WO2020228657A1 - 喹啉衍生物与抗体联合治疗软组织肉瘤 - Google Patents

喹啉衍生物与抗体联合治疗软组织肉瘤 Download PDF

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WO2020228657A1
WO2020228657A1 PCT/CN2020/089546 CN2020089546W WO2020228657A1 WO 2020228657 A1 WO2020228657 A1 WO 2020228657A1 CN 2020089546 W CN2020089546 W CN 2020089546W WO 2020228657 A1 WO2020228657 A1 WO 2020228657A1
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Prior art keywords
antibody
soft tissue
compound
pharmaceutically acceptable
tissue sarcoma
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PCT/CN2020/089546
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English (en)
French (fr)
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吴荻
王欢
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正大天晴药业集团股份有限公司
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Priority to US17/610,212 priority Critical patent/US20220313685A1/en
Priority to EP20805823.0A priority patent/EP3967309A4/en
Priority to CN202080030334.7A priority patent/CN113747897B/zh
Publication of WO2020228657A1 publication Critical patent/WO2020228657A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • This application belongs to the field of medical technology, and relates to a combination therapy that can be used for anti-soft tissue sarcoma. Specifically, this application relates to the use of a combination of quinoline derivatives and antibodies to treat soft tissue sarcoma.
  • Soft tissue sarcoma is a group of malignant tumors derived from connective tissues such as mucus, fiber, fat, smooth muscle, synovium, striated muscle, mesothelium, blood vessels and lymphatic vessels. There are currently 19 tissue types and There are more than 100 different subtypes. The most common type of STS is undifferentiated pleomorphic sarcoma (UPS), which was previously named malignant fibrous histiocytoma (MFH). MFH was discovered and proposed by O'Brien and Stout in 1964. The essence of MFH is UPS whose histological origin and differentiation direction are still unclear.
  • UPS undifferentiated pleomorphic sarcoma
  • UPS benign tumor originating from mesenchymal tissues, and it is more likely to occur in limbs, trunk, head and neck, and The retroperitoneal space is deep, the tumor grade is high, the degree of malignancy is high, and it is easy to relapse after surgery, without typical imaging characteristics.
  • UPS lacks a specific direction of differentiation, and its diagnosis is a diagnosis of exclusion, which excludes the class UPS with a clear direction of differentiation. Compared with other types of STS patients, the 5-year survival rate of UPS patients is often lower, generally 30% to 50%.
  • Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues. They play an important role in intracellular signal transduction. They are involved in the regulation, signal transmission and development of normal cells, and are also related to tumor cells. Proliferation, differentiation, migration and apoptosis are closely related. Many receptor tyrosine kinases are related to the formation of tumors, and can be divided into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial cell growth factor receptor according to the structure of their extracellular region. Body (VEGFR), Fibroblast Growth Factor Receptor (FGFR), etc.
  • EGFR epidermal growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • FGFR Fibroblast Growth Factor Receptor
  • the natural immune system containing T lymphocytes has a strong anti-cancer ability, which has a wide range of abilities and precise specificity, so as to respond to various tumor antigens.
  • Emerging cancer immunotherapy enhances anti-tumor immune response through adoptive transfer of activated effector cells, immunization against related antigens, or the provision of non-specific immunostimulants.
  • researchers have worked hard to develop specific immune checkpoint inhibitors and hope to provide new immunotherapies for the treatment of cancer, but the efficacy of tumor immune tolerance and escape has been poor. Therefore, the combined use of small-molecule anti-tumor compounds and anti-PD-1/PD-L1 antibodies to break the body's established immune tolerance to tumor cells has important theoretical significance and application value.
  • this application provides a combination drug combination for the treatment of soft tissue sarcoma, which includes (i) compound I represented by formula I or a pharmaceutically acceptable salt thereof; and (ii) at least one antibody drug:
  • the application also provides the use of the drug combination in the preparation of a drug for the treatment of soft tissue sarcoma.
  • the present application also provides a method for treating soft tissue sarcoma, which comprises administering a therapeutically effective amount of the drug combination of the present application to a subject in need.
  • the drug combination includes (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one antibody drug.
  • this application provides a pharmaceutical combination for the treatment of soft tissue sarcoma, which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one antibody drug.
  • the pharmaceutical combination includes: (i) a pharmaceutical composition of Compound I or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutical composition of at least one antibody drug.
  • a pharmaceutical combination for the treatment of soft tissue sarcoma which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) PD-1 receptor and its ligand Inhibitor of the interaction between PD-L1, and optionally in combination with radiotherapy.
  • a pharmaceutical combination for the treatment of soft tissue sarcoma which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) platelet-derived growth factor receptor alpha (PDGFR) - ⁇ ) Inhibitors, and optionally in combination with radiotherapy.
  • a pharmaceutical combination for the treatment of soft tissue sarcoma which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) teriprizumab.
  • a pharmaceutical combination for the treatment of soft tissue sarcoma which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) Pembrolizumab.
  • a pharmaceutical combination for the treatment of soft tissue sarcoma is provided, which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) Olamumab.
  • a pharmaceutical combination for the treatment of soft tissue sarcoma which includes: (i) a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg of compound I or a pharmaceutically acceptable salt thereof And (ii) a pharmaceutical composition with a single dose of 120-600 mg of teriprizumab.
  • a pharmaceutical combination for the treatment of soft tissue sarcoma which includes: (i) a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg of compound I or a pharmaceutically acceptable salt thereof And (ii) a single dose of 120, 140, 160, 180, 200, 240, 300, 360, 400, 480 and/or 600 mg of a pharmaceutical composition of teriprizumab.
  • a pharmaceutical combination for the treatment of soft tissue sarcoma which comprises (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) Tereprizumab, wherein Terepre Lizumab is prepared to be suitable for administering a single dose or multiple doses of 240 mg to the patient at the first administration, and the compound I or a pharmaceutically acceptable salt thereof is prepared to be suitable for administering 6 mg to the patient every day for 14 consecutive days.
  • Single dose pharmaceutical composition of 8mg, 10mg and/or 12mg.
  • the application provides the use of a drug combination in the preparation of a medicament for the treatment of soft tissue sarcoma, the drug combination comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one Antibody drugs, and optionally combined with radiation therapy.
  • the present application provides a method for treating soft tissue sarcoma, which comprises: administering to a subject in need a therapeutically effective amount of (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least An antibody drug.
  • the application also provides a method for treating soft tissue sarcoma, which comprises: administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a subject in need; and a therapeutically effective An inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1, and optionally radiotherapy.
  • the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody that binds to the programmed death receptor 1 (PD-1) and/or inhibits the activity of PD-1
  • the antibody or antigen-binding portion thereof is, for example, an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • the antibody drug is an anti-PD-1 antibody and an anti-PD-L1 antibody.
  • the present application also provides a method for treating a subject suffering from soft tissue sarcoma, the method comprising: (i) measuring PD-1 and/or PD-L1 levels in a sample from the subject, wherein the subject Is PD-1 and/or PD-L1 positive; and (ii) administering to the subject a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one anti-PD-1 antibody and / Or anti-PD-L1 antibodies or their antigen binding parts.
  • the soft tissue sarcoma includes soft tissue sarcoma that has not previously been treated with a tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • the tyrosine kinase inhibitor is, for example, anlotinib, imatinib, sunitinib, pazopanib or similar drugs.
  • the soft tissue sarcoma includes soft tissue sarcoma that has not previously received immunotherapy. In some embodiments, the soft tissue sarcoma includes a soft tissue sarcoma that has not previously been treated with an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1. In some embodiments, the soft tissue sarcoma includes soft tissue sarcoma that has not previously been treated with a CTLA-4 inhibitor.
  • the subject is, for example, a patient diagnosed with undifferentiated pleomorphic sarcoma or alveolar soft tissue sarcoma.
  • the soft tissue sarcoma is a recurrent soft tissue sarcoma.
  • the soft tissue sarcoma is a metastatic soft tissue sarcoma.
  • the soft tissue sarcoma is a refractory soft tissue sarcoma.
  • the soft tissue sarcoma is an unresectable soft tissue sarcoma.
  • the soft tissue sarcoma described in the present application is an undifferentiated pleomorphic sarcoma. In some specific embodiments, the soft tissue sarcoma described in this application is an unresectable and/or metastatic undifferentiated pleomorphic sarcoma. In other specific embodiments, the soft tissue sarcoma described in the present application is an alveolar soft tissue sarcoma.
  • the soft tissue sarcomas described in this application include soft tissue sarcomas under the 2013 edition of the WHO, including but not limited to angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, and carina Dermatofibrosarcoma, malignant peripheral nerve sheath tumor, clear cell sarcoma, malignant mesenchymal tumor, epithelioid sarcoma, undifferentiated sarcoma, gastrointestinal stromal tumors.
  • angiosarcoma fibrosarcoma
  • leiomyosarcoma fibrosarcoma
  • liposarcoma liposarcoma
  • rhabdomyosarcoma synovial sarcoma
  • carina Dermatofibrosarcoma malignant peripheral nerve sheath tumor
  • clear cell sarcoma malignant mesenchymal tumor
  • the subject has previously received surgery, chemotherapy, and/or radiation therapy.
  • the subject is a subject who has recurred disease progression after obtaining complete remission through surgery, chemotherapy, and/or radiotherapy.
  • the subject is a subject that has failed to completely relieve or failed to partially relieve after surgery, chemotherapy, and/or radiotherapy.
  • the subject has not previously received systemic chemotherapy.
  • the subject has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the subject has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the subject undergoes surgical treatment, radiotherapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy, and disease progression occurs again after obtaining complete remission.
  • the subject fails to complete or partially relieve after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the subject has undergone cancer metastasis after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the anti-PD-1 antibody or anti-PD-L1 antibody and Compound I or a pharmaceutically acceptable salt thereof, each in the form of a pharmaceutical composition can be administered simultaneously, sequentially or at intervals .
  • the anti-PD-1 antibody or anti-PD-L1 antibody and Compound I or a pharmaceutically acceptable salt thereof are each administered at intervals. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and Compound I or a pharmaceutically acceptable salt thereof are administered in the same or different dosing schedules, respectively. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and Compound I or a pharmaceutically acceptable salt thereof are administered in different dosage regimens, respectively.
  • the anti-PD-1 antibody or anti-PD-L1 antibody may be weekly (q1w), every 2 weeks (q2w), every 3 weeks ( q3w), or every 4 weeks (q4w). In a specific embodiment, the anti-PD-1 antibody or anti-PD-L1 antibody is administered once every 3 weeks.
  • the compound I or a pharmaceutically acceptable salt thereof can be administered in a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day; continuous administration for 2 weeks, with a 1-week stop; and/or, continuous administration for 2 weeks , Stop the administration for 2 weeks.
  • the anti-PD-1 antibody or anti-PD-L1 antibody and Compound I or a pharmaceutically acceptable salt thereof have the same or different treatment cycles, respectively.
  • the anti-PD-L1 antibody or anti-PD-L1 antibody and Compound I or a pharmaceutically acceptable salt thereof have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle.
  • the first treatment cycle is 4 weeks, compound I or a pharmaceutically acceptable salt thereof is continuously administered for 2 weeks, and then the drug is stopped for 2 weeks; anti-PD-1 antibody or anti-PD -L1 antibody is administered once on the 8th day of the first treatment cycle.
  • each treatment cycle is three weeks, and Compound I or a pharmaceutically acceptable salt thereof is continuously administered for 2 weeks, and then stopped for 1 week; anti-PD-1 The antibody or anti-PD-L1 antibody is administered on the first day of the treatment cycle.
  • the teriprizumab may be administered to the patient at a dose of 120 mg to 600 mg, for example, at 120, 140, 160, 180, 200, 240, 300, 360, 400 , 480 and/or 600 mg doses are administered to the patient.
  • Compound I can be administered in its free base form, or in the form of its salts, hydrates and prodrugs.
  • the prodrug of Compound I is converted into the free base form of Compound I in vivo.
  • the pharmaceutically acceptable salt of Compound I can be produced from various organic acids and inorganic acids according to methods known in the art. "Pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, trifluoroacetic acid, and propionic acid.
  • the pharmaceutically acceptable salt of Compound I is the hydrochloride salt of Compound I. In some embodiments, the pharmaceutically acceptable salt of Compound I is the monohydrochloride salt of Compound I. In some embodiments, the pharmaceutically acceptable salt of Compound I is the dihydrochloride salt of Compound I. In some embodiments, the hydrochloride salt of Compound I is in crystalline form. In some embodiments, the pharmaceutically acceptable salt of Compound I is a crystal of Compound I dihydrochloride. In some embodiments, the pharmaceutically acceptable salt of Compound I is the maleate salt of Compound I. In this application, all references to Anlotinib refer to Compound I.
  • the dosage of Compound I or its salt involved in this application is based on the molecular weight of Compound I free base.
  • the dosage regimen can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • the administration is in the form of interval administration; the interval administration includes the administration period and the withdrawal period, and the administration may be one or more times per day during the administration period.
  • the ratio of the administration period and the withdrawal period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, more preferably 2:0.5-1.
  • the administration is continued for 2 weeks and the drug is stopped for 1 week.
  • the compound I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 8, 10, and/or 12 mg once a day for 2 weeks of continuous administration and one week off. .
  • the target of the antibody drug includes but not limited to PD-1, PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), platelet Derived growth factor receptor alpha (PDGFR- ⁇ ), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR), ganglioside GD2, B cell surface Any one or more of protein CD20, B cell surface protein CD52, B cell surface protein CD38, B cell surface protein CD319, B cell surface protein CD30, and B cell surface protein CD19/CD3.
  • CTLA-4 cytotoxic T-lymphocyte antigen 4
  • PDGFR- ⁇ platelet Derived growth factor receptor alpha
  • VEGF vascular endothelial growth factor
  • HER2 human epidermal growth factor receptor-2
  • EGFR epidermal growth factor receptor
  • ganglioside GD2 B cell surface Any one or more of protein CD20, B cell surface protein CD52, B cell surface protein CD38,
  • the antibody drug is an inhibitor of the interaction between PD-1 receptor and its ligand PD-L1.
  • the antibody drug is a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor.
  • CTLA-4 cytotoxic T-lymphocyte antigen 4
  • the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR- ⁇ ) inhibitor.
  • the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody that binds to programmed death receptor 1 (PD-1) and/or an antibody that inhibits PD-1 activity Or an antigen binding portion thereof; or, an antibody that binds to programmed death receptor 1 (PD-L1) and/or an antibody that inhibits the activity of PD-L1 or an antigen binding portion thereof, such as anti-PD-1 antibody or anti-PD-L1 antibody.
  • the antibody or antigen-binding portion thereof is (a) a monoclonal antibody, or an antigen-binding fragment thereof, which specifically binds to human PD-1 and blocks the interaction between human PD-L1 and human PD-1 Binding; or (b) a monoclonal antibody, or an antigen-binding fragment thereof, which specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.
  • the antibody drugs are anti-PD-1 antibodies and anti-PD-L1 antibodies.
  • the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.
  • the anti-PD-1 or PD-L1 antibody is a human antibody or a murine antibody.
  • the anti-PD-1 antibody may be selected from the group consisting of Nivolumab, Pembrolizumab, Durvalumab, and Treprizumab ( toripalimab, JS-001), Sintilizumab (IBI308), Camrelizumab (Camrelizumab), Tirelizumab (BGB-A317), AK105 (Kangfang Biological), Genolizumab ( GB226), Livzonumab (LZM009), HLX-10, BAT-1306, AK103 (HX008), AK104 (Kangfang Bio), CS1003, SCT-I10A, F520, SG001, GLS-010 or any one of them Many kinds.
  • the anti-PD-L1 antibody may be selected from Atezolizumab, Avelumab, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014 (ZKAB0011), KN035, MSB2311, HLX-20 , Any one or more of CS-1001.
  • the anti-PD-1 antibody is teriprizumab.
  • the anti-PD-1 antibody is pembrolizumab.
  • the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor is an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.
  • the anti-CTLA-4 antibody may be selected from the group consisting of Ipilimumab, Tremelimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI310 Any one or more of.
  • the anti-CTLA-4 antibody is ipilimumab.
  • the platelet-derived growth factor receptor alpha (PDGFR- ⁇ ) inhibitor is an anti-PDGFR ⁇ antibody.
  • the anti-PDGFR ⁇ antibody is an anti-PDGFR ⁇ monoclonal antibody.
  • the anti-PDGFRa antibody is Olaratumab.
  • the antibody drug may also include, but is not limited to, Bevacizumab, Ramucirumab, Pertuzumab, Trastuzumab Anti-(Trastuzmab), Cetuximab (Cotuximab), Nimotuzumab (Nimotuzumab), Panitumumab (Panitumumab), Necitumumab (Necitumumab), Dinutuximab, Rituximab (Rituximab) ), Ibritumomab, Ofatumumab, Obinutuzumab, Alemtuzumab, Daratumumab, Gemtuzumab, Erotuzumab Elotuzumab (Elotuzumab), Bentuximab (Brentuximab), Ointuzumab (Inotuzumab Ozogamicin), Bonatumomab (Blinatumomab
  • the histological types of the soft tissue sarcoma described in this application include but are not limited to undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma), angiosarcoma, desmoid tumor, and fibrosarcoma ( fibrosarcoma), gastrointestinal stromal tumor, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, Dermofibrosarcoma protuberans, nerve sheath tumors, malignant peripheral nerve sheath tumors, alveolar soft-part sarcoma, clear cell sarcoma, malignant mesenchymal tumors Tumors (malignant mesenchymoma), epithelioid sarcoma, alveolar soft tissue sarcoma, dedifferentiated liposarcoma, myxoid liposarcoma,
  • the soft tissue sarcoma is undifferentiated pleomorphic sarcoma, alveolar soft tissue sarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, and protruding skin Fibrosarcoma, malignant peripheral nerve sheath tumor, clear cell sarcoma, malignant mesenchymal tumor, epithelioid sarcoma, undifferentiated sarcoma, gastrointestinal stromal tumor.
  • the soft tissue sarcoma is an undifferentiated pleomorphic sarcoma.
  • the soft tissue sarcoma is an alveolar soft tissue sarcoma.
  • the clinical stages of the soft tissue sarcoma include, but are not limited to, locally advanced, and/or advanced (for example, stage IIIB/IV) and/or metastatic soft tissue sarcoma.
  • the metastatic soft tissue sarcoma includes but is not limited to single metastasis, disseminated metastasis, and diffuse metastasis; the metastatic focus includes but is not limited to lymph nodes, pleura, bone, brain, pericardium, adrenal gland, and liver.
  • the soft tissue sarcoma is a soft tissue sarcoma with brain metastasis.
  • the drug combination is used to treat soft tissue sarcoma.
  • the soft tissue sarcoma may be a primary soft tissue sarcoma or a secondary soft tissue sarcoma.
  • the soft tissue sarcoma is a soft tissue sarcoma that has progressed or recurred after receiving at least one chemotherapy.
  • the soft tissue sarcoma is a soft tissue sarcoma that cannot tolerate chemotherapy.
  • the soft tissue sarcoma is a soft tissue sarcoma that has not previously received systemic treatment.
  • the soft tissue sarcoma is an undifferentiated pleomorphic sarcoma, and in other specific embodiments, the soft tissue sarcoma described in the present application is an alveolar soft tissue sarcoma.
  • Each component of the pharmaceutical combination described in the present application can optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components can each independently, or part or all of them together contain pharmaceutically acceptable The carrier and/or excipient.
  • the drug combinations described in this application can be formulated separately, or part or all of them can be formulated together.
  • each component of the pharmaceutical combination is formulated separately, or each is formulated into a suitable pharmaceutical composition.
  • the pharmaceutical combination of the present application can be formulated into a pharmaceutical composition suitable for single or multiple administration.
  • the pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof may be selected from solid pharmaceutical compositions including but not limited to tablets or capsules.
  • the components in the pharmaceutical combination of the present application may be administered individually, or part or all of them may be administered together.
  • the components of the pharmaceutical combination of the present application may be administered substantially at different times, or some or all of them may be administered substantially simultaneously.
  • the components of the pharmaceutical combination of the present application can be administered independently, or part or all of them can be administered together by a suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes) .
  • the components of the pharmaceutical combination of the present application may be individually administered orally or by injection, such as intravenous injection or intraperitoneal injection.
  • the components of the pharmaceutical combination of the present application can be independently, or some or all of them together are suitable dosage forms, including, but not limited to, tablets, troches, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • suitable dosage forms including, but not limited to, tablets, troches, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • suitable dosage forms including, but not limited to, tablets, troches, pills, capsules
  • the drug combination is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
  • the drug combination is a non-fixed combination.
  • the antibody drug and Compound I or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition.
  • kits for the treatment of soft tissue sarcoma with a drug combination which contains (a) the first pharmaceutical composition containing anti-PD-1/PD-L1 antibody as an active ingredient; and (b ) The second pharmaceutical composition, which contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • kits for the treatment of soft tissue sarcoma with a drug combination which contains (a) the first pharmaceutical composition containing anti-CTLA-4 antibody as an active ingredient; and (b) the second A pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit for the treatment of soft tissue sarcoma with a drug combination which contains (a) a first pharmaceutical composition containing an anti-PDGFR ⁇ antibody as an active ingredient; and (b) a second drug The composition contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the purpose of this application is at least to provide the use of an antagonist of PD-1 or PD-L1 in the preparation of a medicament for the treatment of soft tissue sarcoma, which is used in combination with Compound I or a pharmaceutically acceptable salt thereof.
  • the purpose of this application is at least to provide the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of soft tissue sarcoma, which is used in combination with an antagonist of PD-1 or PD-L1.
  • the PD-1 antagonist is a PD-1 monoclonal antibody or an antigen-binding fragment thereof, which specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; and/or,
  • the PD-L1 antagonist is a PD-L1 monoclonal antibody or an antigen-binding fragment thereof, which specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.
  • the application also provides a pharmaceutical package, which contains a pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof in one container, and contains a PD-1 antagonist or PD-L1 antagonist in a second container Pharmaceutical composition.
  • Tereprizumab (JS-001, Junshi Bio) is a new recombinant humanized anti-PD-1 monoclonal antibody injection.
  • Junshi Biotech On December 17, 2018, Junshi Biotech’s PD-1 antibody drug "Treprimumab Injection” was officially approved for marketing by the National Medical Products Administration (NMPA) of China. It is used for the failure of previous systemic treatments. Resection or treatment of metastatic melanoma.
  • the term "antibody” refers to a binding protein having at least one antigen binding domain.
  • the antibodies and fragments of the present application may be whole antibodies or any fragments thereof. Therefore, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, and immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof can also include recombinant polypeptides, fusion proteins and bispecific antibodies.
  • the anti-PD-1/PD-L1 antibodies and fragments thereof disclosed herein may be of IgG1, IgG2, IgG3, or IgG4 isotype.
  • the term "isotype" refers to the antibody species encoded by the heavy chain constant region genes.
  • the anti-PD-1/PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype.
  • the anti-PD-1/PD-L1 antibodies and fragments thereof of the present application can be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans.
  • the PD-1/PD-L1 antibody and its fragments can be chimeric antibodies, humanized antibodies or whole human antibodies.
  • humanization means that the antigen binding site in the antibody is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may contain substitutions in the framework regions so that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.
  • isolated antibody refers to an antibody that contains substantially no other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds PD-1/PD-L1 contains substantially no specific binding other Antibodies to antigens other than PD-1/PD-L1).
  • an isolated antibody that specifically binds PD-1/PD-L1 may have cross-reactivity with other antigens, such as PD-1/PD-L1 molecules from different species.
  • the isolated antibody may be substantially free of other cellular materials and/or chemical substances.
  • the term "monoclonal antibody”("mAb”) refers to antibody molecules of a single molecular composition.
  • the monoclonal antibody composition shows a single binding specificity and affinity for a specific epitope, or in the case of a bispecific monoclonal antibody, shows a dual binding specificity for two different epitopes.
  • mAb is an example of an isolated antibody.
  • the mAb can be produced by hybridoma technology, recombinant technology, transgenic technology, or other technologies known to those skilled in the art.
  • isolated monoclonal antibodies include but are not limited to Nivolumab (Nivolumab) Pembrolizumab (Pembrolizumab) Teriplizumab (JS-001, Junshi Bio), Sintilimab (Sintilimab, IBI308, Xinda Biological), Carrelizumab (SHR-1210, Camrelizumab, Hengrui Medicine, see CN105026428B or WO2015085847A1), Tileli strain monoclonal antibody (BGB-A317, BeiGene), AK105 (Zhongshan Kangfang), Genozumab (GB226, Jiahe Biological), Livzonumab (LZM009, Livzon Pharmaceutical) , HLX-10 (Fuhong Henlius), BAT-1306 (Biotech), HX008 (AK103, Kangfang Bio/Hanzhong Bio), AK104 (Zhongshan Kangfang), CS1003 (Cornerstone Pharmaceuticals
  • the "antigen-binding portion" (also referred to as “antigen-binding fragment”) of an antibody refers to one or more fragments of the antibody that retain the ability to specifically bind to the antigen bound by the intact antibody.
  • the term "subject” means mammals, such as rodents, felines, canines, and primates.
  • the subject according to the present application is a human.
  • administering/administration/administration means that a composition containing a therapeutic agent is physically introduced to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • the route of administration/administration/administration of immune checkpoint inhibitors includes intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration/administration/ The route of administration, for example, by injection or infusion.
  • parenteral administration/administration/administration refers to modes of administration/administration/administration other than enteral and local administration, which are usually performed by injection, and include, but are not limited to, intravenous, intramuscular Internal, intraarterial, intrathecal, intralymphatic, intralesional, intrasaccular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, Epidural and intrasternal injections and infusions, as well as in vivo electroporation.
  • the immune checkpoint inhibitor eg, anti-PD-1 antibody or anti-PD-L1 antibody
  • non-parenteral routes include topical, epidermal or mucosal administration/administration/administration routes, for example, intranasal, vaginal, rectal, sublingual or topical.
  • Administration/administration/administration can also be performed, for example, once, multiple times, and/or over one or more extended periods of time.
  • PD-1 Programmed death receptor-1
  • PD-1 is mainly expressed on previously activated T cells in the body and binds two ligands, PD-L1 and PD-L2.
  • the term "PD-1” as used herein includes human PD-1 (hPD-1), variants, homologs and species homologs of hPD-1, and analogs that have at least one common epitope with hPD-1.
  • P-L1 Programmed Death Ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), which down-regulates T cells after binding to PD-1 Activation and cytokine secretion.
  • Subject includes any human or non-human animal.
  • non-human animal includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the subject is human.
  • the terms “subject” and “patient” and “subject” are used interchangeably in certain contexts herein.
  • a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is any amount of a drug that protects the subject from the onset of disease or promotes the regression of the disease when used alone or in combination with another therapeutic agent.
  • the regression of the disease is evidenced by a decrease in the severity of the disease symptoms, an increase in the frequency and duration of the symptom-free phase, or the prevention of injury or disability caused by the torture of the disease.
  • the ability of therapeutic agents to promote disease regression can be evaluated using a variety of methods known by skilled practitioners, such as in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or by in vitro assays The activity of the agent is determined in the
  • Recurrent or recurrent cancer is cancer that regenerates at the original site or at a remote site after responding to an initial treatment (such as surgery).
  • "Locally recurrent” cancer is cancer that appears in the same place as the previously treated cancer after treatment.
  • Metalstatic cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts includes salts formed by alkali ions and free acids or salts formed by acid ions and free bases, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, Formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, or p-toluene Sulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluene Sulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the molar ratio of the free acid to the base ion is about 1:0.5 to 1:8, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • the ratio of the molar amount of the free base to the acid radical ion is about 1:0.5 to 1:8, preferably 1:0.5, 1:1, 1:2, 1. :3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • fixed combination refers to the active ingredients (for example, anti-PD-1/PD-L1 antibody or Compound I or a pharmaceutically acceptable salt thereof) in a fixed total dose or dose ratio, or in a single entity, pharmaceutical composition or formulation The form of administering to the subject at the same time.
  • non-fixed combination means that two or more active ingredients are administered to a subject simultaneously, concurrently, or sequentially without any specific time limit as separate entities (eg, pharmaceutical compositions, preparations), wherein The active ingredients reach the therapeutically effective level.
  • An example of a non-fixed combination is cocktail therapy, for example, the administration of 3 or more active ingredients.
  • the respective active components can be packaged, sold or administered as completely independent pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of the "fixed combination” or the "fixed combination” with any one or more independent entities of the active ingredient.
  • combined use or “combined use” means that two or more active substances can be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially as a single formulation in any order.
  • pharmaceutical composition refers to one or more of the active ingredients of the application (for example, anti-PD-1/PD-L1 antibody or Compound I or a pharmaceutically acceptable salt thereof) or a pharmaceutical combination thereof and a pharmaceutically acceptable A mixture of excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the application or its pharmaceutical combination to a subject.
  • progression-free survival defined as the time from the first administration to the objective progression or death of the tumor.
  • CR Complete Remission
  • partial remission refers to a reduction in the total diameter of the target lesion by at least 30% from the baseline level.
  • disease progression refers to the minimum value of the sum of the diameters of all target lesions measured during the entire study process, with a relative increase of at least 20% in the diameter sum (if the baseline measurement value is the smallest, the baseline value is used as the reference ).
  • stable disease refers to the extent of the reduction of the target lesion without reaching the PR level, and the degree of increase without reaching the PD level, which is somewhere in between.
  • ORR object response rate
  • CBR Cosmetic Benefit Rate
  • overall survival defined as the time from the start of the first administration to death due to any cause, in days. Subjects who are lost to follow-up usually count the last follow-up time as the time of death.
  • RECIST refers to the evaluation criteria for the efficacy of solid tumors.
  • ECOG refers to a simplified activity status scoring table developed by the Eastern Cooperative Oncology Group (ECOG).
  • the components in the pharmaceutical combination of the present application can be formulated separately, or part or all of them can be formulated together.
  • the pharmaceutical combination of the present application can be formulated into a pharmaceutical composition suitable for single or multiple administration.
  • the components in the pharmaceutical combination of the present application may be administered individually, or part or all of them may be administered together.
  • the components of the pharmaceutical combination of the present application may be administered substantially at different times, or some or all of them may be administered substantially simultaneously.
  • the components of the pharmaceutical combination of the present application can be administered independently, or part or all of them can be administered by various suitable routes, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous way).
  • the components of the pharmaceutical combination of the present application may be individually administered orally or by injection, such as intravenous injection or intraperitoneal injection.
  • the components of the pharmaceutical combination of the present application can be independently, or some or all of them together are suitable dosage forms, including, but not limited to, tablets, troches, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • suitable dosage forms including, but not limited to, tablets, troches, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • suitable dosage forms including, but not limited to, tablets, troches, pills, capsules
  • the components in the pharmaceutical combination of the present application may each independently, or part or all of them together contain a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical combination of the present application may also include additional therapeutic agents.
  • the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a soft tissue sarcoma cancer therapeutic agent.
  • anlotinib hydrochloride combined with teriprizumab for the treatment of undifferentiated pleomorphic sarcoma
  • the main target population is patients with unresectable or metastatic undifferentiated pleomorphic sarcoma.
  • Primary study endpoint PFS [time limit: 3 months after the implementation of the treatment plan]; secondary study endpoint: ORR [time limit: 3 months, 6 months and 12 months after the start of treatment], CBR [time limit: 3 months after the start of treatment Months, 6 months and 12 months], OS [time limit: end of study, average 12 months], and safety and toxicity [time limit: to 30 days after the end of treatment].
  • Anlotinib hydrochloride capsules active ingredient is Anlotinib dihydrochloride:
  • the patient will be given Anlotinib hydrochloride, orally before breakfast, 12 mg/day (each Once a day, 1 capsule each time), take for 2 consecutive weeks, stop the drug for 2 weeks; the subsequent course of treatment is every 3 weeks (21 days) as a course of treatment, take 2 consecutive weeks, stop the drug for 1 week.
  • Antibody drug administration dose Teriprizumab
  • the 240 mg dose of teriprizumab was administered intravenously.
  • the administration time was the 8th day of the first course of treatment (28 days), and the first day of each subsequent course (21 days), with an injection every 21 days.
  • Anlotinib (12 mg po qd d1-d14 for two weeks, stop for one week) combined with teriprizumab (240 mg, once every 21 days).
  • the first medication time is: 2019.11.22.
  • the total diameter of the measurable target lesions is 44.3mm (of which, the left lower lobe is 32.3mm, and the right middle lobe is 12.0mm).
  • the patient's three efficacy evaluations were all SD.
  • the PFS of progression-free survival is close to 5 months.
  • the treatment plan and efficacy evaluation are shown in Table 1 below.

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Abstract

本发明属于医药领域，提供了喹啉衍生物与抗体联合治疗软组织肉瘤，具体涉及治疗有效量的喹啉衍生物化合物I或其药学上可接受的盐与至少一种抗体药物联合在制备用于治疗软组织肉瘤的药物中的用途；喹啉衍生物化合物I的化学名称为1-[[[4-（4-氟-2-甲基-1H-吲哚-5-基）氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺。

Description

喹啉衍生物与抗体联合治疗软组织肉瘤
相关申请的交叉引用
本申请要求于2019年05月10日向中国国家知识产权局提交的第201910395694.6号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于医药技术领域，涉及可用于抗软组织肉瘤的联合治疗。具体而言，本申请涉及基于喹啉衍生物与抗体联合治疗软组织肉瘤的用途。
背景技术
软组织肉瘤(soft tissue sarcoma，STS)是一组源于黏液、纤维、脂肪、平滑肌、滑膜、横纹肌、间皮、血管和***等***的恶性肿瘤，目前软组织肉瘤有19个组织类型及100多种的不同亚型，STS最常见的一种类型是未分化多形性肉瘤(undifferentiated pleomorphic sarcoma，UPS)，之前被命名为恶性纤维组织细胞瘤(malignant fibrous histiocytoma，MFH)。MFH于1964年被O’Brien和Stout发现并提出，MFH的本质是组织学来源及分化方向仍不明确的UPS，起源于间叶组织的恶性肿瘤，好发于四肢、躯干、头颈部和腹膜后间隙，位置较深，肿瘤级别高，恶性程度高，术后易复发，无典型的影像特征。UPS缺乏具体的分化方向，其诊断属于排除性诊断，排除掉具有明确分化方向的类UPS。与其他类型的STS患者相比，UPS患者的5年生存率往往较低，一般为30％～50％。
酪氨酸激酶是一组催化蛋白质酪氨酸残基磷酸化的酶，在细胞内的信号转导中起着重要的作用，它参与正常细胞的调节、信号传递和发育，也与肿瘤细胞的增殖、分化、迁移和凋亡密切相关。许多受体酪氨酸激酶都与肿瘤的形成相关，根据其细胞外区域结构的不同可分为表皮生长因子受体(EGFR)、血小板衍化生长因子受体(PDGFR)、血管内皮细胞生长因子受体(VEGFR)、成纤维细胞生长因子受体(FGFR)等。
文献WO2008112407在实施例24中公开了该喹啉衍生物类酪氨酸激酶抑制剂1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺(即，安罗替尼)及其制备方法，它的结构式如式I所示：
Figure PCTCN2020089546-appb-000001
包含T淋巴细胞的天然免疫***具有强大的抗癌能力，其具有广泛的能力和精确的特异性，从而对各种肿瘤抗原做出响应。新兴的癌症免疫疗法通过激活的效应细胞的过继转移、针对相关抗原的免疫接种或提供非特异性免疫刺激剂来增强抗肿瘤免疫应答。在过去的近20年中，研究者努力开发特异性免疫检查点抑制剂并期望提供用于治疗癌症的新免疫治疗方案，但是由于肿瘤免疫耐受和逃逸导致的疗效不佳。因此，通过基于小分子抗肿瘤化合物与抗PD-1/PD-L1抗体的联合使用以打破机体已经建立的对肿瘤细胞的免疫耐受，具有重要的理论意义和应用价值。
发明内容
一方面，本申请提供用于治疗软组织肉瘤的联用药物组合，其包括(i)式I所示的化合物I或其药学上可接受的盐；和(ii)至少一种抗体药物：
Figure PCTCN2020089546-appb-000002
另一方面，本申请还提供药物组合在制备用于治疗软组织肉瘤的药物中的用途。
再一方面，本申请还提供治疗软组织肉瘤的方法，其包括向有需要的受试者给予治疗有效量的本申请的药物组合。所述药物组合包括(i)化合物I或其药学上可接受的盐；和(ii)至少一种抗体药物。
一方面，本申请提供了一种用于治疗软组织肉瘤的药物组合，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种抗体药物。
在本申请的一些实施方案中，所述药物组合包括：(i)化合物I或其药学上可接受的盐的药物组合物；和(ii)至少一种抗体药物的药物组合物。
在一些的实施方案中，提供了一种用于治疗软组织肉瘤的药物组合，其包括：(i)化合物I或其药学上可接受的盐；和(ii)PD-1受体和其配体PD-L1之间的相互作用的抑制剂，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗软组织肉瘤的药物组合，其包括：(i)化合物I或其药学上可接受的盐；和(ii)血小板衍生生长因子受体α(PDGFR-α)抑制剂，以及任选地与放射治疗联合。在一些具体的实施方案中，提供了一种用于治疗软组织肉瘤的药物组合，其包括：(i)化合物I或其药学上可接受的盐；和(ii)特瑞普利单抗。在一些具体的实施方案中，提供了一种用于治疗软组织肉瘤的药物组合，其包括：(i)化合物I或其药学上可接受的盐；和(ii)帕博利珠单抗。在一些具体的实施方案中，提供了一种用于治疗软组织肉瘤的药物组合，其包括：(i)化合物I或其药学上可接受的盐；和(ii)奥拉单抗。
在一些具体的实施方案中，提供了一种用于治疗软组织肉瘤的药物组合，其包括：(i)单剂量为6mg、8mg、10mg和/或12mg的化合物I或其药学上可接受的盐的药物组合物；和(ii)单剂量为120～600mg的特瑞普利单抗的药物组合物。
在一些具体的实施方案中，提供了一种用于治疗软组织肉瘤的药物组合，其包括：(i)单剂量为6mg、8mg、10mg和/或12mg的化合物I或其药学上可接受的盐的药物组合物；和(ii)单剂量为120、140、160、180、200、240、300、360、400、480和/或600mg的特瑞普利单抗的药物组合物。
在一些实施方案中，提供了一种用于治疗软组织肉瘤的药物组合，其包括(i)化合物I或其药学上可接受的盐；和(ii)特瑞普利单抗，其中特瑞普利单抗被制备为适合第一次给药时向患者给予240mg的单剂量或多剂量，所述化合物I或其药学上可接受的盐被制备为适合连续14天、每天向患者给予6mg、8mg、10mg和/或12mg的单剂量药物组合物。
另一方面，本申请提供了药物组合在制备用于治疗软组织肉瘤的药物中的用途，所述药物组合包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种抗体药物，以及任选地与放射治疗联合。
再一方面，本申请提供了一种治疗软组织肉瘤的方法，其包括：向有需要的受试者给予治疗有效量的(i)化合物I或其药学上可接受的盐；和(ii)至少一种抗体药物。
在一些实施方案中，本申请还提供了一种用于治疗软组织肉瘤的方法，其包括：向有需要的受试者施用治疗有效量的化合物I或其药学上可接受的盐；和治疗有效量的PD-1受体和其配体PD-L1之间的相互作用的抑制剂，以及任选地放射治疗。在一些实施方案中，PD-1受体和其配体PD-L1之间的相互作用的抑制剂是结合程序性死亡受体1(PD-1)的抗体和/或抑制PD-1活性的抗体或其抗原结合部分，例如是抗PD-1抗体或抗PD-L1抗体。在一些实施方案中，所述抗体药物为抗PD-1抗体和抗PD-L1抗体。
本申请也提供了一种治疗患有软组织肉瘤的主体的方法，所述方法包括：(i)测量来自所述主体的样品中的PD-1和/或PD-L1水平，其中，所述主体是PD-1和/或PD-L1阳性的；以及(ii)向所述主体施用治疗 有效量的化合物I或其药学上可接受的盐和治疗有效量的至少一种抗PD-1抗体和/或抗PD-L1抗体或它们的抗原结合部分。
在一些实施方案中，所述的软组织肉瘤包括在先未接受过酪氨酸激酶抑制剂(TKI)治疗的软组织肉瘤。在一些实施方案中，酪氨酸激酶抑制剂例如为安罗替尼、伊马替尼、舒尼替尼、帕唑帕尼或类似药物。
在一些实施方案中，所述的软组织肉瘤包括在先未接受过免疫治疗的软组织肉瘤。在一些实施方案中，所述的软组织肉瘤包括在先未接受过PD-1受体和其配体PD-L1之间的相互作用的抑制剂治疗的软组织肉瘤。在一些实施方案中，所述的软组织肉瘤包括在先未接受过CTLA-4抑制剂治疗的软组织肉瘤。
本申请提供了一种用于治疗患有软组织肉瘤的主体的方法。在某些实施方案中，所述主体例如是被确诊为未分化多形性肉瘤或腺泡状软组织肉瘤的患者。例如，在某些实施方案中，所述软组织肉瘤是复发性的软组织肉瘤。在某些实施方案中，所述软组织肉瘤是转移性的软组织肉瘤。在某些实施方案中，所述软组织肉瘤是难治性的软组织肉瘤。在某些实施方案中，所述软组织肉瘤为不可切除的软组织肉瘤。在一些具体实施方案中，本申请所述的软组织肉瘤是未分化多形性肉瘤。在一些具体实施方案中，本申请所述的软组织肉瘤是不可切除的和/或转移性的未分化多形性肉瘤。在另一些具体实施方案中，本申请所述的软组织肉瘤是腺泡状软组织肉瘤。在一些具体的方案中，本申请所述的软组织肉瘤包括WHO第2013版规定下的软组织肉瘤，包括但不限于血管肉瘤、纤维肉瘤、平滑肌肉瘤、脂肪肉瘤、横纹肌肉瘤、滑膜肉瘤、隆突性皮肤纤维肉瘤、恶性外周神经鞘膜瘤、透明细胞肉瘤、恶性间叶瘤、上皮样肉瘤、未分化肉瘤、胃肠道间质肿瘤。
在本申请的一些方案中，所述主体先前已接受手术、化疗和/或放射治疗。在一些具体实施方式中，所述主体为经手术、化疗和/或放射治疗获得完全缓解后再次出现疾病进展的主体。在一些具体实施方式中，所述主体为经手术、化疗和/或放射治疗后未能完全缓解或未能部分缓解的主体。
在本申请的一些方案中，所述主体先前未接受过***化疗。在一些方案中，所述主体先前已接受手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。在一些具体实施方式中，所述主体先前未接受过***化疗，但是接受过手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。在一些具体实施方式中，所述主体经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，获得完全缓解后再次出现疾病进展。在一些具体实施方式中，所述主体经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，未能完全缓解或未能部分缓解。在一些具体实施方式中，所述主体经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后癌症发生转移。
在本申请的一些实施方案中，所述抗PD-1抗体或抗PD-L1抗体以及化合物I或其药学上可接受的盐，各自呈药物组合物的形式，可同时、顺序或间隔给药。
在本申请的一些实施方案中，所述抗PD-1抗体或抗PD-L1抗体以及化合物I或其药学上可接受的盐，各自以间隔给药的方式给药。在一些实施方案中，所述抗PD-1抗体或抗PD-L1抗体和化合物I或其药学上可接受的盐分别以相同或者不同的给药方案进行给药。在一些实施方案中，所述抗PD-1抗体或抗PD-L1抗体和化合物I或其药学上可接受的盐分别以不同的给药方案进行给药。
在本申请的一些实施方案中，在本申请的用途或治疗方法中，所述抗PD-1抗体或抗PD-L1抗体可以每周(q1w)、每2周(q2w)、每3周(q3w)、或者每4周(q4w)施用一次。在一个具体的实施方案中，每3周给予抗PD-1抗体或抗PD-L1抗体一次。
所述化合物I或其药学上可接受的盐可以每日一次6mg、8mg、10mg或者12mg的剂量；连续用药2周，停1周的给药方案给药；和/或，以连续用药2周，停2周的给药方案给药。
在一些实施方案中，抗PD-1抗体或抗PD-L1抗体和化合物I或其药学上可接受的盐分别具有相同或者不同的治疗周期。在一些具体的实施方案中，抗PD-L1抗体或抗PD-L1抗体和化合物I或其药学上可接受的盐具有相同的治疗周期，例如每1周、每2周、每3周或者每4周为一个治疗周期。
在一些具体的实施方案中，第一个治疗周期为4个星期，化合物I或其药学上可接受的盐连续给药2个星期，然后停药2个星期；抗PD-1抗体或抗PD-L1抗体在第一个治疗周期的第8天给药一次。在一些 具体的实施方案中，从第二个治疗周期起，每个治疗周期为三个星期，化合物I或其药学上可接受的盐连续给药2周，然后停1周；抗PD-1抗体或抗PD-L1抗体在治疗周期的第一天给药。
在本申请的治疗方法的一些具体实施方案中，所述特瑞普利单抗可以120mg至600mg的剂量施用于患者，例如以120、140、160、180、200、240、300、360、400、480和/或600mg的剂量施用于患者。
化合物I或其药学上可接受的盐
本申请中，化合物I的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2020089546-appb-000003
本申请中，化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，化合物I的前药在体内转换成化合物I的游离碱形式。化合物I的药学上可接受的盐，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。“药学上可接受的盐”包括，但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸等形成的酸加成盐。在一些实施方案中，化合物I的药学上可接受的盐为化合物I的盐酸盐。在一些实施方案中，化合物I的药学上可接受的盐为化合物I的一盐酸盐。在一些实施方案中，化合物I的药学上可接受的盐为化合物I的二盐酸盐。在一些实施方案中，化合物I的盐酸盐为晶体形式。在一些实施方案中，化合物I的药学上可接受的盐为化合物I二盐酸盐的晶体。在一些实施方案中，化合物I的药学上可接受的盐为化合物I的马来酸盐。本申请中，凡是涉及安罗替尼，均是指化合物I。
本申请中涉及的化合物I或其盐的剂量，除非另有说明，均基于化合物I游离碱的分子量。
化合物I或其药学上可接受的盐，其给药方案可根据药物的活性、毒性以及患者的耐受性等来综合确定。在一些实施方案中，以间隔给药的方式给予；所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予。在一些实施方案中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。在一些实施方案中，连续给药2周停药1周。在某些特定的实施方案中，以每日一次8、10和/或12mg的剂量口服给药，连续用药2周，停1周的给药方式，给予化合物I或其药学上可接受的盐。
抗体药物
在本申请的一些实施方案中，所述的抗体药物的靶点包括但不限于PD-1、PD-L1、细胞毒性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4，CTLA-4)、血小板衍生生长因子受体α(PDGFR-α)、血管内皮生长因子(VEGF)、人表皮生长因子受体-2(HER2)、表皮生长因子受体(EGFR)、神经节苷脂GD2、B细胞表面蛋白CD20、B细胞表面蛋白CD52、B细胞表面蛋白CD38、B细胞表面蛋白CD319、B细胞表面蛋白CD30、B细胞表面蛋白CD19/CD3中的任意一种或多种。
在一些实施方案中，所述的抗体药物为PD-1受体和其配体PD-L1之间的相互作用的抑制剂。在一些实施方案中，所述的抗体药物为细胞毒性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4，CTLA-4)抑制剂。在一些实施方案中，所述的抗体药物为血小板衍生生长因子受体α(PDGFR-α)抑制剂。
在一些方案中，PD-1受体和其配体PD-L1之间的相互作用的抑制剂是结合程序性死亡受体1(PD-1)的抗体和/或抑制PD-1活性的抗体或其抗原结合部分；或者，是结合程序性死亡受体1(PD-L1)的抗体和/或抑制PD-L1活性的抗体或其抗原结合部分，例如抗PD-1抗体或者抗PD-L1抗体。在一些具体实施方案中，所述抗体或其抗原结合部分是(a)单克隆抗体，或其抗原结合片段，其特异地结合人PD-1且阻断人PD-L1与人PD-1的结合；或(b)单克隆抗体，或其抗原结合片段，其特异地结合人PD-L1且阻断人PD-L1与人PD-1的结合。
在一些方案中，所述抗体药物为抗PD-1抗体和抗PD-L1抗体。
在一些方案中，所述抗PD-1或PD-L1抗体是抗PD-1或PD-L1单克隆抗体。
在一些方案中，所述抗PD-1或PD-L1抗体为人源性抗体或鼠源性抗体。
在一些方案中，所述抗PD-1抗体可为选自纳武利尤单抗(Nivolumab)、帕博利珠单抗(Pembrolizumab)、德瓦鲁单抗(Durvalumab)、特瑞普利单抗(toripalimab，JS-001)、信迪利单抗(IBI308)、卡瑞利株单抗(Camrelizumab)、替雷利株单抗(BGB-A317)、AK105(康方生物)、杰诺单抗(GB226)、丽珠单抗(LZM009)、HLX-10、BAT-1306、AK103(HX008)、AK104(康方生物)、CS1003、SCT-I10A、F520、SG001、GLS-010中的任意一种或多种。
在一些方案中，所述抗PD-L1抗体可为选自Atezolizumab、Avelumab、Durvalumab、KL-A167、SHR-1316、BGB-333、JS003、STI-A1014(ZKAB0011)、KN035、MSB2311、HLX-20、CS-1001中的任意一种或多种。
在一些具体的实施方案中，所述抗PD-1抗体为特瑞普利单抗。
在一些具体的实施方案中，所述抗PD-1抗体为帕博利珠单抗。
在一些方案中，所述细胞毒性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4，CTLA-4)抑制剂是抗CTLA-4抗体。在一些具体实施方案中，所述的抗CTLA-4抗体是抗CTLA-4单克隆抗体。
在一些方案中，所述抗CTLA-4抗体可为选自伊匹单抗(Ipilimumab)、替西木单抗(Tremelimumab)、AGEN-1884、BMS-986249、BMS-986218、AK-104、IBI310中的任意一种或多种。
在一些具体的实施方案中，所述抗CTLA-4抗体为伊匹单抗。
在一些方案中，所述血小板衍生生长因子受体α(PDGFR-α)抑制剂是抗-PDGFRα抗体。在一些具体实施方案中，所述的抗-PDGFRα抗体是抗-PDGFRα单克隆抗体。
在一些具体的实施方案中，所述抗-PDGFRα抗体为奥拉单抗(Olaratumab)。
在一些具体的实施方案中，所述的抗体药物还可以包括但不限于贝伐珠单抗(Bevacizumab)、雷莫芦单抗(Ramucirumab)、帕妥珠单抗(Pertuzumab)、曲妥珠单抗(Trastuzmab)、西妥昔单抗(Cotuximab)、尼妥珠单抗(Nimotuzumab)、帕尼单抗(Panitumumab)、耐昔妥珠单抗(Necitumumab)、Dinutuximab、利妥昔单抗(Rituximab)、替依莫单抗(Ibritumomab)、奥法木单抗(Ofatumumab)、Obinutuzumab、阿仑单抗(Alemtuzumab)、达雷木单抗(Daratumumab)、吉妥单抗(Gemtuzumab)、埃罗妥珠单抗(Elotuzumab)、本妥昔单抗(Brentuximab)、奥英妥珠单抗(Inotuzumab Ozogamicin)、博纳吐单抗(Blinatumomab)中的任意一种或几种。
软组织肉瘤
本申请所述的软组织肉瘤，其组织学分型包括但不限于未分化多形性肉瘤(Undifferentiated pleomorphic sarcoma)(又称恶性纤维组织细胞瘤)、血管肉瘤(angiosarcoma)、硬纤维瘤、纤维肉瘤(fibrosarcoma)、胃肠道间质瘤(gastrointestinal stromal tumor)、卡波西肉瘤(Kaposi's sarcoma)、平滑肌肉瘤(leiomyosarcoma)、脂肪肉瘤(liposarcoma)、横纹肌肉瘤(rhabdomyosarcoma)、滑膜肉瘤(synovial sarcoma)、隆突性皮肤纤维肉瘤、神经鞘膜肿瘤(nerve sheath tumours)、恶性周围神经鞘瘤(malignant peripheral nerve sheath tumour)、腺泡状软组织肉瘤(alveolar soft-part sarcoma)、透明细胞肉瘤、恶性间叶瘤(malignant mesenchymoma)、上皮样肉瘤(epithelioid sarcoma)、肺泡样软组织肉瘤、去分化脂肪肉瘤(dedifferentiated liposarcoma)、粘液样脂肪肉瘤(myxoid liposarcoma)、多形性脂肪肉瘤(pleomorphic liposarcoma)、混合型脂肪肉瘤(mixed-type liposarcoma)成人纤维肉瘤(adult fibrosarcoma)、低级别纤维 粘液样肉瘤(low grade fibromyxoid sarcoma)、透明性梭形细胞肿瘤(hyalinizing spindle cell tumour)、硬化性上皮样纤维肉瘤(sclerosing epithelioid fibrosarcoma)、周细胞(血管周细胞)肿瘤(pericytic(perivascular)tumoues)、血管球瘤(和变型)(glomus tumour and variants)、血管球血管瘤病(glomangiomatosis)、恶性血管球瘤(malignant glomus tumour)、肌周细胞瘤(myopericytoma)、肌纤维瘤(myofibroma)、血管平滑肌瘤(angioleiomyoma)、胚胎性横纹肌肉瘤(embryonal rhabdomyosarcoma)(包括葡萄簇状、间变性)、腺泡状横纹肌肉瘤(alveolar rhabdomyosarcoma)(包括实性、间变性)、多形性横纹肌肉瘤(pleomorphic rhabdomyosarcoma)、梭形细胞/硬化性横纹肌肉瘤(spindle cell/sclerosing rhabdomyosarcoma)、上皮样血管内皮瘤(epithelioid haemangioendothelioma)、软组织血管肉瘤(angiosarcoma of soft tissue)、上皮样恶性外周神经鞘膜瘤(epithelioid malignant peripheral nerve sheath tumour)、恶性蝾螈瘤(malignant Triton tumour)、恶性颗粒细胞瘤(malignant granular cell tumour)、非特殊性滑膜肉瘤(synovial sarcoma NOS)、梭形细胞型滑膜肉瘤(synovial sarcoma，spindle cell)、双相分化滑膜肉瘤(synovial sarcoma，biphasic)、软组织透明细胞肉瘤(clear cell sarcoma of soft tissue)、促纤维组织增生性小圆细胞肿瘤(desmoplastic small round cell tumour)、肾外横纹样肿瘤(extra-renal rhabdoid tumour)、具有血管周上皮样细胞分化的肿瘤(neoplasms with perivascular epithelioid cell differentiation，PEComa)、血管内膜肉瘤(intimal sarcoma)、未分化/不能分类的肉瘤(Undifferentiated/Unclassified Sarcomas)、未分化梭形细胞肉瘤(Undifferentiated spindle cell sarcoma)、未分化圆形细胞肉瘤(Undifferentiated round cell sarcoma)、未分化上皮样肉瘤(Undifferentiated epithelioid cell sarcoma)、***增生性小圆形细胞瘤、低级别纤维性粘液样肉瘤、交界性软组织肿瘤。
在一些具体的实施方案中，所述的软组织肉瘤为未分化多形性肉瘤、腺泡状软组织肉瘤、血管肉瘤、纤维肉瘤、平滑肌肉瘤、脂肪肉瘤、横纹肌肉瘤、滑膜肉瘤、隆突性皮肤纤维肉瘤、恶性外周神经鞘膜瘤、透明细胞肉瘤、恶性间叶瘤、上皮样肉瘤、未分化肉瘤、胃肠道间质肿瘤。
在一些具体的实施方案中，所述的软组织肉瘤为未分化多形性肉瘤。
在一些具体的实施方案中，所述的软组织肉瘤为腺泡状软组织肉瘤。
本申请中，所述的软组织肉瘤，其临床分期包括但不限于局部晚期、和/或晚期(例如IIIB/IV期)和/或转移性的软组织肉瘤。其中转移性软组织肉瘤包括但不限于病灶单个转移、播散性转移、弥漫性转移；所述转移病灶包括但不限于***、胸膜、骨、脑、心包、肾上腺、肝脏。在一些实施方案中，所述的软组织肉瘤为脑转移的软组织肉瘤。在一些实施方案中，所述药物组合用于治疗软组织肉瘤。所述软组织肉瘤可为原发性软组织肉瘤或继发性软组织肉瘤。在一些实施方案中，所述的软组织肉瘤为在先接受过至少一种化疗后出现进展或复发的软组织肉瘤。在一些实施方案中，所述的软组织肉瘤为无法耐受化疗的软组织肉瘤。在优选的实施方案中，所述的软组织肉瘤为在先未接受过***治疗的软组织肉瘤。在一些实施方案中，所述的软组织肉瘤是未分化多形性肉瘤，在另一些具体实施方案中，本申请所述的软组织肉瘤是腺泡状软组织肉瘤。
药物组合
本申请所述的药物组合中的各组分可任选地与一种或者多种药学上可接受的载体并用，其中组分可以各自独立地，或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。本申请所述的药物组合可以各自分开配制，或者其中的部分或全部共同配制。优选的，所述药物组合的各组分分开配制，或各自配制成合适的药物组合物。在一些实施方案中，本申请的药物组合可以配制成适合于单次或多次施用的药物组合物。在一些特定的实施方案中，含有化合物I或其药学上可接受的盐的药物组合物可选自固体药物组合物，所述固体药物组合物包括但不限于片剂或胶囊。
本申请的药物组合中的组分可以各自单独施用，或者其中的部分或全部共同施用。本申请的药物组合中的组分可以基本上不同时施用，或者其中的部分或全部基本上同时施用。
本申请的药物组合中的组分可以各自独立地，或者其中的部分或全部共同以适合的途径施用，包括，但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在一些实施方案中，本申请的药物组合的组分可以各自独立地，或者其中的部分或全部共同口服施用或注射施用，例如静脉注射或腹腔注射。
本申请的药物组合中的组分可以各自独立地，或者其中的部分或全部共同是适合的剂型，包括，但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、 注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
在本申请的一些方案中，所述药物组合是固定组合。在一些方案中，所述固定组合呈固体药物组合物形式或液体药物组合物形式。
在本申请的一些方案中，所述药物组合是非固定组合。在一些方案中，所述非固定组合中的抗体药物和化合物I或其药学上可接受的盐各自呈药物组合物形式。
在一些方案中，还提供一种用于治疗软组织肉瘤的药物组合的试剂盒，其中含有(a)第一种药物组合物，含有抗PD-1/PD-L1抗体作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。
在一些方案中，还提供一种用于治疗软组织肉瘤的药物组合的试剂盒，其中含有(a)第一种药物组合物，含有抗CTLA-4抗体作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。在一些方案中，还提供一种用于治疗软组织肉瘤的药物组合的试剂盒，其中含有(a)第一种药物组合物，含有抗-PDGFRα抗体作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。
本申请的目的还至少在于提供PD-1或PD-L1的拮抗剂在制备用于治疗软组织肉瘤的药物中的用途，所述药物与化合物I或其药学上可接受的盐组合使用。
本申请的目的还至少在于提供化合物I或其药学上可接受的盐在制备用于治疗软组织肉瘤的药物中的用途，所述药物与PD-1或PD-L1的拮抗剂组合使用。在一些方案中，PD-1拮抗剂是PD-1单克隆抗体或其抗原结合片段，其特异地结合人PD-1且阻断人PD-L1与人PD-1的结合；和/或，PD-L1拮抗剂是PD-L1单克隆抗体或其抗原结合片段，其特异地结合人PD-L1且阻断人PD-L1与人PD-1的结合。
本申请还提供一种药物包，其在一个容器中包含含有化合物I或其药学上可接受的盐的药物组合物，在第二个容器中包含含有PD-1拮抗剂或PD-L1拮抗剂的药物组合物。
特瑞普利单抗
如本申请所用，特瑞普利单抗(JS-001，君实生物)是新型重组人源化抗PD-1单克隆抗体注射液。2018年12月17日，君实生物的PD-1抗体药物“特瑞普利单抗注射液”正式被中国国家药品监督管理局(NMPA)批准上市，用于既往接受全身***治疗失败的不可切除或转移性黑色素瘤的治疗。
定义和说明
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本申请中出现商品名时，意在指代其对应的商品、组合物或其活性成分。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本申请的抗体和其片段可以是整个抗体或其任何片段。因此，本申请的抗体和片段包括单克隆抗体或其片段和抗体变体或其片段，以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab)'片段、Fv片段、分离的CDR区、单链Fv分子(scFv)和本领域已知的其他抗体片段。抗体和其片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文公开的抗PD-1/PD-L1抗体和其片段可以是IgG1、IgG2、IgG3或IgG4同种型。
术语“同种型”是指由重链恒定区基因编码的抗体种类。在一个实施方案中，本文公开的抗PD-1/PD-L1抗体和其片段是IgG1或IgG4同种型。本申请的抗PD-1/PD-L1抗体和其片段可以衍生自任何物种，其包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。PD-1/PD-L1抗体和其片段可以是嵌合抗体、人源化抗体或完整的人抗体。
术语“人源化”是指抗体中抗原结合位点来源于非人物种且可变区框架来源于人免疫球蛋白序列。人源化抗体在框架区中可包含置换，使得该框架可能不是表达的人免疫球蛋白或种系基因序列的精确拷贝。
“分离的抗体”表示这样的抗体：其基本上不含有具有不同抗原特异性的其它抗体(例如，分离的特异性地结合PD-1/PD-L1的抗体基本上不含有特异性地结合除PD-1/PD-L1以外的抗原的抗体)。但是，分 离的特异性地结合PD-1/PD-L1的抗体可以具有与其它抗原(诸如来自不同物种的PD-1/PD-L1分子)的交叉反应性。此外，分离的抗体可以基本上不含有其它细胞材料和/或化学物质。
术语“单克隆抗体”(“mAb”)是指单分子组合物的抗体分子。单克隆抗体组合物显示出对于特定表位的单一结合特异性和亲和力，或就双特异性单克隆抗体而言，显示出对于两种不同表位的双重结合特异性。mAb是分离的抗体的一个例子。通过本领域技术人员已知的杂交瘤技术、重组技术、转基因技术或其它技术，可以生产mAb。分离的单克隆抗体的例子包括但不限于纳武利尤单抗(Nivolumab)
Figure PCTCN2020089546-appb-000004
帕博利珠单抗(Pembrolizumab)
Figure PCTCN2020089546-appb-000005
特瑞普利单抗(JS-001，君实生物)、信迪利单抗(Sintilimab，IBI308，信达生物)、卡瑞利株单抗(SHR-1210，Camrelizumab，恒瑞医药，可以参见CN105026428B或WO2015085847A1)、替雷利株单抗(BGB-A317，百济神州)、AK105(中山康方)、杰诺单抗(GB226，嘉和生物)、丽珠单抗(LZM009，丽珠制药)、HLX-10(复宏汉霖)、BAT-1306(百奥泰)、HX008(AK103，康方生物/翰中生物)、AK104(中山康方)、CS1003(基石药业)、SCT-I10A(神州细胞)、F520(山东新时代药业/鲁南制药)、SG001(尚健生物)、GLS-010(誉衡药业)、Atezolizumab(
Figure PCTCN2020089546-appb-000006
罗氏)、Avelumab(
Figure PCTCN2020089546-appb-000007
默克/辉瑞)、Durvalumab(
Figure PCTCN2020089546-appb-000008
阿斯利康)、KL-A167(科伦药业)、SHR-1316(恒瑞医药)、BGB-333(百济神州)、JS003(君实生物)、STI-A1014(ZKAB0011，兆科药业)、KN035(康宁杰瑞/思路迪)、MSB2311(迈博斯生物)、HLX-20(复宏汉霖)、CS-1001(基石药业)等。
抗体的“抗原结合部分”(也称为“抗原结合片段”)表示抗体的一个或多个片段，其保留特异性地结合被完整抗体结合的抗原的能力。
如本文所用，术语“受试者”表示哺乳动物，诸如啮齿动物、猫科动物、犬科动物和灵长类动物。优选地，根据本申请的受试者是人。
“施用/给予/给药”表示，使用本领域技术人员已知的多种方法和递送***中的任一种，向主体物理引入包含治疗剂的组合物。免疫检验点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)的施用/给予/给药途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用/给予/给药途径，例如通过注射或输注。本文中使用的短语“胃肠外施用/给予/给药”是指，通常通过注射进行的除了肠内和局部施用以外的施用/给予/给药模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、***内、病灶内、囊内、眶内、心内、真皮内、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。在某些实施方案中，所述免疫检验点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)通过非胃肠外途径施用/给予/给药；在某些实施方案中，口服施用/给予/给药。其它非胃肠外途径包括局部、表皮或粘膜施用/给予/给药途径，例如，鼻内地、***地、直肠地、舌下地或局部地。还可以执行施用/给予/给药，例如，一次、多次，和/或在一个或多个延长的时间段中。
“程序性死亡受体-1(PD-1)”表示属于CD28家族的免疫抑制性受体。PD-1主要在体内先前活化的T细胞上表达，并且结合两种配体PD-L1和PD-L2。本文使用的术语“PD-1”包括人PD-1(hPD-1)，hPD-1的变体、同种体和物种同系物，以及与hPD-1具有至少一个共同表位的类似物。
“程序性死亡配体-1(PD-L1)”是针对PD-1的两种细胞表面糖蛋白配体(另一种是PD-L2)之一，其在结合PD-1后下调T细胞活化和细胞因子分泌。
“主体”包括任何人或非人动物。术语“非人动物”包括、但不限于脊椎动物诸如非人灵长类动物、绵羊、狗，和啮齿类动物诸如小鼠、大鼠和豚鼠。在某些实施方案中，所述主体是人。术语“主体”和“患者”和“受试者”在本文中的某些语境下可互换地使用。
药物或治疗剂的“治疗有效量”或“治疗上有效的剂量”是当单独使用或与另一种治疗剂联合使用时保护主体免于疾病发作或促进疾病消退的药物的任何量，所述疾病消退通过疾病征状的严重程度的降低、无疾病征状阶段的频率和持续时间的增加、或由疾病折磨引起的损伤或失能的预防来证明。使用熟练的从业人员已知的多种方法可以评价治疗剂的促进疾病消退的能力，诸如在临床试验期间在人主体中，在预测对于人类的效力的动物模型***中，或通过在体外测定法中测定所述药剂的活性。
“复发的”或“复发性”癌症是在对初始治疗(例如手术)产生应答后，在初始部位或远处部位再生的癌症。“局部复发性”癌症是在治疗后，在与先前治疗的癌症相同的位置出现的癌症。
“不可切除的”癌症是无法通过手术去除的。
“转移性”癌症是指从身体的一部分(例如肺部)扩散到身体的另一部分的癌症。
备选方案(例如，“或”)的应用应当被理解为是指备选方案中的任一个、两个或它们的任意组合。本文中使用的不定冠词“一个”或“一种”应当理解为表示任何列举或枚举的组分中的“一个或多个/一种或多种”。
本申请中，凡是涉及安罗替尼，均是指化合物I。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”，包括碱根离子与自由酸形成的盐或酸根离子与自由碱形成的盐，例如包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐，优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐等。本申请中，当形成药学上可接受的盐时，所述自由酸与碱根离子的摩尔量之比为约1:0.5～1:8，优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。本申请中，当形成药学上可接受的盐时，所述自由碱与酸根离子的摩尔量之比为约1:0.5～1:8，优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。
术语“固定组合”指活性组分(例如抗PD-1/PD-L1抗体或化合物I或其药学上可接受的盐)以固定总剂量或剂量比例，或以单一实体、药物组合物或制剂的形式同时给予受试者。
术语“非固定组合”指两种以上活性组分作为独立的实体(例如药物组合物、制剂)同时、并行或依序且无具体时间限制地给予受试者，其中所述给予受试者的活性成份达到治疗有效量水平。非固定组合可列举的例子是鸡尾酒疗法，例如给予3种或以上之活性组分。在非固定组合中，所述各个活性组分可以作为完全独立的药物组合物进行包装、销售或给药。所述“非固定组合”也包括“固定组合”之间、或“固定组合”与任一或多种活性组分的独立实体的联合使用。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以在混合物中一起、作为单一制剂同时地或作为单一制剂以任何顺序依次地施用于受试者。
术语“药物组合物”是指一种或多种本申请的活性成分(例如抗PD-1/PD-L1抗体或化合物I或其药学上可接受的盐)或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
如本文所用，术语“无进展生存期(PFS)”：定义为从首次给药直至肿瘤客观进展或死亡时间。
术语“完全缓解(CR)”：是指所有靶病灶消失，全部病理***(包括靶结节和非靶结节)短直径必须减少至＜10mm。
术语“部分缓解(PR)”：是指靶病灶直径之和比基线水平减少至少30％。
术语“疾病进展(PD)”：是指以整个研究过程中所有测得的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)。
术语“疾病稳定(SD)”：是指靶病灶减小的程度没达到PR水平，增加的程度也没达到PD水平，介于两者之间。
术语“客观缓解率(ORR)”：是指为完全缓解和部分缓解比例之和，即，ORR＝CR+PR。
术语“临床受益率(CBR)”：是指根据RECIST 1.1版标准，达到完全缓解(CR)、部分缓解(PR)或疾病稳定(SD)的受试者的比例。
术语“总生存期(OS)”：定义为首次给药开始至因任何原因引起死亡的时间，以天数计，失访的受试者，通常将最后一次随访时间计算为死亡时间。
术语“RECIST”：是指实体瘤疗效评价标准。
术语“ECOG”：是指美国东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)制定的一个较简化的活动状态评分表。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
施用方式
下述内容并非限制本申请药物组合的施用方式。
本申请的药物组合中的组分可以各自分开配制，或者其中的部分或全部共同配制。在一个实施方案中，本申请的药物组合可以配制成适合于单次或多次施用的药物组合物。
本申请的药物组合中的组分可以各自单独施用，或者其中的部分或全部共同施用。本申请的药物组合中的组分可以基本上不同时施用，或者其中的部分或全部基本上同时施用。
本申请的药物组合中的组分可以各自独立地，或者其中的部分或全部共同以适合的各种途径施用，包括，但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在一些实施方案中，本申请的药物组合的组分可以各自独立地，或者其中的部分或全部共同口服施用或注射施用，例如静脉注射或腹腔注射。
本申请的药物组合中的组分可以各自独立地，或者其中的部分或全部共同是适合的剂型，包括，但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本申请的药物组合中的组分可以各自独立地，或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。
本申请的药物组合还可以包含另外的治疗剂。在一个实施方式中，所述另外的治疗剂可以是本领域已知的癌症治疗剂，优选软组织肉瘤癌治疗剂。
具体实施方式
下面结合具体实施例对本申请进行进一步的描述，然而，本申请中这些实施例仅用于阐明而不限制本申请的范围。同样，本申请不限于本文描述的任何具体优选的实施方案。本领域技术人员应该理解，对本申请技术特征所作的等同替换，或相应的改进，仍属于本申请的保护范围之内。除特别说明的以外，以下实施例采用的试剂均为市售产品，溶液的配制可以采用本领域常规技术。
实施例1 盐酸安罗替尼联合用药治疗未分化多形性肉瘤
开展了盐酸安罗替尼联合特瑞普利单抗用于治疗未分化多形性肉瘤的研究，主要目标人群为在手术不可切除或转移性未分化多形性肉瘤患者。
主要研究终点：PFS[时限：治疗方案实施后3个月]；次要研究终点：ORR[时限：治疗开始后3个月、6个月和12个月]、CBR[时限：治疗开始后3个月、6个月和12个月]、OS[时限：研究结束，平均12个月]，以及安全性和毒性[时限：至治疗结束后30天]。
关键入选标准：组织学确诊为肉瘤的患者，仅未经治疗、并且拒绝一线标准化疗的组织学类型为高级别多形性未分化肉瘤，存在符合RECIST 1.1标准的可测量病灶，ECOG体力状况0-1分，且无法通过手术完全切除病灶。
药物给药剂量：安罗替尼
盐酸安罗替尼胶囊(活性成分为安罗替尼二盐酸盐)：在初始的第一个疗程(28天)，将给予患者盐酸安罗替尼，早餐前口服，12mg/天(每日1次，每次1粒)，连续服用2周，停药2周；随后的疗程为每3个星期(21天)为一疗程，连续服用2周，停药1周。
抗体药物给药剂量：特瑞普利单抗
240mg剂量的特瑞普利单抗通过静脉内给药。给药时间为第一个疗程(28天)的第8天，以及随后每个疗程(21天)的第1天，每21天注射一次。
对患者进行初始安全性评估后，将进行安罗替尼联合特瑞普利的自体剂量递增研究。
初步结果显示，盐酸安罗替尼联合特瑞普利单抗可有效治疗未分化多形性肉瘤。
患者病例
女，72岁，无吸烟史，2018年5月行左大腿肿物切除术，病理诊断：左大腿恶性肿瘤，2018年8月30日行软组织肿物切除术后扩大切除术，临床诊断：左大腿未分化肉瘤，左大腿未分化肉瘤二次术后、双肺转移瘤。
给药：安罗替尼(12mg po qd d1-d14给药两周，停用一周)联合特瑞普利单抗(240mg，每21天一次)。
首次用药时间为：2019.11.22。可测量的靶病灶直径之和44.3mm(其中，左肺下叶32.3mm，右肺中叶12.0mm)。该患者三次疗效评价均为SD。无进展生存期PFS接近5个月。其治疗方案以及疗效评价见下表1。
表1
Figure PCTCN2020089546-appb-000009
根据本申请所公开的内容，虽然根据优选实施方案对本申请的组合物和方法进行了描述，但对本领域技术人员而言，在不背离本申请的概念、精神和范围的情况下，可对在此所述的组合物和/或方法以及所述方法的步骤或步骤的顺序进行改变。
本文所引用的所有文献的公开内容通过引用结合于此，引用程度为，他们提供示例性的、程序上和其他的细节补充本文所述内容。

Claims (13)

  1. 一种用于治疗软组织肉瘤的药物组合，其包括：(i)式I所示的化合物I或其药学上可接受的盐；和(ii)至少一种抗体药物，
    Figure PCTCN2020089546-appb-100001
  2. 根据权利要求1所述的药物组合，其特征在于，所述软组织肉瘤包括在先未接受过酪氨酸激酶抑制剂和/或PD-1受体和其配体PD-L1之间的相互作用的抑制剂和/或细胞毒性T淋巴细胞抗原4抑制剂治疗的软组织肉瘤。
  3. 根据权利要求1或2所述的药物组合，其特征在于，所述抗体药物为PD-1受体和其配体PD-L1之间的相互作用的抑制剂、细胞毒性T淋巴细胞抗原4抑制剂、血小板衍生生长因子受体α抑制剂中的一种或多种。
  4. 根据权利要求3所述的药物组合，其特征在于，所述PD-1受体和其配体PD-L1之间的相互作用的抑制剂为抗PD-1抗体或者抗PD-L1抗体，优选为抗PD-1单克隆抗体或抗PD-L1单克隆抗体；优选选自纳武利尤单抗、帕博利珠单抗、德瓦鲁单抗、特瑞普利单抗、信迪利单抗、卡瑞利株单抗、替雷利株单抗、AK105、杰诺单抗、丽珠单抗、HLX-10、BAT-1306、AK103、AK104、CS1003、SCT-I10A、F520、SG001、GLS-010、Atezolizumab、Avelumab、Durvalumab、KL-A167、SHR-1316、BGB-333、JS003、STI-A1014、KN035、MSB2311、HLX-20、CS-1001中的任意一种或多种。
  5. 根据权利要求3所述的药物组合，其特征在于，所述细胞毒性T淋巴细胞抗原4抑制剂是抗CTLA-4抗体，优选选自伊匹单抗、替西木单抗、AGEN-1884、BMS-986249、BMS-986218、AK-104、IBI310中的任意一种或多种。
  6. 根据权利要求1-5中任一项所述的药物组合，其特征在于，所述抗体药物选自奥拉单抗、贝伐珠单抗、雷莫芦单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、尼妥珠单抗、帕尼单抗、耐昔妥珠单抗、Dinutuximab、利妥昔单抗、替依莫单抗、奥法木单抗、Obinutuzumab、阿仑单抗、达雷木单抗、吉妥单抗、埃罗妥珠单抗、本妥昔单抗、奥英妥珠单抗、博纳吐单抗中的任意一种或多种。
  7. 根据权利要求4所述的药物组合，其特征在于，所述抗PD-1抗体或抗PD-L1抗体每周、每2周、每3周、或者每4周施用一次，优选每3周施用一次；所述化合物I或其药学上可接受的盐以每日一次6mg、8mg、10mg或者12mg的剂量进行施用。
  8. 根据权利要求7所述的药物组合，其特征在于，所述抗PD-1抗体为特瑞普利单抗。
  9. 根据权利要求8所述的药物组合，其特征在于，包括：(i)单剂量为6mg、8mg、10mg和/或12mg的化合物I或其药学上可接受的盐的药物组合物；和(ii)单剂量为120～600mg的特瑞普利单抗的药物组合物；优选地，特瑞普利单抗被制备为适合第一次给药时向患者给予240mg的单剂量或多剂量，所述化合物I或其药学上可接受的盐被制备为适合连续14天、每天向患者给予6mg、8mg、10mg和/或12mg的单剂量药物组合物。
  10. 根据权利要求1-9中任一项所述的药物组合，其特征在于，所述化合物I或其药学上可接受的盐以给药期和停药期间隔的给药方式；优选的给药期和停药期以天数计的比值为2:0.5～5，更优选2:0.5～3，较优选2:0.5～2，进一步优选2:0.5～1；作为更进一步优选的间隔给药方式，为如下方式中的一种：连续给药2周停药2周、连续给药2周停药1周或连续给药5天停药2天；所述间隔给药方式可以反复进行多次。
  11. 一种包含如权利要求1-10中任一项所述的药物组合的试剂盒，其中含有(a)第一种药物组合物，含有 抗PD-1抗体和/或抗PD-L1抗体作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。
  12. 一种如权利要求1-10中任一项所述的药物组合在制备用于治疗软组织肉瘤的药物中的用途。
  13. 一种用于治疗软组织肉瘤的方法，所述方法包括向需要治疗的受试者给予治疗有效量的化合物I或其药学上可接受的盐以及治疗有效量的至少一种抗体药物。
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