharmaceutical combination of the present invention is administered approximately once a day, once every two days, once every three days, once every four days, twice a week, and weekly One time, once every two weeks for continuous administration, or two times a week for three weeks and one week off every three weeks, two times a week for two weeks and two weeks off for one week. The dosage of the HDAC inhibitor is 10 to 50 mg/time, for example, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 45 mg/time, or 50 mg/time.
在一个实施方案中，本发明的药物组合可以施用至少一个周期，例如2-12或更多个治疗周期，优选地其中所述一个周期施用1-2个剂量的抗PD-1抗体，且至少在每个周期的第1至10天施用HDAC抑制剂、优选在第1至14天或在第1至21天施用HDAC抑制剂，优选每周施用两次，且优选地每个周期为至少15至30天、更优选为21天或28天。In one embodiment, the pharmaceutical combination of the present invention can be administered for at least one cycle, for example 2-12 or more treatment cycles, preferably wherein the one cycle is administered 1-2 doses of anti-PD-1 antibody, and at least The HDAC inhibitor is administered on days 1 to 10 of each cycle, preferably on days 1 to 14 or on days 1 to 21, preferably twice a week, and preferably at least 15 per cycle To 30 days, more preferably 21 days or 28 days.
优选地，本发明的药物组合中的HDAC抑制剂以10至50mg/次，例如10mg/次、15mg/次、20mg/次、25mg/次、30mg/次、35mg/次、40mg/次、45mg/次或50mg/次的剂量每周两次口服，连续施用2、3或4周停1周或者在使用周期内连续施用，且抗PD-1抗体以100-300mg、例如200mg静脉输注，每3、4或5周一次，每3、4或5周为一个周期。Preferably, the HDAC inhibitor in the pharmaceutical combination of the present invention is at a dose of 10 to 50 mg/time, for example, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 45 mg A dose of 50 mg/time or 50 mg/time is taken orally twice a week, continuously administered for 2, 3 or 4 weeks and stopped for 1 week or continuously administered during the use cycle, and the anti-PD-1 antibody is administered intravenously at 100-300 mg, such as 200 mg, Once every 3, 4, or 5 weeks, every 3, 4, or 5 weeks is a cycle.
优选地，本发明的药物组合中的HDAC抑制剂以20mg的剂量每周两次口服，连续施用，且抗PD-1抗体以200mg静脉输注，每3周一次。Preferably, the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally at a dose of 20 mg twice a week for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks.
优选地，本发明的药物组合中的HDAC抑制剂以25mg的剂量每周两次口服，连续施用，且抗PD-1抗体以200mg静脉输注，每3周一次。Preferably, the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally at a dose of 25 mg twice a week for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks.
优选地，本发明的药物组合中的HDAC抑制剂以30mg的剂量每周两次口服，连续施用，且抗PD-1抗体以200mg静脉输注，每3周一次，每3周一个周期。Preferably, the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally twice a week at a dose of 30 mg for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks, once every 3 weeks.
优选地，本发明的药物组合中的抗PD-1抗体可以在开始施用HDAC抑制剂之前、同时、或者之后施用。当抗PD-1抗体在开始施用HDAC抑制剂“之前”施用时，抗PD-1抗体可以在开始施用HDAC抑制剂之前大于150小时、约150小时、约100小时、约72小时、约60小时、约48小时、约36小时、约24小时、约12小时、约10小时、约8小时、约6小时、约4小时、约2小时、约1小时、或约30分钟、约15分钟或约10分钟施用。当在开始施用HDAC抑制剂之后施用时，抗PD-1抗体可以在开始施用HDAC抑制剂之后约10分钟、约15分钟、约30分钟、约1小时、约2小时、约4小时、约6小时、约8小时、约10小时、约12小时、约24小时、约36小时、约48小时、约60小时、约72小时或多于72小时施用。与开始施用HDAC抑制剂“同时”施用意味着抗PD-1抗体在开始施用HDAC抑制剂的少于10分钟以内(之前、之后或同时)施用于个体。优选地，本发明的药物组合中的抗PD-1抗体在开始施用HDAC抑制剂之后施用，例如，抗PD-1抗体在开始施用HDAC抑制剂之后约1小时、约3小时、约6小时、约12小时、约15小时施用。Preferably, the anti-PD-1 antibody in the pharmaceutical combination of the present invention may be administered before, at the same time, or after the start of administration of the HDAC inhibitor. When the anti-PD-1 antibody is administered "before" the start of the HDAC inhibitor, the anti-PD-1 antibody may be greater than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours before the start of the HDAC inhibitor. , About 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes, about 15 minutes or Approximately 10 minutes to apply. When administered after the HDAC inhibitor starts to be administered, the anti-PD-1 antibody may be about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 minutes after the start of administration of the HDAC inhibitor. Hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours. Administration "simultaneously" with the start of administration of the HDAC inhibitor means that the anti-PD-1 antibody is administered to the individual within less than 10 minutes (before, after, or simultaneously) of the start of administration of the HDAC inhibitor. Preferably, the anti-PD-1 antibody in the pharmaceutical combination of the present invention is administered after the HDAC inhibitor starts to be administered, for example, the anti-PD-1 antibody is administered about 1 hour, about 3 hours, about 6 hours after the start of the HDAC inhibitor administration. About 12 hours, about 15 hours administration.
优选地，本发明的药物组合中的抗PD-1抗体为注射剂，如果以静脉输注方式施用，则施用时间可以为约15-60分钟。Preferably, the anti-PD-1 antibody in the pharmaceutical combination of the present invention is an injection, and if it is administered by intravenous infusion, the administration time may be about 15-60 minutes.
在一些实施方案中，与施用抗PD-1抗体的单一疗法或施用HDAC抑制剂的单一疗法的患者相比，施用至少一个周期的本发明的药物组合导致提高、优选协同地提高患者的ORR(客观缓解率)、CRR(完全缓解率)、无进展生存(PFS)或总体生存(OS)。在一些实施方案中，与施用抗PD-1抗体的单一疗法或施用HDAC抑制剂的单一疗法的患者相比，施用至少一个周期的本发明的药物组合导致患者的PFS增加至少约1个月、约2个月、约3个月、约4个月、约5个月、约6个月、约7个月、约8个月、约9个月、约10个月、约11个月、约1年、 约2年或更长时间。在一些实施方案中，与施用抗PD-1抗体的单一疗法或施用HDAC抑制剂的单一疗法的患者相比，施用至少一个周期的本发明的药物组合导致患者的OS增加至少约1个月、约2个月、约3个月、约4个月、约5个月、约6个月、约7个月、约8个月、约9个月、约10个月、约11个月、约1年、约2年或更长时间。In some embodiments, the administration of at least one cycle of the drug combination of the present invention results in an increased, preferably synergistically increased, ORR of the patient compared to a patient administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy ( Objective response rate), CRR (complete response rate), progression-free survival (PFS) or overall survival (OS). In some embodiments, the administration of at least one cycle of the drug combination of the present invention results in an increase in the patient's PFS by at least about 1 month, compared to a patient administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy. About 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, About 1 year, about 2 years or more. In some embodiments, the administration of at least one cycle of the drug combination of the present invention results in an increase in the patient's OS by at least about 1 month, compared to patients who are administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy. About 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, About 1 year, about 2 years or more.
与施用抗PD-1抗体的单一疗法或施用HDAC抑制剂的单一疗法相比，本发明的药物组合导致提高、优选协同地提高对癌症的治疗效果。在一些实施方案中，与施用抗PD-1抗体的单一疗法或施用HDAC抑制剂的单一疗法相比，本发明的药物组合导致患者的ORR(客观缓解率)提高约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约90％、约100％、约110％、约120％、约130％、约140％、约150％、约200％或约300％。在一些实施方案中，与施用抗PD-1抗体的单一疗法或施用HDAC抑制剂的单一疗法相比，本发明的药物组合导致患者的CRR(完全缓解率)提高约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约90％、约100％、约110％、约120％、约130％、约140％、约150％、约200％或约300％。Compared with monotherapy with the administration of anti-PD-1 antibodies or monotherapy with the administration of HDAC inhibitors, the drug combination of the present invention results in an improved, preferably synergistically improved, therapeutic effect on cancer. In some embodiments, compared with the administration of anti-PD-1 antibody monotherapy or the administration of HDAC inhibitor monotherapy, the drug combination of the present invention results in a patient's ORR (objective response rate) increased by about 10%, about 20%, About 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150 %, about 200%, or about 300%. In some embodiments, compared with the administration of anti-PD-1 antibody monotherapy or the administration of HDAC inhibitor monotherapy, the drug combination of the present invention results in a patient's CRR (complete remission rate) increased by about 10%, about 20%, About 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150 %, about 200%, or about 300%.
与施用抗PD-1抗体的单一疗法或施用HDAC抑制剂的单一疗法相比，本发明的药物组合导致增加、优选协同地增加对肿瘤生长的抑制作用。在一些实施方案中，与施用抗PD-1抗体的单一疗法或施用HDAC抑制剂的单一疗法相比，本发明的药物组合导致肿瘤生长被抑制至少约10％、约20％、约30％、约40％、约50％、约60％、约70％或约80％。在一些实施方案中，本发明的药物组合的施用导致增加肿瘤消退、肿瘤缩小和/或消失。在一些实施方案中，与未治疗的个体或与使用抗PD-1抗体的单一疗法或使用HDAC抑制剂的单一疗法相比，本发明的药物组合预防个体的肿瘤复发和/或增加生存持续时间，例如，将生存持续时间增加多于15天、多于1个月、多于3个月、多于6个月、多于12个月、多于18个月、多于24个月、多于36个月、或多于48个月。在一些实施方案中，本发明的药物组合可增加无进展生存或总体生存。Compared with the monotherapy of administration of anti-PD-1 antibodies or monotherapy of administration of HDAC inhibitors, the drug combination of the present invention results in an increase, preferably a synergistic increase in the inhibitory effect on tumor growth. In some embodiments, the drug combination of the present invention results in tumor growth being inhibited by at least about 10%, about 20%, about 30%, compared with the administration of anti-PD-1 antibody monotherapy or the administration of HDAC inhibitor monotherapy. About 40%, about 50%, about 60%, about 70%, or about 80%. In some embodiments, administration of the drug combination of the invention results in increased tumor regression, tumor shrinkage and/or disappearance. In some embodiments, the drug combination of the present invention prevents tumor recurrence and/or increases the duration of survival in an individual compared with an untreated individual or with a monotherapy with an anti-PD-1 antibody or a monotherapy with an HDAC inhibitor For example, increase the duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more Within 36 months, or more than 48 months. In some embodiments, the drug combination of the present invention can increase progression-free survival or overall survival.
在一些实施方案中，向患有癌症的个体施用本发明的药物组合导致肿瘤的完全消失(“完全反应”)。在一些实施方案中，向患有癌症的个体施用本发明的药物组合导致肿瘤细胞或肿瘤大小减少至少30％或更多(“部分反应”)。可以通过本领域已知的任何方法测量肿瘤的减少，例如X-线、正电子发射断层扫描(PET)、计算机断层扫描(CT)、磁共振成像(MRI)、细胞学、组织学或分子遗传分析。In some embodiments, administration of the drug combination of the invention to an individual suffering from cancer results in the complete disappearance of the tumor ("complete response"). In some embodiments, administration of the drug combination of the invention to an individual suffering from cancer results in a reduction in tumor cells or tumor size by at least 30% or more ("partial response"). The tumor reduction can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computer tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetics analysis.
在一些实施方案中，本发明的药物组合可以减少由施用抗PD-1抗体和/或HDAC抑制剂导致的不良事件，例如血液学毒性反应、非血液学毒性反应或其他毒性反应，例如肺炎、腹泻、小肠结肠炎、肾功能不全、皮疹、肝炎、内分泌疾病和外周或中枢神经炎、肝功能异常等。In some embodiments, the pharmaceutical combination of the present invention can reduce adverse events caused by the administration of anti-PD-1 antibodies and/or HDAC inhibitors, such as hematological toxic reactions, non-hematological toxic reactions or other toxic reactions, such as pneumonia, Diarrhea, enterocolitis, renal insufficiency, skin rash, hepatitis, endocrine disease and peripheral or central neuritis, liver function abnormalities, etc.
本发明的药盒The kit of the present invention
本发明的另一个目的是提供一种成套药盒，其包含本发明的药物组合，优选地所述药盒为单次药物剂量单元形式。Another object of the present invention is to provide a kit of medicines comprising the drug combination of the present invention, preferably the kit is in the form of a single drug dosage unit.
在一个实施方案中，本发明的成套药盒在同一包装内包含：In one embodiment, the kit of the present invention contains in the same package:
-含有用于胃肠外施用的药物组合物的第一容器，所述药物组合物包含上面所述的抗PD-1抗体；-A first container containing a pharmaceutical composition for parenteral administration, the pharmaceutical composition comprising the anti-PD-1 antibody described above;
-含有用于口服施用的药物组合物的第二容器，所述药物组合物包含上面所述的HDAC抑制剂。-A second container containing a pharmaceutical composition for oral administration, said pharmaceutical composition containing the HDAC inhibitor described above.
本发明所述的各个实施方案/技术方案以及各个实施方案/技术方案中的特征应当被理解为可以任意进行相互组合，这些相互组合得到的各个方案均包括在本发明的范围内，就如同在本文中具体地且逐一地列出了这些相互组合而得到的方案一样，除非上下文清楚地显示并非如此。The various embodiments/technical solutions described in the present invention and the features in the various embodiments/technical solutions should be understood to be arbitrarily combined with each other, and the various solutions obtained by these mutual combinations are all included in the scope of the present invention, just like in This article specifically and one by one lists the solutions obtained by combining these mutually, unless the context clearly shows otherwise.
描述以下实施例以辅助对本发明的理解。不意在且不应当以任何方式将实施例解释成对本发明的保护范围的限制。The following examples are described to assist the understanding of the present invention. It is not intended and should not be construed in any way to limit the scope of protection of the present invention.
附图说明Description of the drawings
图1.14例可评价疗效患者病灶变化Figure 1.14 Changes in lesions in patients with evaluable efficacy
图2.受试者0101病灶变化Figure 2. Changes in the lesions of subject 0101
图3.受试者0103病灶变化Figure 3. Changes in the lesions of subject 0103
具体实施方式Detailed ways
进一步通过以下非限制性实例来说明本发明，其不旨在限制本发明所涵盖的范围。The present invention is further illustrated by the following non-limiting examples, which are not intended to limit the scope of the present invention.
实施例1Example 1
1.受试药物1. Test drug
信迪利单抗注射液(Sintilimab Injection)：规格10ml:100mg，信达生物制药(苏州)有限公司。Sintilimab Injection: Specification 10ml:100mg, Xinda Biopharmaceutical (Suzhou) Co., Ltd.
西达本胺(Chidamide)：规格5mg，深圳微芯生物科技股份有限公司。Chidamide: Specification 5mg, Shenzhen Chipset Biotechnology Co., Ltd.
2.入组受试者标准2. Criteria for enrolled subjects
入选标准：standard constrain:
1)自愿参加临床研究；完全了解、知情本研究并签署知情同意书(Informed Consent Form，ICF)；愿意遵循并有能力完成所有试验程序。1) Volunteer to participate in clinical research; fully understand and know the research and sign the Informed Consent Form (ICF); willing to follow and have the ability to complete all trial procedures.
2)签署ICF时年龄≥18岁，且≤75周岁。2) The age at the time of signing the ICF is ≥18 years old and ≤75 years old.
3)经研究中心组织病理学确认的ENKTL。3) ENKTL confirmed by research center histopathology.
4)可供使用的既往或者新鲜的粗针穿刺或切除获得的肿瘤组织样本(10-15张未经染色、新鲜冷冻、石蜡包埋[FFPE]的玻片)。4) Available tumor tissue samples (10-15 unstained, fresh-frozen, paraffin-embedded [FFPE] glass slides) obtained from past or fresh coarse needle puncture or excision.
5)经过以门冬酰胺酶为基础的化疗或放化疗方案治疗失败的难治复发ENKTL。5) Refractory and relapsed ENKTL that has failed the treatment of asparaginase-based chemotherapy or radiotherapy and chemotherapy.
难治定义：i)经含门冬酰胺酶方案化疗后疗效未达PR；或ii)末次含门冬酰胺酶方案6个月内疾病进展。Definition of refractory: i) The curative effect did not reach PR after chemotherapy with asparaginase-containing regimen; or ii) the disease progressed within 6 months of the last asparaginase-containing regimen.
6)ECOG评分为0～1。6) The ECOG score is 0 to 1.
7)预计生存大于3个月。7) Expected survival is greater than 3 months.
8)必须有至少1个符合RECIL 2017淋巴瘤标准的可评价或可测量病灶【可评价病灶：18氟去氧葡萄糖-正电子发射断层扫描(18F-Fluorodeoxyglucose/Positron Emission Tomography，18FDG/PET)检查显示***或结外局部摄取增高(高于肝脏)且PET和/或计算机断层扫描(Computed Tomography，CT)特征符合淋巴瘤表现；可测量病灶：结节病灶长径>15mm或结外病灶长径>10mm(如果唯一的可测量病灶既往接受过放疗，须有放疗后影像学进展证据)，且伴有18FDG摄取增高】。需除外没有可测量病灶、且肝脏弥漫性18FDG摄取增高的情况。8) There must be at least 1 evaluable or measurable lesion that meets the RECIL 2017 lymphoma standard [evaluable lesion: 18F-Fluorodeoxyglucose/Positron Emission Tomography, 18FDG/PET) examination Shows increased local uptake in lymph nodes or extranodal areas (higher than liver) and PET and/or Computed Tomography (CT) features are consistent with lymphoma; measurable lesions: nodular lesions longer than 15mm or extranodal lesions longer diameter >10mm (if the only measurable lesion has received radiotherapy in the past, there must be evidence of imaging progression after radiotherapy) and accompanied by increased 18FDG uptake]. It is necessary to exclude the case where there is no measurable lesion and the diffuse 18FDG uptake in the liver is increased.
9)足够的器官及骨髓功能，无严重的造血功能异常及心、肺、肝、肾、甲状腺功能异常和免疫缺陷(在使用研究药物前14天内，未接受输血、粒细胞集落刺激因子或其他相关医学支持)：9) Sufficient organ and bone marrow function, no serious hematopoietic dysfunction, abnormal heart, lung, liver, kidney, thyroid dysfunction and immunodeficiency (without receiving blood transfusion, granulocyte colony stimulating factor or other within 14 days before using the study drug) Related medical support):
a)中性粒细胞绝对值≥1.0×10 9/L； a) The absolute value of neutrophils ≥1.0×10 9 /L;
b)血小板≥75×10 9/L； b) Platelets ≥75×10 9 /L;
c)血红蛋白≥9g/dL；c) Hemoglobin ≥9g/dL;
d)血清肌酐≤1.5倍正常值上限(Upper Limit Normal，ULN)，或肌酐清除率≥40mL/min(依据Cockcroft-Gault公式估算)；d) Serum creatinine ≤ 1.5 times the upper limit of normal (Upper Limit Normal, ULN), or creatinine clearance ≥ 40 mL/min (estimated based on the Cockcroft-Gault formula);
e)血清总胆红素≤1.5倍ULN；e) Serum total bilirubin ≤ 1.5 times ULN;
f)天冬氨酸氨基转移酶(Aspartate Aminotransferase，AST)、丙氨酸氨基转移酶(Alanine Aminotransferase，ALT)≤2.5倍ULN；f) Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) ≤2.5 times ULN;
g)凝血功能：国际标准化比值(International Normalized Ratio，INR)≤1.5倍ULN；凝血酶原时间(Prothrombin Time，PT)、活化部分凝血活酶时间(Activated Partial Thromboplastin Time，APTT)≤1.5倍ULN(除非受试者正在接受抗凝剂治疗，并且在筛选时PT和APTT在使用抗凝剂治疗的预期范围内)。g) Coagulation function: International Normalized Ratio (INR) ≤ 1.5 times ULN; Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN ( Unless the subject is receiving anticoagulant therapy, and PT and APTT are within the expected range of anticoagulant therapy at the time of screening).
h)促甲状腺素(TSH)或游离甲状腺素(FT4)或游离三碘甲状腺原氨酸(FT3)均在正常值±10％范围内。h) Thyroid-stimulating hormone (TSH) or free thyroxine (FT4) or free triiodothyronine (FT3) are all within ±10% of the normal value.
10)没有证据显示受试者在静息时呼吸困难，并且在静息时的脉搏血氧测定值＞92％。10) There is no evidence that the subject has difficulty breathing at rest, and the pulse oximetry value at rest is >92%.
11)受试者必须通过肺功能检查(PFT)证实第一秒钟用力呼气量(FEV1)/用力肺活量(FVC)＞60％，除非是因霍奇金淋巴瘤引起的大纵膈肿块而无法达到这一标准；一氧化碳弥散量(DLCO)、FEV1和FVC均超出预测值50％以上；所有PFT结果必须是在信迪利单抗首次给药前4周内获得的。11) Subjects must pass pulmonary function tests (PFT) to confirm that forced expiratory volume (FEV1)/forced vital capacity (FVC)> 60% in the first second, unless it is caused by a large mediastinal mass caused by Hodgkin’s lymphoma This standard cannot be met; the diffusion of carbon monoxide (DLCO), FEV1 and FVC are more than 50% above the predicted value; all PFT results must be obtained within 4 weeks before the first administration of Sintilimab.
12)受试者如既往接受过抗肿瘤治疗，应在以往治疗的毒性反应恢复至常见不良反应事件评价标准(Common Terminology Criteria for Adverse Events，CTCAE)v4.03等级评分≤1级或基线水平后才可入组；既往抗肿瘤治疗造成的不可逆转且预期不会在接受研究治疗期间恶化的2级毒性(如血小板减少、贫血、神经毒性、脱发和听力下降)，经研究者同意后，可以入组。12) Subjects who have received anti-tumor therapy in the past should return to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grade score ≤ level 1 or baseline level after the toxicity of the previous treatment has returned to the evaluation criteria for common adverse events (CTCAE) Entry into the group; Grade 2 toxicity (such as thrombocytopenia, anemia, neurotoxicity, alopecia, and hearing loss) caused by previous anti-tumor therapy that is irreversible and is not expected to worsen during the study treatment period, with the consent of the investigator, you can Join the group.
13)有生育能力的女性(Women of Childbearing Potential，WOBCP)必须在首次用药前7天内进行血清妊娠试验，且结果为阴性；WOBCP或男性及其WOBCP伴侣应同意从签署 ICF开始直至使用最后一剂研究药物后6个月内采取有效的避孕措施。13) Women of Childbearing Potential (WOBCP) must undergo a serum pregnancy test within 7 days before the first medication, and the result is negative; WOBCP or men and their WOBCP partners should agree from signing the ICF to the last dose Take effective contraceptive measures within 6 months after the study drug.
3.给药方法及过程3. Administration method and process
本研究为Ib/Ⅱ期临床研究，分为两个部分。在Ib期阶段，受试者接受西达本胺和信迪利单抗，该阶段主要进行西达本胺剂量探索。西达本胺初始剂量：设置3个剂量组(20mg、25mg、30mg)，每组3-6名受试者。起始剂量：20mg/次，2次/周，连续口服。如果未出现DLT(Dose-LimitingToxicities，剂量限制性毒性)，按照既定的剂量递增方案，继续下一剂量水平试验。若出现1例DLT，在该剂量水平上增加3名受试者，当未再出现新的DLT，则继续下一剂量水平试验。如果出现≥2例DLT，该剂量水平的前一剂量水平定义为MTD(Maximum Tolerated Dose，最大耐受剂量)。信迪利单抗剂量：200mg/次(固定剂量)、1次/3周、静脉输注。This study is a phase Ib/II clinical study, divided into two parts. In phase Ib, subjects received chidamide and sintilizumab, and the dose of chidamide was explored in this phase. The initial dose of chidamide: 3 dose groups (20mg, 25mg, 30mg) are set up, with 3-6 subjects in each group. Starting dose: 20 mg/time, 2 times/week, for continuous oral administration. If DLT (Dose-Limiting Toxicities) does not appear, follow the established dose escalation plan to continue the next dose level test. If there is 1 case of DLT, add 3 subjects to this dose level. When no new DLT appears, continue to the next dose level test. If there are ≥ 2 cases of DLT, the previous dose level of this dose level is defined as MTD (Maximum Tolerated Dose). Sintilimab dose: 200mg/time (fixed dose), 1 time/3 weeks, intravenous infusion.
II期研究的给药方法：西达本胺剂量为RP2D剂量(Recommended Phase II Dose，推荐II期临床研究剂量)，2次/周，连续口服；信迪利单抗剂量：200mg/次(固定剂量)、1次/3周、静脉输注。The administration method of the phase II study: the dose of chidamide is RP2D dose (Recommended Phase II Dose, the recommended phase II clinical study dose), 2 times a week, continuous oral; Sintilizumab dose: 200 mg/time (fixed Dose), 1 time/3 weeks, intravenous infusion.
DLT定义：受试者接受连续治疗2个疗程(6周)内出现与研究药物有关的以下分级的毒性反应(按NCI CTCAE v5.0毒性评价标准，包括但不限于)：Ⅳ级的血液性毒性，包括但不限于以下：发热性中性粒细胞减少(ANC＜1.0×10 9/L伴单次体温＞38.3℃，或持续体温≥38℃超过1h)；Ⅲ级或以上的非血液学毒性(不包括脱发及3天内可以纠正的电解质紊乱)；尽管对症处理，仍出现≥Ⅲ级的恶心、呕吐或腹泻。 DLT definition: The subject has the following graded toxicity related to the study drug (according to the NCI CTCAE v5.0 toxicity evaluation standard, including but not limited to) within 2 consecutive courses of treatment (6 weeks): grade IV blood Toxicity, including but not limited to the following: febrile neutropenia (ANC<1.0×10 9 /L with a single body temperature >38.3℃, or continuous body temperature ≥38℃ for more than 1h); non-hematology of grade Ⅲ or above Toxicity (excluding hair loss and electrolyte imbalance that can be corrected within 3 days); despite symptomatic treatment, nausea, vomiting or diarrhea of grade ≥ III still occurs.
4.试验结果4. Test results
Ib期研究：Phase Ib study:
2019年3月29日-2019年6月21日，中山大学肿瘤防治中心共入组9例受试者。9例受试者分为3组，每组3例进行西达本胺剂量爬升研究。3个剂量级分别是20mg、25mg、30mg，biw(每周两次)。9例受试者中除受试者0106、0107因疾病进展(分别接受了5、3疗程)，未能完成6疗程治疗以外，其余7例受试者均完成6疗程以上联合治疗。3个剂量组受试者均未出现MTD、DLT，因此推荐RP2D剂量为30mg biw。From March 29, 2019 to June 21, 2019, the Sun Yat-sen University Cancer Center enrolled a total of 9 subjects. The 9 subjects were divided into 3 groups, and 3 patients in each group were subjected to a study of chidamide dose climbing. The three dosage levels are 20mg, 25mg, 30mg, biw (twice a week). Except for subjects 0106 and 0107 who failed to complete 6 courses of treatment due to disease progression (received 5 and 3 courses of treatment respectively) among the 9 subjects, the remaining 7 subjects all completed more than 6 courses of combined treatment. Subjects in the three dose groups did not have MTD or DLT, so the recommended dose of RP2D is 30 mg biw.
Ib期9例受试者均可进行疗效评价，其中7例受试者(0101、0102、0103、0104、0105、0108、0109)获得CR(Complete Response，完全缓解)，1例受试者(0106)获得PR(Partial Response，部分缓解)后再次进展，1例受试者(0107)疗效PD(Progressive Disease，疾病进展)。Ib期研究ORR(Objective Response Rate，客观缓解率)为88.9％(8/9)，CRR(Complete Response Rate，完全缓解率)为77.8％(7/9)。9 subjects in stage Ib can be evaluated for efficacy, of which 7 subjects (0101, 0102, 0103, 0104, 0105, 0108, 0109) obtained CR (Complete Response), and 1 subject ( 0106) After obtaining PR (Partial Response), it progressed again, and 1 subject (0107) had the effect of PD (Progressive Disease, disease progression). In the phase Ib study, ORR (Objective Response Rate, objective response rate) was 88.9% (8/9), and CRR (Complete Response Rate, complete response rate) was 77.8% (7/9).
II期研究：Phase II study:
II期研究采用simon两阶段最优设计方法，第一阶段入组7例患者，如果只有4例或更少的患者有效，则终止试验。否则，进入第二阶段，第二阶段再入组21例患者，即II期研究共入组28例患者。Ib期研究结束后随后进行了II期临床研究，截止到2019年11月4日，II期研究已入组11例受试者。0117-0120受试者仅接受1程治疗，尚未进行疗效评价。其中， 0110-0116受试者中5例患者可进行疗效评价，2例CR，2例SD(疾病稳定)，1例PD。The phase II study adopted the simon two-phase optimal design method. In the first phase, 7 patients were enrolled. If only 4 or fewer patients are effective, the trial will be terminated. Otherwise, enter the second phase, and 21 patients will be enrolled in the second phase, that is, a total of 28 patients will be enrolled in the phase II study. After the end of the Phase Ib study, a Phase II clinical study was conducted. As of November 4, 2019, 11 subjects have been enrolled in the Phase II study. Subject 0117-0120 received only one course of treatment, and the efficacy has not been evaluated yet. Among them, 5 of the 0110-0116 subjects can be evaluated for efficacy, 2 cases of CR, 2 cases of SD (stable disease), and 1 case of PD.
综合目前Ib和II期研究入组情况，已入组20例受试者(一般临床特征见表1)，其中14例可进行疗效评价，ORR 71.4％(10/14)，CR率64.3％(9/14)，PR率7.1％(1/14)。CR率较既往PD-1单抗治疗难治复发ENKTL显著提高(图1)，组合治疗产生显著的协同效果。Based on the current enrollment status of Phase Ib and II studies, 20 subjects have been enrolled (see Table 1 for general clinical characteristics), 14 of which can be evaluated for efficacy, ORR 71.4% (10/14), CR rate 64.3% ( 9/14), the PR rate was 7.1% (1/14). The CR rate was significantly higher than that of previous PD-1 monoclonal antibody treatment of refractory and relapsed ENKTL (Figure 1), and the combined treatment produced a significant synergistic effect.
安全性：safety:
本研究总体安全性较高，未出现治疗相关死亡。The overall safety of this study was relatively high, and there were no treatment-related deaths.
实施例2Example 2
受试者0101，男，52岁。Subject 0101, male, 52 years old.
NK/T细胞淋巴瘤放化疗后2年余右肺复发。NK/T cell lymphoma recurred in the right lung more than 2 years after radiotherapy and chemotherapy.
2016年11月，患者确诊鼻腔NK/T细胞淋巴瘤I期，行P-Gemox方案化疗4程，局部放疗50Gy，疗效CR。2019年3月，因“咳嗽”发现右下肺团块影，大小约4.9×5.8×6.0cm。2019.3.22我院肺肿物穿刺病理为NK/T细胞淋巴瘤。2019.3.29患者入组本研究，1程治疗后7天咳嗽症状消失，2程后复查PET/CT疗效CR(图2)，目前已完成11程治疗，持续CR中。In November 2016, the patient was diagnosed with nasal cavity NK/T cell lymphoma stage I, and received 4 cycles of P-Gemox chemotherapy, local radiotherapy 50Gy, and the curative effect was CR. In March 2019, a lump in the right lower lung was found due to "cough", the size of which was about 4.9×5.8×6.0cm. 2019.3.22 The pathology of lung tumor puncture in our hospital was NK/T cell lymphoma. The patient was enrolled in this study on March 29, 2019. The cough symptoms disappeared 7 days after 1 course of treatment, and the PET/CT curative effect CR was rechecked after 2 courses (Figure 2). At present, 11 courses of treatment have been completed and the CR continues.
Figure PCTCN2020138343-appb-000006
Figure PCTCN2020138343-appb-000006
实施例3Example 3
受试者0103，女，20岁。Subject 0103, female, 20 years old.
NK/T细胞淋巴瘤合并嗜血细胞综合征，化疗后及抗PD-1抗体注射液维持后复发。NK/T cell lymphoma complicated with hematopoietic syndrome, recurrence after chemotherapy and maintenance of anti-PD-1 antibody injection.
患者在2018年3月确诊NK/T细胞淋巴瘤合并嗜血细胞综合征，经过HLH2004方案治疗后嗜血现象纠正，再行P-Gemox方案化疗3程，疗效PR。2018.6-2018.8行Pembrolizumab治疗4程，疗效CR。后因经济原因，停止治疗。2019年4月患者因“持续高热”就诊，2019-4-28我院PET/CT提示：右锁骨上、双侧锁骨下、纵膈、右肺门、肝门、门腔间隙、右肾后方多发肿大***。双肺多发结节代谢浓聚，肝脏多个低密度影，代谢活跃。2019-5-6肝脏穿刺活检为NK/T细胞淋巴瘤。患者同时合并三系轻度下降，EBV-DNA＝3.6×10 4copy/ml。确诊后，患者于2019.5.8入组本研究，目前已完成10程治疗，2程后疗效CR(图3)。1程后发热消失，EBV-DNA降为0。 The patient was diagnosed with NK/T-cell lymphoma with hemophagocytic syndrome in March 2018. After treatment with HLH2004 regimen, the bloodthirsty phenomenon was corrected, and then the P-Gemox regimen was given 3 cycles of chemotherapy, and the curative effect was PR. From 2018.6-2018.8, Pembrolizumab was treated for 4 courses, and the effect was CR. Later, the treatment was stopped due to economic reasons. In April 2019, the patient went to the doctor due to "continuous high fever". On April 28, 2019, PET/CT in our hospital showed: right supraclavicular, bilateral subclavian, mediastinum, right hilum, hepatic hilum, portal space, right kidney posterior Multiple enlarged lymph nodes. Multiple nodules in both lungs have concentrated metabolism, multiple low-density shadows in the liver, and active metabolism. 2019-5-6 Liver biopsy was NK/T cell lymphoma. The patient combined with three lines at the same time slightly decreased, EBV-DNA=3.6×10 4 copy/ml. After the diagnosis, the patient was enrolled in the study on May 2019. At present, he has completed 10 courses of treatment, and the curative effect is CR after 2 courses (Figure 3). The fever disappeared after 1 cycle, and the EBV-DNA dropped to zero.
Figure PCTCN2020138343-appb-000007
Figure PCTCN2020138343-appb-000007
Figure PCTCN2020138343-appb-000008
Figure PCTCN2020138343-appb-000008
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尽管已经出于说明本发明的目的显示了某些代表性实施方案和细节，但是本领域技术人员显而易见的是可以对它们进行多种变化和修改而不脱离主题发明的范围。在这个方面，本发明范围仅由以下权利要求限定。Although certain representative embodiments and details have been shown for the purpose of illustrating the present invention, it will be obvious to those skilled in the art that various changes and modifications can be made to them without departing from the scope of the subject invention. In this regard, the scope of the invention is limited only by the following claims.

Claims (14)

  1. 一种药物组合，其包含PD-1抗体或其抗原结合片段和HDAC抑制剂，A pharmaceutical combination comprising a PD-1 antibody or an antigen-binding fragment thereof and an HDAC inhibitor,
    其中抗PD-1抗体包含6个CDR，其中LCDR1、LCDR2和LCDR3分别由氨基酸序列RASQGISSWLA(SEQ ID NO:9)、SAASSLQS(SEQ ID NO:10)和QQANHLPFT(SEQ ID NO:11)组成，且其中HCDR1、HCDR2和HCDR3分别由氨基酸序列KASGGTFSSYAIS(SEQ ID NO:2)、LIIPMFDTAGYAQKFQG(SEQ ID NO:5)和ARAEHSSTGTFDY(SEQ ID NO:8)组成；或The anti-PD-1 antibody contains 6 CDRs, and LCDR1, LCDR2, and LCDR3 are composed of the amino acid sequences RASQGISSWLA (SEQ ID NO: 9), SAASSLQS (SEQ ID NO: 10) and QQANHLPFT (SEQ ID NO: 11), respectively, and Wherein HCDR1, HCDR2 and HCDR3 are respectively composed of amino acid sequences KASGGTFSSYAIS (SEQ ID NO: 2), LIIPMFDTAGYAQKFQG (SEQ ID NO: 5) and ARAEHSSTGTFDY (SEQ ID NO: 8); or
    其中抗PD-1抗体选自信迪利单抗、帕博利珠单抗、纳武利尤单抗、特瑞普利单抗和卡瑞利珠单抗；The anti-PD-1 antibody is selected from sintilizumab, pembrolizumab, nivolizumab, teriprizumab and carrelizumab;
    其中HDAC抑制剂选自下述式I化合物或其可药用盐：Wherein the HDAC inhibitor is selected from the following compounds of formula I or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020138343-appb-100001
    Figure PCTCN2020138343-appb-100001
    其中，A为苯环或杂环，可以含有1至4个取代基，其取代基可以是卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酰氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基、苯基或杂环取代基；Among them, A is a benzene ring or heterocyclic ring, which can contain 1 to 4 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, 1 to 4 Carbon atom alkoxy group, 1 to 4 carbon atom aminoalkyl group, 1 to 4 carbon atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acyl group, 1 to 4 A thioalkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a perfluoroalkoxy group of 1 to 4 carbon atoms, a carboxyl group of 1 to 4 carbon atoms, and a perfluoroalkyl group of 1 to 4 carbon atoms Alkoxycarbonyl, phenyl or heterocyclic substituents;
    B为苯环或杂环，可以含有1至3个取代基，其取代基可以是卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酰氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基、苯基或杂环取代基:B is a benzene ring or heterocyclic ring, which can contain 1 to 3 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, and 1 to 4 carbon atoms Alkoxy, aminoalkyl of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, acyl of 2 to 4 carbon atoms, acylamino of 2 to 4 carbon atoms, 1 to 4 carbons Atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 carbon atom perfluoroalkoxy group, 1 to 4 carbon atom carboxyl group, 1 to 4 carbon atom alkoxy group Carbonyl, phenyl or heterocyclic substituents:
    Z为共价键、1至4个碳原子的烷撑或含有-O-、-S-、-NH、-CO-、-CS-、-SO-、-SO 2-的线性结构、环状结构或线性结构与环状结构的组合； Z is a covalent bond, an alkylene of 1 to 4 carbon atoms, or a linear structure or a ring containing -O-, -S-, -NH, -CO-, -CS-, -SO-, -SO 2- Structure or a combination of linear structure and cyclic structure;
    Y为含有-CO-、-CS-、-SO-、-SO 2-的线性结构、环状结构或线性结构与环状结构的组合，其中环A的中心点(W1)、环B的中心点(W2)与Y中所含的作为氢键受体的O原子或S原子(W3)之间的距离满足下列条件：
    Figure PCTCN2020138343-appb-100002
    Figure PCTCN2020138343-appb-100003
    它们之间较佳的距离为
    Figure PCTCN2020138343-appb-100004
    Y is a linear structure, a cyclic structure or a combination of a linear structure and a cyclic structure containing -CO-, -CS-, -SO-, -SO 2 -, wherein the center point (W1) of ring A and the center of ring B The distance between the point (W2) and the O atom or S atom (W3) contained in Y as the hydrogen bond acceptor satisfies the following conditions:
    Figure PCTCN2020138343-appb-100002
    Figure PCTCN2020138343-appb-100003
    The better distance between them is
    Figure PCTCN2020138343-appb-100004
    R 1、R 2分别为氢或含有1至4个碳原子的烷基，R 1、R 2还可以一起构成一个共价键； R 1 and R 2 are respectively hydrogen or an alkyl group containing 1 to 4 carbon atoms, and R 1 and R 2 can also form a covalent bond together;
    R 3为氢或含有1至4个碳原子的烷基； R 3 is hydrogen or an alkyl group containing 1 to 4 carbon atoms;
    R 4为氢、卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷 氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酰氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基； R 4 is hydrogen, halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 Alkylamino of to 4 carbon atoms, acyl of 2 to 4 carbon atoms, amido of 2 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, perfluoroalkane of 1 to 4 carbon atoms Group, perfluoroalkoxy group of 1 to 4 carbon atoms, carboxyl group of 1 to 4 carbon atoms, alkoxycarbonyl group of 1 to 4 carbon atoms;
    X 1、X 2、X 3、X 4其中之一为卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酰氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基；其余分别为氢、卤素、氨基、羟基、硝基、氰基、1至4个碳原子的烷基、1至4个碳原子的烷氧基、1至4个碳原子的氨烷基、1至4个碳原子的烷氨基、2至4个碳原子的酰基、2至4个碳原子的酸氨基、1至4个碳原子的硫代烷基、1至4个碳原子的全氟烷基、1至4个碳原子的全氟烷氧基、1至4个碳原子的羧基、1至4个碳原子的烷氧基羰基； One of X 1 , X 2 , X 3 , and X 4 is halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, 1 to Aminoalkyl groups of 4 carbon atoms, alkylamino groups of 1 to 4 carbon atoms, acyl groups of 2 to 4 carbon atoms, acylamino groups of 2 to 4 carbon atoms, thioalkyl groups of 1 to 4 carbon atoms, Perfluoroalkyl groups of 1 to 4 carbon atoms, perfluoroalkoxy groups of 1 to 4 carbon atoms, carboxyl groups of 1 to 4 carbon atoms, alkoxycarbonyl groups of 1 to 4 carbon atoms; the rest are hydrogen , Halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 to 4 carbons Atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acid amino group, 1 to 4 carbon atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 Perfluoroalkoxy with 4 carbon atoms, carboxyl with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms;
    或选自伏立诺他、罗米地辛、贝利司他、帕比司他、西达本胺、恩替诺特和Mocetinostat或其可药用盐。Or selected from vorinostat, romidepsin, belisstat, pabirestat, chidamide, entinostat and Mocetinostat or a pharmaceutically acceptable salt thereof.
  2. 根据权利要求1所述的药物组合，其中The drug combination according to claim 1, wherein
    抗PD-1抗体包含重链可变区VH和轻链可变区VL，其中重链可变区包含SEQ ID NO:13的序列或与其具有至少90％,95％,98％或99％同一性的序列，和/或轻链可变区包含SEQ ID NO:15的序列或与其具有至少90％,95％,98％或99％同一性的序列；The anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 13 or is at least 90%, 95%, 98% or 99% identical to it Sexual sequence, and/or the variable region of the light chain comprises the sequence of SEQ ID NO: 15 or a sequence that is at least 90%, 95%, 98% or 99% identical to it;
    优选地，所述抗PD-1抗体包含SEQ ID NO:17或与之具有至少90％,95％,98％或99％同一性的重链序列和/或SEQ ID NO：22或与之具有至少90％,95％,98％或99％同一性的轻链序列。Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 17 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and/or SEQ ID NO: 22 or has A light chain sequence that is at least 90%, 95%, 98%, or 99% identical.
  3. 根据权利要求1或2所述的药物组合，其中所述抗PD-1抗体或其抗原结合片段选自信迪利单抗、帕博利珠单抗、纳武利尤单抗、特瑞普利单抗和卡瑞利珠单抗；优选地，所述抗PD-1抗体为信迪利单抗；和/或The pharmaceutical combination according to claim 1 or 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of sintilizumab, pembrolizumab, nivolizumab, and teriprizumab And carrelizumab; preferably, the anti-PD-1 antibody is sintilizumab; and/or
    所述HDAC抑制剂选自伏立诺他、罗米地辛、贝利司他、帕比司他、西达本胺、恩替诺特和Mocetinostat或其可药用盐，更优选地，所述HDAC抑制剂为西达本胺。The HDAC inhibitor is selected from the group consisting of vorinostat, romidepsin, belisstat, pabisstat, chidamide, entinostat and Mocetinostat or a pharmaceutically acceptable salt thereof, more preferably, The HDAC inhibitor is Chidamide.
  4. 根据权利要求1-3中任何一项所述的药物组合，所述药物组合用于预防或治疗癌症，优选非霍奇金淋巴瘤，更优选结外NK/T细胞淋巴瘤，最优选晚期或难治复发的结外NK/T细胞淋巴瘤。The pharmaceutical combination according to any one of claims 1 to 3, which is used for the prevention or treatment of cancer, preferably non-Hodgkin’s lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably advanced or Refractory and relapsed extranodal NK/T cell lymphoma.
  5. 根据权利要求1-4中任何一项所述的药物组合，所述药物组合中抗PD-1抗体或其抗原结合片段为100-300mg、优选为100mg、150mg、200mg、250mg或300mg、更优选地为200mg的剂量单元的形式，优选为胃肠外、更优选静脉内施用剂型；和/或The pharmaceutical combination according to any one of claims 1 to 4, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, more preferably In the form of a 200 mg dosage unit, preferably a parenteral, more preferably intravenous administration form; and/or
    HDAC抑制剂为10至50mg、优选为10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg的剂量单元的形式，优选为口服施用剂型。The HDAC inhibitor is in the form of a dosage unit of 10 to 50 mg, preferably 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, preferably in a dosage form for oral administration.
  6. 根据权利要求1-5中任何一项所述的药物组合，其中所述抗PD-1抗体或其抗原结合片段的单次施用剂量选自100-300mg，例如100mg、150mg、200mg、250mg或300mg，优选每二至四周施用一次，优选通过静脉输注施用；The pharmaceutical combination according to any one of claims 1-5, wherein the single administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from 100-300 mg, such as 100 mg, 150 mg, 200 mg, 250 mg or 300 mg , Preferably once every two to four weeks, preferably by intravenous infusion;
    优选地，所述抗PD-1抗体或其抗原结合片段每三周静脉输注一次，单次输注剂量为200mg。Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is intravenously infused once every three weeks, and the single infusion dose is 200 mg.
  7. 根据权利要求1-6中任何一项所述的药物组合，其中所述HDAC抑制剂的单次施用剂量选自10mg-50mg，优选每周施用1-4次，优选通过口服施用；The pharmaceutical combination according to any one of claims 1-6, wherein the single administration dose of the HDAC inhibitor is selected from 10mg-50mg, preferably 1-4 times a week, preferably by oral administration;
    优选地，所述HDAC抑制剂的口服剂量选自20mg、25mg和30mg；Preferably, the oral dose of the HDAC inhibitor is selected from 20 mg, 25 mg and 30 mg;
    更优选地，所述HDAC抑制剂每周口服2次，每次口服剂量为30mg。More preferably, the HDAC inhibitor is taken orally twice a week, and each oral dose is 30 mg.
  8. 根据权利要求1-7中任何一项所述的药物组合，其中所述抗PD-1抗体或其抗原结合片段和HDAC抑制剂分开、同时或依次施用。The pharmaceutical combination according to any one of claims 1-7, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the HDAC inhibitor are administered separately, simultaneously or sequentially.
  9. 根据权利要求1-8中任何一项所述的药物组合在制备用于预防或治疗癌症的药物中的用途，所述癌症优选选自非霍奇金淋巴瘤，更优选结外NK/T细胞淋巴瘤，最优选晚期或难治复发的结外NK/T细胞淋巴瘤。The use of the pharmaceutical combination according to any one of claims 1 to 8 in the preparation of a medicament for the prevention or treatment of cancer, the cancer is preferably selected from non-Hodgkin's lymphoma, more preferably extranodal NK/T cells Lymphoma, most preferably extranodal NK/T cell lymphoma that is advanced or refractory to relapse.
  10. 用于预防或治疗癌症的方法，所述方法包括向有需要的患者施用治疗有效量的根据权利要求1-8中任何一项所述的药物组合，所述癌症优选选自非霍奇金淋巴瘤，更优选结外NK/T细胞淋巴瘤，最优选晚期或难治复发的结外NK/T细胞淋巴瘤。A method for preventing or treating cancer, the method comprising administering a therapeutically effective amount of the drug combination according to any one of claims 1 to 8 to a patient in need, and the cancer is preferably selected from non-Hodgkin's lymph Tumor, more preferably extranodal NK/T cell lymphoma, most preferably late or refractory extranodal NK/T cell lymphoma.
  11. 一种单次药物剂量单元，其包括治疗有效量的根据权利要求1-8中任何一项所述的药物组合。A single drug dosage unit comprising a therapeutically effective amount of the drug combination according to any one of claims 1-8.
  12. 一种药物组合物，包含治疗有效量的根据权利要求1-8中任何一项所述的药物组合和可药用的赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of the pharmaceutical combination according to any one of claims 1-8 and pharmaceutically acceptable excipients.
  13. 一种成套药盒，其包含治疗有效量的根据权利要求1-8中任何一项所述的药物组合。A kit of medicines comprising a therapeutically effective amount of the drug combination according to any one of claims 1-8.
  14. 根据权利要求11所述的单次药物剂量单元、根据权利要求12所述的药物组合物或根据权利要求13所述的成套药盒在制备预防或治疗癌症的药物中的用途，所述癌症优选选自非霍奇金淋巴瘤，更优选结外NK/T细胞淋巴瘤，最优选晚期或难治复发的结外NK/T细胞淋巴瘤。The use of the single drug dosage unit according to claim 11, the pharmaceutical composition according to claim 12, or the kit according to claim 13 in the preparation of drugs for preventing or treating cancer, the cancer is preferably It is selected from non-Hodgkin's lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably late or refractory extranodal NK/T cell lymphoma.
PCT/CN2020/138343 2019-12-23 2020-12-22 Pharmaceutical combination of anti-pd-1 antibody and histone deaceylase inhibitor, use thereof, and usage method therefor WO2021129616A1 (en)

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