WO2020233602A1 - 用于联合治疗小细胞肺癌的喹啉衍生物 - Google Patents

用于联合治疗小细胞肺癌的喹啉衍生物 Download PDF

Info

Publication number
WO2020233602A1
WO2020233602A1 PCT/CN2020/091312 CN2020091312W WO2020233602A1 WO 2020233602 A1 WO2020233602 A1 WO 2020233602A1 CN 2020091312 W CN2020091312 W CN 2020091312W WO 2020233602 A1 WO2020233602 A1 WO 2020233602A1
Authority
WO
WIPO (PCT)
Prior art keywords
lung cancer
pharmaceutical composition
small cell
cell lung
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/091312
Other languages
English (en)
French (fr)
Inventor
王东
戴楠
罗皓
徐萍
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to AU2020279289A priority Critical patent/AU2020279289B2/en
Priority to US17/595,519 priority patent/US20220193066A1/en
Priority to JP2021568907A priority patent/JP7761490B2/ja
Priority to CN202080034910.5A priority patent/CN113811298B/zh
Priority to EP20810457.0A priority patent/EP3973964A4/en
Priority to CA3141167A priority patent/CA3141167A1/en
Priority to KR1020217039271A priority patent/KR102936318B1/ko
Publication of WO2020233602A1 publication Critical patent/WO2020233602A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], 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 [IG], 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • This application belongs to the field of medical technology, and this application relates to the use of quinoline derivatives for anti-tumor. Specifically, this application relates to the use of quinoline derivatives for combined treatment of small cell lung cancer.
  • SCLC Small cell lung cancer
  • the SCLC staging system developed by the Veterans Administration Lung Study Group (VALG) has been used for a long time and is simple and easy to implement.
  • This staging divides SCLC into limited disease (LD) and extensive disease (ED).
  • LD limited disease
  • ED extensive disease
  • the former is defined as lesions confined to one side of the thoracic cavity, including those with contralateral mediastinum and bilateral supraclavicular lymph nodes with metastasis , And those with pleural effusion on the same side implies a complete radiation field that can be tolerated. On the contrary, those with lesions beyond the above range are defined as extensive, and the former accounts for about 30%-40%.
  • the median survival time (MST) of untreated SCLC is only 2 months to 4 months; after treatment, the MST of patients with limited stage is about 15 months to 20 months, and the MST of patients with extensive stage For 8 months-13 months.
  • SCLC is more sensitive to chemotherapy and radiotherapy.
  • this application provides a combination pharmaceutical composition for the treatment of small cell lung cancer, which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic drug.
  • the application also provides the use of the pharmaceutical composition in the preparation of a medicament for treating small cell lung cancer.
  • the application also provides the use of the pharmaceutical composition for treating small cell lung cancer.
  • the application also provides a method for treating small cell lung cancer, which comprises administering the pharmaceutical composition of the application to a subject.
  • the pharmaceutical composition includes: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic drug.
  • the application provides a combination pharmaceutical composition for the treatment of small cell lung cancer, which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic drug,
  • the pharmaceutical composition includes: (i) a pharmaceutical composition of Compound I or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutical composition of at least one second therapeutic agent.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one chemotherapeutic drug, and Optionally combined with radiotherapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one small molecule target Anti-tumor drugs, and optionally combined with radiotherapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one immunotherapy drug, And optionally combined with radiotherapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one macromolecular antibody drug , And optionally combined with radiation therapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) a fluoropyrimidine derivative, and Optionally combined with radiotherapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) Tiggio, and any Select the place to combine with radiotherapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer is provided, which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) Podophyllum and at least one A platinum drug, and optionally combined with radiation therapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) etoposide and at least one A platinum drug, and optionally combined with radiation therapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) etoposide and cisplatin , And optionally combined with radiation therapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) etoposide and carboplatin , And optionally combined with radiation therapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) Etoposide and Lebain , And optionally combined with radiation therapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer is provided, which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) an anti-PD-1 antibody, And optionally combined with radiotherapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) sintilimab, And optionally combined with radiotherapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer is provided, which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) camptothecin drugs, And optionally combined with radiotherapy.
  • a pharmaceutical composition for the treatment of small cell lung cancer is provided, which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) irinotecan, and any Select the place to combine with radiotherapy.
  • the present application provides the use of a pharmaceutical composition in the preparation of a medicament for the treatment of small cell lung cancer, which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one A second therapeutic agent, and optionally combined with radiation therapy.
  • a pharmaceutical composition in the preparation of a medicament for the treatment of small cell lung cancer, which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one A second therapeutic agent, and optionally combined with radiation therapy.
  • the application also provides the use of the pharmaceutical composition for treating small cell lung cancer.
  • the application also provides a method for treating small cell lung cancer, which comprises administering the pharmaceutical composition of the application to a subject.
  • the pharmaceutical composition includes: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic drug.
  • This application provides a method for treating a subject suffering from small cell lung cancer.
  • the subject has previously received surgery, chemotherapy, and/or radiation therapy.
  • the subject has recurred disease progression after achieving complete remission after surgery, chemotherapy, and/or radiotherapy.
  • the subject has not been completely relieved or failed to partially relieve after surgery, chemotherapy, and/or radiation therapy.
  • This application provides a method for treating small cell lung cancer, which comprises administering Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic drug to a patient in need of treatment.
  • the application provides a method of treating small cell lung cancer that has not received chemotherapy regimens, the method comprising administering Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, and at least one 2. Therapeutic drugs.
  • the application provides a method for small cell lung cancer that has progressed or recurred after receiving at least one chemotherapy, the method comprising administering Compound I or a pharmaceutically acceptable compound thereof to a patient in need of treatment Salt, and at least one second therapeutic agent.
  • the application provides a method of treating small cell lung cancer that has previously received at least two chemotherapy regimens, the method comprising administering Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, and At least one second therapeutic drug.
  • the application provides a method of treating refractory and relapsed small cell lung cancer, the method comprising administering Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, and at least one second medicine.
  • the compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic drug are used in combination to treat primary small cell lung cancer or secondary small cell lung cancer.
  • the small cell lung cancer is small cell lung cancer that cannot tolerate chemotherapy.
  • 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 surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy, and disease progression occurs again after complete remission.
  • the subject fails to complete or partially relieve after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the subject undergoes surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy after cancer metastasis.
  • the method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the subject.
  • the second therapeutic drug in the use or treatment method, including but not limited to, may be daily (qd), every other day (qod), every 3 days (q3d), every 4 days (q4d) ), every 5 days (q5d), every week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w), or twice a day (bid), weekly Two times (biw), three times a day (tid), four times a day (qid), etc.
  • the second therapeutic drug in the use or treatment method, may also be administered in an interval administration manner.
  • the intermittent administration includes a dosing period and a drug withdrawal period.
  • the second therapeutic drug is given every day during the drug administration period, and then the drug administration is stopped for a period of time during the drug withdrawal period, followed by the dosing period, and then the drug withdrawal period. It can be repeated many times.
  • the compound I or a pharmaceutically acceptable salt thereof in the use or treatment method, including but not limited to, can be administered at a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for continuous administration 2 Weeks, one-week off regimen; and/or, two-week continuous medication, two-week off regimen.
  • the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof have the same or different treatment cycles, respectively. In some specific embodiments, the second therapeutic agent 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. In some specific embodiments, the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof are treated every 3 weeks.
  • the present application provides a combination pharmaceutical composition, which is a formulation suitable for administration within a single treatment cycle (for example, a treatment cycle of 3 weeks), including 84-168 mg, preferably 112-168 mg Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent.
  • Compound I or a pharmaceutically acceptable salt thereof can be separately packaged in multiple equal parts (for example, 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more).
  • the present application provides a kit for the treatment of small cell lung cancer, the kit comprising Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic drug, and optional instructions .
  • the small cell lung cancer is recurrent; in some embodiments, the small cell lung cancer is refractory; in some embodiments, the small cell lung cancer is refractory Lung cancer is unresectable; in certain embodiments, the small cell lung cancer is advanced small cell lung cancer. In some embodiments, the small cell lung cancer is small cell lung cancer that has failed treatment with chemotherapeutic drugs and/or targeted drugs. In some embodiments, the small cell lung cancer is small cell lung cancer that has received at least two chemotherapy regimens.
  • the small cell lung cancer is refractory and relapsed small cell lung cancer, wherein the "refractory and relapsed small cell lung cancer” refers to small cell lung cancer that is not remitted by chemotherapy, and chemotherapy is effective but not Small cell lung cancer that has progressed within 3 months after the end of chemotherapy.
  • the small cell lung cancer is small cell lung cancer that is sensitive to relapse.
  • the small cell lung cancer is drug-resistant relapsed small cell lung cancer.
  • the clinical stages of the small cell lung cancer include, but are not limited to, locally advanced, and/or advanced (for example, stage IIIB/IV) and/or metastatic small cell lung cancer.
  • metastatic small cell lung cancer includes but is not limited to single metastasis, disseminated metastasis, diffuse metastasis; the metastatic focus includes but not limited to lymph nodes, pleura, bone, brain, pericardium, adrenal gland, liver; in some embodiments
  • the said small cell lung cancer is small cell lung cancer with brain metastasis.
  • the small cell lung cancer is small cell lung cancer that cannot tolerate chemotherapy. Those skilled in the art can understand that the patient can also receive radiotherapy simultaneously or sequentially with the chemotherapy.
  • the small cell lung cancer is extensive-stage small cell lung cancer.
  • the small cell lung cancer is limited-stage small cell lung cancer.
  • the small cell lung cancer is metastatic small cell lung cancer, wherein the metastatic lesions include but are not limited to lymph nodes, pleura, bone, pericardium, adrenal glands, liver, and brain. In some embodiments, the small cell lung cancer is small cell lung cancer with brain metastases.
  • the small cell lung cancer is refractory and relapsed small cell lung cancer that has previously received one or more of irinotecan, platinum drugs, paclitaxel and docetaxel.
  • the small cell lung cancer is previously received irinotecan and platinum drugs (for example, including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, bicycloplatin, Leplatin , Triplatin tetranitrate, phenanthroplatin, picoplatin, miplatin, saplatin) treatment of refractory and relapsed small cell lung cancer.
  • platinum drugs for example, including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, bicycloplatin, Leplatin , Triplatin tetranitrate, phenanthroplatin, picoplatin, miplatin, saplatin
  • the second therapeutic drugs described in this application include, but are not limited to, chemotherapy drugs, small molecule targeted anti-tumor drugs, immunotherapy drugs, and macromolecular antibody drugs.
  • the second therapeutic drug is a chemotherapy drug, including but not limited to platinum drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, One or more of podophyllum and antimetabolites antitumor drugs, examples that can be cited include but are not limited to platinum drugs (such as oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin ), Lobaplatin, triplatin tetranitrate, phenanthroplatin, picoplatin, miplatin, satraplatin), fluoropyrimidine derivatives (e.g.
  • gemcitabine capecitabine, amcitabine, fluorouracil, difurofluorouracil, de Oxfluridine, tegafur, carmofur, trifluridine, tigeo), taxanes (e.g. paclitaxel, albumin-bound paclitaxel and docetaxel), camptothecins (e.g.
  • camptothecin Alkali hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan
  • vinblastines vinorelbine, vinblastine, vincristine, vindesine, Vinflunine
  • anthracyclines epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, arubicin Star, valrubicin, zorubicin, pitoxan
  • pemetrexed carmustine, melphalan
  • etoposide etoposide
  • teniposide mitomycin
  • Ifosfamide, cyclophosphamide azacitidine, methotrexate, bendamustine, liposomal adriamycin, actinomycin D (dactinomycin), ble
  • the second therapeutic drug is one or more of platinum drugs, including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, Triplatin tetranitrate, phenanthroplatin, picoplatin, satraplatin, miplatin, leplatin, etc.
  • the chemotherapeutic agent is selected from the group consisting of etoposide, irinotecan, cisplatin, carboplatin, loboplatin, nedaplatin, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, Gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, amrubicin, tegafur, gemepyrimidine, otirazide, tigeo One or more of.
  • the second therapeutic drug is used in conjunction with chemotherapy adjuvant drugs
  • the chemotherapy adjuvant drugs include but are not limited to calcium leucovorin (CF), folate, mesna, bisphosphonate, and ammonia Phospstin, hematopoietic cell colony stimulating factors (CSFs).
  • the chemotherapeutic adjuvant drug is calcium leucovorin (CF), mesna, and aldofolate.
  • the second therapeutic drug is an immunotherapeutic drug, including but not limited to interferon (interferon alpha, interferon alpha-1b, interferon alpha-2b), interleukin, temsirolimus (temsirolimus ), one or more of everolimus, ridaforolimus, and temsirolimus.
  • interferon interferon alpha, interferon alpha-1b, interferon alpha-2b
  • interleukin interleukin
  • temsirolimus temsirolimus
  • everolimus temsirolimus
  • ridaforolimus ridaforolimus
  • temsirolimus temsirolimus
  • the second therapeutic drug is a small molecule targeted anti-tumor drug, including but not limited to protein kinase inhibitors.
  • the protein kinase inhibitors include but are not limited to tyrosine kinase inhibitors, serine and/or threonine kinase inhibitors, poly ADP-ribose polymerase (PARP, poly ADP-ribose polymerase) inhibitors.
  • PARP poly ADP-ribose polymerase
  • the targets targeted by inhibitors include but are not limited to Fascin-1 protein, HDAC (histone deacetylase), proteasome, CD38, SLAMF7 (CS1/CD319/CRACC), RANKL, EGFR (epidermal growth factor receptor).
  • anaplastic lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (disc death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1 ), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene;
  • the targets of the small molecule targeted anti-tumor drugs also include COX-2 (cyclooxygenase-2), APE1 (depurinating Pyrimidine endonuclease), VEGFR (vascular endothelial growth factor receptor), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), Ezrin , PEDF (Pigment Epithelium Derived Factor), AS, ES, OPG (Bone Protective Factor), Src, IFN, ALCAM (Leukocyte Activated Adhesion
  • the small molecule targeted anti-tumor drugs that can be enumerated include, but are not limited to, Imatinib, Sunitinib, Nilotinib, Bosutinib, Secatinib (Saracatinib), Pazopanib (Pazopanib), Trabectedin (Trabectedin), Regorafenib (Regorafenib), Cediranib (Cediranib), Bortezomib (Bortezomib), Pabirestat (Panobinostat) , Carfilzomib (Carfilzomib), Ixazomib (Ixazomib), Apatinib (apatinib), Erlotinib (Erlotinib), Afatinib (Afatinib), Crizotinib (Crizotinib), color Ceritinib, Vemurafenib, Dabrafenib, Cabozantin
  • the small-molecule targeted anti-tumor drug is sorafenib, erlotinib, afatinib, crizotinib, ceritinib, velofenib, dalafi Ni, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, loratinib, trametinib, larotinib, icotinib Ni, Lapatinib, Vandetanib, Smeltinib, Omotinib, Volitinib, Fruquintinib, Entratinib, Dasatinib, Ensatinib, Levatinib Ni, itacitinib, pyrrotinib, bimetinib, erdatinib, axitinib, lenatinib, cobitinib, acatin
  • the second therapeutic drug is a macromolecular antibody drug.
  • the targets targeted by the macromolecular antibody drug include but are not limited to PD-1, PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), platelet-derived growth factor receptor ⁇ (PDGFR- ⁇ ), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR), ganglioside GD2, B cell surface protein CD20, B cells Any one or more of 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 ⁇
  • VEGF vascular endothelial growth factor
  • HER2 human epidermal growth factor receptor-2
  • EGFR epidermal growth factor receptor
  • ganglioside GD2 B cell surface protein CD20
  • the antibody drug is an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1; in some embodiments, the antibody drug is a cytotoxic T lymphocyte Antigen 4 (cytotoxic T-lymphocyte antigen 4, CTLA-4) inhibitor. In some embodiments, the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR- ⁇ ) inhibitor.
  • 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 inhibits the activity of PD-1 or its
  • the antigen-binding portion alternatively, is an antibody or antigen-binding portion thereof that binds to programmed death ligand 1 (PD-L1) and/or inhibits the activity of PD-L1, for example, an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • the antibody or antigen-binding portion thereof is (a) an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof, which specifically binds to human PD-1 and blocks human PD-L1 and human PD -1; or (b) an anti-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 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 Toripalimab , JS-001), Sintilimab (IBI308, Sintilimab), Carrelizumab (Camrelizumab), Tirelizumab (BGB-A317), Genolizumab (GB226), Livizumab Anti-(LZM009), HLX-10, BAT-1306, AK103 (HX008), AK104 (Kangfang Bio), CS1003, SCT-I10A, F520, SG001, GLS-010 any one or more.
  • the anti-PD-L1 antibody can 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.
  • 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 Any one or more of Elotuzumab, Brentuximab, Inotuzumab Ozogamicin, and Blinatumomab.
  • the second therapeutic agent is Tiggio.
  • the second therapeutic agent is etoposide and at least one platinum-based drug.
  • the second therapeutic agent is one or both of etoposide and cisplatin. In a specific embodiment, the second therapeutic agent is an EP regimen (etoposide + cisplatin).
  • the second therapeutic agent is one or both of carboplatin and etoposide. In a specific embodiment, the second therapeutic agent is an EC regimen (carboplatin + etoposide).
  • the second therapeutic agent is one or both of etoposide and leplatin.
  • the second therapeutic agent is one, two, three, or four of cyclophosphamide, vincristine, methotrexate, and etoposide.
  • the second therapeutic agent is the COME regimen (cyclophosphamide + vincristine + methotrexate + etoposide).
  • the second therapeutic agent is one, two or three of cyclophosphamide, doxorubicin, and vincristine.
  • the second therapeutic agent is a CAV regimen (cyclophosphamide + adriamycin + vincristine).
  • the second therapeutic agent is one, two or three of cyclophosphamide, doxorubicin, and etoposide.
  • the second therapeutic agent is a CAE regimen (cyclophosphamide + adriamycin + etoposide).
  • the second therapeutic agent is one, two or three of ifosfamide, etoposide, and cisplatin.
  • the second therapeutic agent is an IEP regimen (ifosfamide + etoposide + cisplatin).
  • the second therapeutic agent is one, two or three of carboplatin, paclitaxel, and etoposide.
  • the second therapeutic agent is a CPE regimen (carboplatin + paclitaxel + etoposide).
  • the second therapeutic agent is one, two, three or four of cisplatin, vincristine, doxorubicin, and etoposide.
  • the second therapeutic agent is the CODE regimen (cisplatin + vincristine + adriamycin + etoposide).
  • the second therapeutic agent is topotecan.
  • Compound I can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of Compound I in vivo.
  • the pharmaceutically acceptable salt of Compound I can be produced from different organic acids and inorganic acids according to methods well known in the art within the scope of this application.
  • the administration is in the form of Compound I hydrochloride. In some embodiments, the administration is in the form of Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, the administration is in the crystalline form of Compound I hydrochloride. In a specific embodiment, it is administered in the crystal form of Compound I dihydrochloride.
  • Compound I, or a pharmaceutically acceptable salt thereof, and the second therapeutic drug can be administered by a variety of routes, including but not limited to routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, and transfusion. Skin, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vagina, intraocular, topical, subcutaneous, intra-fat, intra-articular, intraperitoneal and intrathecal. In a specific embodiment, it is administered orally.
  • the amount of compound I or its pharmaceutically acceptable salt and the second therapeutic agent administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the subject.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 3 mg to 30 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 6 mg to 12 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 6 mg. In a specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In a specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In a specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In this application, for example, for tablets or capsules, "contains 12 mg of Compound I or a pharmaceutically acceptable salt thereof on a unit dose basis" means that each tablet or capsule is finally made The preparation contains 12 mg of compound I.
  • Compound I or a pharmaceutically acceptable salt thereof, and the second therapeutic agent can be administered one or more times a day.
  • Compound I or a pharmaceutically acceptable salt thereof is administered once a day.
  • the oral solid formulation is administered once a day.
  • the method of administration can be comprehensively determined according to the activity, toxicity of the drug, and tolerance of the subject.
  • Compound I or a pharmaceutically acceptable salt thereof is administered at intervals.
  • the interval administration includes an administration period and a drug withdrawal period.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day.
  • Compound I or its pharmaceutically acceptable salt is administered every day during the administration period, and then the administration is stopped during the withdrawal period for a period of time, followed by the administration period, and then the withdrawal period, which can be repeated many times.
  • 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 2 weeks.
  • the drug is administered once a day for 14 days, and then the drug is stopped for 14 days; then once a day, the drug is administered for 14 days, then the drug is stopped for 14 days, and the drug is continuously administered for 2 weeks.
  • the two-week interval dosing method can be repeated many times.
  • the administration is continued for 2 weeks and the drug is stopped for 1 week.
  • the drug is administered once a day for 14 days, and then the drug is stopped for 7 days; then once a day, the drug is administered for 14 days, then the drug is stopped for 7 days, and the drug is continuously administered for 2 weeks.
  • the one-week interval administration can be repeated many times.
  • Compound I or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each cycle, and every 21 days is a dosing cycle.
  • the drug is discontinued for 2 days for 5 consecutive days. In some embodiments, the drug is administered once a day for 5 days, and then the drug is stopped for 2 days; then once a day, the drug is administered for 5 days, then the drug is stopped for 2 days, and the drug is stopped for 5 consecutive days.
  • the two-day interval administration method can be repeated many times.
  • it is administered orally at a dose of 12 mg once a day for 2 consecutive weeks and a one-week stop for administration.
  • Compound I or a pharmaceutically acceptable salt thereof is combined with surgical resection and/or radiation therapy.
  • Each component of the pharmaceutical combination described in this application may optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components may each independently, or part or all of them may contain pharmaceutically acceptable carriers.
  • 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 composition 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 by a suitable route, including but not limited to oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes).
  • the components of the pharmaceutical composition of the present application may be individually administered orally or by injection, for example, intravenous injection or intraperitoneal injection, or part or all of them may be administered jointly.
  • the components of the pharmaceutical combination of the present application can be independently, or some or all of them can be a suitable dosage form, including but not limited to tablets, troches, pills, capsules (such as hard capsules, soft capsules, enteric capsules). Capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration The dosage form of sustained-release preparations.
  • 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 second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition.
  • Compound I or a pharmaceutically acceptable salt thereof and one or more second therapeutic agents are administered simultaneously or sequentially.
  • one or more second therapeutic agents have been administered to the subject before administration of Compound I or a pharmaceutically acceptable salt thereof or before combination with Compound I or a pharmaceutically acceptable salt thereof.
  • one or more second therapeutic agents are administered to the subject after administration of Compound I or a pharmaceutically acceptable salt thereof or after combination with Compound I or a pharmaceutically acceptable salt thereof.
  • Compound I or a pharmaceutically acceptable salt thereof has been administered to the subject before the administration of one or more second therapeutic agents or before combination with one or more second therapeutic agents.
  • Compound I or a pharmaceutically acceptable salt thereof is administered to the subject after administration of one or more second therapeutic agents or after combination with one or more second therapeutic agents. In some embodiments, when Compound I or a pharmaceutically acceptable salt thereof is administered to a subject in combination with one or more second therapeutic agents, the subject is sequentially administered Compound I or a pharmaceutically acceptable salt thereof and One or more second therapeutic drugs.
  • kits of a pharmaceutical composition for the treatment of small cell lung cancer which contains: (a) a first pharmaceutical composition containing a chemotherapeutic drug as an active ingredient; and (b) a second A pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit of a pharmaceutical composition for the treatment of small cell lung cancer which contains: (a) a first pharmaceutical composition containing a small molecule targeted antitumor drug as an active ingredient; and ( b) A second pharmaceutical composition, which contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • kits of a pharmaceutical composition for the treatment of small cell lung cancer which contains: (a) a first pharmaceutical composition containing an immunotherapeutic drug as an active ingredient; and (b) a second pharmaceutical composition; A pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit of a pharmaceutical composition for the treatment of small cell lung cancer which contains: (a) a first pharmaceutical composition containing a macromolecular antibody drug as an active ingredient; and (b) a Two pharmaceutical compositions, which contain Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • kits of a pharmaceutical composition for the treatment of small cell lung cancer which contains: (a) a first pharmaceutical composition containing tigeo as an active ingredient; and (b) a second pharmaceutical composition; A pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit of a pharmaceutical composition for the treatment of small cell lung cancer which contains: (a) a first pharmaceutical composition containing etoposide and platinum drugs as active ingredients; and ( b) A second pharmaceutical composition, which contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • kits of a pharmaceutical composition for the treatment of small cell lung cancer which contains: (a) a first pharmaceutical composition containing etoposide and cisplatin as active ingredients; and (b ) The second pharmaceutical composition, which contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit of a pharmaceutical composition for the treatment of small cell lung cancer which contains: (a) the first pharmaceutical composition, containing etoposide and leplatin as active ingredients; and (b ) The second pharmaceutical composition, which contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect can be therapeutic based on partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a subject's disease, including: (a) inhibiting the symptoms of the disease, that is, preventing its development; or (b) alleviating the symptoms of the disease, that is, causing the disease or symptoms to degenerate.
  • treatment failure refers to intolerable side effects, disease progression during treatment, or relapse after treatment ends.
  • the term "subject” means mammals, such as rodents, felines, canines, and primates.
  • the subject according to the present application is a human.
  • administering refers to the physical introduction of a composition containing a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion.
  • parenteral administration refers to modes of administration other than enteral and local administration that are usually performed by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, and intralymphatic , Intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injections and infusions , And electroporation in vivo.
  • the drug is administered via a non-parenteral route, and in certain embodiments, it is administered orally.
  • Non-parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasal, vaginal, rectal, sublingual, or topical. Administration can also be performed, for example, once, multiple times, and/or over one or more extended periods of time.
  • 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 “subject” are used interchangeably in certain contexts herein.
  • anticancer drugs promote regression of cancer in the subject or prevent further tumor growth.
  • the drug promotes cancer regression to the point where the cancer is eliminated.
  • Promote cancer regression refers to the administration of drugs alone or in combination with an antitumor agent, resulting in a reduction in tumor growth or size, tumor necrosis, reduction in the severity of at least one disease symptom, and frequency of disease-free stages And the increase in duration.
  • the terms "effective” and “effective” with respect to treatment include pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of a drug to promote cancer regression in a subject.
  • Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cell, organ, and/or biological level caused by drug administration.
  • anticancer drugs can inhibit cell growth or tumor growth by at least about 10 relative to an untreated subject, or, in certain embodiments, relative to a subject treated with standard-of-care therapy. %, at least about 20%, at least about 40%, at least about 60%, or at least about 80%. In other embodiments of the application, tumor regression can be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these final measures of therapeutic effectiveness, drug evaluation must also consider "immune-related" response patterns.
  • Immunotherapeutic response pattern refers to a clinical response pattern frequently observed in cancer subjects treated with immunotherapeutic agents that produce anti-tumor effects by inducing cancer-specific immune responses or by altering innate immune processes effect. This response pattern is characterized by a beneficial therapeutic effect after the initial increase in tumor burden or the appearance of new lesions, which will be classified as disease progression in the evaluation of traditional chemotherapeutics and will be synonymous with drug failure. Therefore, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on target diseases.
  • 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)'2 fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), Fd fragments, 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-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 an antibody molecule composed of a single molecule.
  • 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) Durvalumab, Avelumab, Tereprizumab (JS-001, Junshi Bio), Sintilimab (Sintilimab, IBI308, Xinda Biological), Carrelizumab (SHR-1210, Camrelizumab, Hengrui
  • CN105026428B or WO2015085847A1 tisleli strain monoclonal antibody
  • BGB-A317, BeiGene genozumab (GB226, Jiahe Biologics)
  • HLX- 10 Fuhong Henlius
  • BAT-1306 Biotech
  • HX008 AK103, Kangfang Biological/Hanzhong Biological
  • AK104 Zahongshan Kangfang
  • CS Chem
  • 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.
  • 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.
  • 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, p-toluene Sulfonate, sodium, potassium, ammonium or amino acid salt, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate Acid salt, methanesulfonate, p-toluenesulfonate, 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 1:5, 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 1:5, preferably 1:0.5, 1:1, 1:2, 1. :3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • fixed combination means that the active ingredients (for example, chemotherapeutics or Compound I) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or preparation.
  • 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 ingredient reaches 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 a mixture of one or more of the active ingredients of the application (for example, the second therapeutic drug or Compound I) or its drug combination and pharmaceutically acceptable 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.
  • Chronic benefits in this application include but are not limited to: clinical patient progression-free survival (PFS) prolonged, overall survival (OS) prolonged, objective response rate (ORR) improved, disease control rate (DCR) ) Is improved, the number and/or degree of adverse reactions are reduced.
  • PFS clinical patient progression-free survival
  • OS overall survival
  • ORR objective response rate
  • DCR disease control rate
  • the combined administration component is two groups, respectively, using EP or EC regimens (etoposide + cisplatin/ Carboplatin) + Anlotinib combined administration group, while EP or EC (etoposide + cisplatin/carboplatin) alone was used as the control administration group.
  • EP or EC etoposide + cisplatin/carboplatin
  • the specific method of administration is as follows:
  • PFS progression-free survival
  • ORR objective response rate
  • OS overall survival
  • DCR disease control rate
  • non-small cell lung cancer In patients with small cell lung cancer diagnosed by histopathology or cytology, who have received a systemic chemotherapy in the past, and include platinum-based chemotherapy, and relapse or fail after treatment, exclude non-small cell lung cancer, including Patients with mixed small cell and non-small cell type are divided into two groups, the combined administration group and the single-agent chemotherapy control group.
  • the specific administration methods are as follows:
  • Anlotinib Hydrochloride Capsule 12mg qd po d1-14 + irinotecan 60 ⁇ 80mg/m 2 ivd1 and d8; q3w, the chemotherapy cycle does not exceed 6 cycles at most;
  • Single-agent chemotherapy control group Irinotecan 60 ⁇ 80mg/m 2 ivd1 and d8; q3w, the chemotherapy cycle does not exceed 6 cycles at most.
  • Efficacy evaluation observation indicators include progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), quality of life score, and drug safety.
  • anlotinib and etoposide are as follows:
  • Etoposide soft capsule once a day, orally before breakfast, 100 mg each time (based on the weight of etoposide), d1-10 of each cycle, 21 days as a treatment cycle;
  • Anlotinib Hydrochloride Capsules once a day, orally before breakfast, 12 mg each time, d1-14 in each cycle, 21 days as a treatment cycle.
  • the interval between the two drugs is more than half an hour. If there is a missed dose, make sure that the time between the next dose is not less than 12 hours, otherwise, no supplementation will be taken.
  • the dosage can be adjusted according to the degree of drug-related toxicity and the possible benefit of the drug.
  • the dose can be adjusted to the following 2 levels: 10mg and 8mg. If it is necessary to reduce more than 2 dose levels, the treatment is terminated. Etoposide dose adjustment can be reduced to 50mg.
  • Every 3 weeks is a dosing cycle for 6 cycles of combined administration of Anlotinib and S-1 (Tiggio) therapy, as well as S-1 maintenance therapy.
  • the above two are administered sequentially on the first day of each cycle.
  • the administration time window can be ⁇ 3 days, but within 3 days before each administration, in addition to imaging examinations, subjects must complete various items including vital signs, physical examinations, laboratory examinations, physical status scores, etc. an examination.
  • Subjects also need to complete the tumor at a frequency of once every 6 weeks ( ⁇ 7 days) within 48 weeks after the first dose, and once every 9 weeks ( ⁇ 7 days) after 48 weeks after the first dose Imaging evaluation (the evaluation method is consistent, CT or MRI).
  • the specific method of administration is as follows:
  • Anlotinib Hydrochloride Capsules 12mg once/day + S-1 60mg/m 2 bid, continuous medication for 2 weeks, stop for 1 week;
  • the subjects After completing the induction therapy and entering the maintenance treatment stage, the subjects will continue to receive S-1 maintenance therapy (20mg/m2bid, continuous medication for 2 weeks and stop for 1 week, 21 days as a cycle) subjects receive maintenance treatment until the disease progresses, Untolerable toxic and side effects, withdrawal notification, or the investigator's decision to withdraw the subject from the study, non-compliance with study treatment or other reasons specified in the study procedure or protocol
  • PFS progression-free survival
  • ORR objective response rate
  • OS overall survival
  • DCR disease control rate
  • Anlotinib Hydrochloride Capsules once a day, orally before breakfast, 12 mg each time, d1-14 administration in each cycle, continuous medication for 2 weeks, withdrawal for 1 week, 21 days as a treatment cycle;
  • Sintilimab 200 mg, intravenous infusion, d1 administration per cycle, 21 days as a treatment cycle.
  • PFS progression-free survival
  • OS overall survival
  • safety indicators include safety indicators.
  • the amount of anlotinib hydrochloride capsule is based on the weight of anlotinib free base contained therein.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

一种用于治疗小细胞肺癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物，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。

Description

用于联合治疗小细胞肺癌的喹啉衍生物 技术领域
本申请属于医药技术领域，本申请涉及喹啉衍生物用于抗肿瘤的用途。具体而言，本申请涉及喹啉衍生物用于联合治疗小细胞肺癌的用途。
背景技术
小细胞肺癌(small cell lung cancer，SCLC)是肺癌中恶性程度最高的一种类型，具有进展快、转移早、易复发等特点，约占新发肺癌15％-20％，其发生与长期吸烟有密切关系。SCLC侵袭性高，早期诊断率低以及缺乏有效的治疗方法，预后较差，未经治疗的SCLC患者的从诊断开始的中位生存期仅为2至4个月，5年生存率不足5％。
美国退伍军人肺癌协会(Veterans Administration Lung Study Group，VALG)制定的SCLC分期系统使用久远，且简单易行。该分期将SCLC简略地分为局限期(limited disease，LD)与广泛期(extensive disease，ED)，前者定义为病变局限于一侧胸腔包括伴有对侧纵隔及双侧锁骨上淋巴结有转移者，以及同侧有胸水者，暗含一个可承受的完整放射野，反之，病变超出上述范围者均定义为广泛期，其中前者约占30％-40％。SCLC未经治疗者的中位生存期(median survival time，MST)仅为2个月-4个月；治疗后，局限期患者的MST约为15个月-20个月，广泛期患者的MST为8个月-13个月。同其它类型肺癌相比，SCLC对化疗和放疗比较敏感，然而，由于存在高复发率和耐药率，因此在治疗方面仍然面临诸多挑战。
发明概述
一方面，本申请提供用于治疗小细胞肺癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物。
另一方面，本申请还提供药物组合物在制备用于治疗小细胞肺癌的药物中的用途。本申请还提供药物组合物用于治疗小细胞肺癌的用途。
再一方面，本申请还提供治疗小细胞肺癌的方法，其包括向受试者给予本申请的药物组合物。所述药物组合物包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物。
发明内容
一方面，本申请提供用于治疗小细胞肺癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物，
Figure PCTCN2020091312-appb-000001
在本申请的一些实施方案中，所述药物组合物包括：(i)化合物I或其药学上可接受的盐的药物组合物；和(ii)至少一种第二治疗药物的药物组合物。在一些的实施方案中，提供了一种用于治疗小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种化疗药物，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种小分子靶向抗肿瘤药物，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种免疫治疗药物，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种大分子抗体药物，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)氟嘧啶衍生物，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)替吉奥，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)鬼臼类和至少一种铂类药物，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)依托泊苷和至少一种铂类药物，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)依托泊苷和顺铂，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)依托泊苷和卡铂，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)依托泊苷和乐铂，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)抗PD-1抗体，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)信迪利单抗，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)喜树碱类药物，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小细胞肺癌的药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)伊立替康，以及任选地与放射治疗联合。
另一方面，本申请提供了一种药物组合物在制备用于治疗小细胞肺癌的药物中的用途，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物，以及任选地与放射治疗联合。本申请还提供药物组合物用于治疗小细胞肺癌的用途。
再一方面，本申请还提供治疗小细胞肺癌的方法，其包括向受试者给予本申请的药物组合物。所述药物组合物包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物。
本申请提供了一种用于治疗患有小细胞肺癌的主体的方法。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，所述主体经手术、化疗和/或放射治疗后获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、化疗和/或放射治疗后未能完全缓解或未能部分缓解。
本申请提供了一种治疗小细胞肺癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐和至少一种第二治疗药物。在一些实施方案中，本申请提供了一种治疗未接受过化疗方案的小细胞肺癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐，和至少一种第二治疗药物。在一些实施方案中，本申请提供了一种在先接受过至少一种化疗后出现进展或复发的小细胞肺癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐，和至少一种第二治疗药物。在一些实施方案中，本申请提供了一种治疗在先接受过至少两种化疗方案的小细胞肺癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐，和至少一种第二治疗药物。在一个实施方案中，本申请提供了一种治疗难治性复发的小细胞肺癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐，和至少一种第二治疗药物。在一些实验方案中，所述化合物I或其药学上可接受的盐和至少一种第二治疗药物联用用于治疗原发性小细胞肺癌或继发性小细胞肺癌。在一些实施方案中，所述的小细胞肺癌为无法耐受化疗的小细胞肺癌。在本申请的一些方案中，主体先前未接受过系统化疗。在一些方案中，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，主体先前未接受过系统化疗，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，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，获完全缓解后再次出现疾病进展。在一些具体实施方式中，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，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。
给药的方法可根据药物的活性、毒性以及受试者的耐受性等来综合确定。在本申请的一些实施方案中，所述用途或治疗方法中，包括但不限于所述第二治疗药物可以每天(qd)、隔日(qod)、每3天(q3d)、每4天(q4d)、每5天(q5d)、每周(q1w)、每2周(q2w)、每3周(q3w)、或者每4周(q4w)施用一次，或者每天施用两次(bid)、每周施用两次(biw)、每天施用三次(tid)、每天施用四次(qid)等。在本申请的一些实施方案中，所述用途或治疗方法中，也可以以间隔给药的方式给予第二治疗药物。所述的间隔给药包括给药期和停药期，例如在给药期内每天给予第二治疗药物，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。
在本申请的一些实施方案中，所述用途或治疗方法中，包括但不限于所述化合物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，第二治疗药物和化合物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，第二治疗药物和化合物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，第二治疗药物和化合物I或其药学上可接受的盐均为每3周一个治疗周期。
在一些实施方案中，本申请提供了一种联用药物组合物，其为适用于在单个治疗周期(例如3周的一个治疗周期)内施用的制剂，包括84～168mg、优选112～168mg的化合物I或其药学上可接受的盐和至少一种第二治疗药物。其中，化合物I或其药学上可接受的盐能够以多个等份(例如2等份、7等份、14等份、28等份或更多等份)分开包装。
又一方面，本申请提供用于治疗小细胞肺癌的试剂盒，所述试剂盒包括各自独立包装的化合物I或其药学上可接受的盐和至少一种第二治疗药物，以及任选的说明书。
小细胞肺癌
在本申请的一些实施方案中，所述的小细胞肺癌为复发性的；在某些实施方案中，所述的小细胞肺癌为难治性的；在某些实施方案中，所述的小细胞肺癌为不可切除的；在某些实施方案中，所述的小细胞肺癌为晚期小细胞肺癌。在一些实施方案中，所述的小细胞肺癌为化疗药物和/或靶向药物治疗失败的小细胞肺癌。在一些实施方案中，所述的小细胞肺癌为接受过至少两种化疗方案的小细胞肺癌。在一个实施方案中，所述的小细胞肺癌为难治性复发的小细胞肺癌，其中所述的“难治性复发的小细胞肺癌”是指化疗无缓解的小细胞肺癌，和化疗有效但在化疗结束后3个月内出现病情进展的小细胞肺癌。在一个实施方案中，所述的小细胞肺癌为敏感性复发的小细胞肺癌。在一个实施方案中，所述的小细胞肺癌为耐药性复发的小细胞肺癌。在一些实施方案中，所述的小细胞肺癌，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/或转移性的小细胞肺癌。其中转移性小细胞肺癌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淋巴结、胸膜、骨、脑、心包、肾上腺、肝脏；在一些实施方案中，所述的小细胞肺癌为脑转移的小细胞肺癌。在一些实施方案中，所述的小细胞肺癌为无法耐受化疗的小细胞肺癌。本领域技术人员可以理解的是，与所述的化疗同时或者先后，患者也可以接受放疗。
在一些实施方案中，所述的小细胞肺癌为广泛期小细胞肺癌。
在一些实施方案中，所述的小细胞肺癌为局限期小细胞肺癌。
在一些实施方案中，所述的小细胞肺癌为转移性小细胞肺癌，其中转移病灶包括但不限于淋巴结、胸膜、骨、心包、肾上腺、肝脏和脑。在一些实施方案中，所述的小细胞肺癌为脑转移的小细胞肺癌。
在一些实施方案中，所述的小细胞肺癌为在先接受过伊立替康、铂类药物、紫杉醇和多西他赛中的一种或者多种治疗的难治性复发的小细胞肺癌。
在一些实施方案中，所述的小细胞肺癌为在先接受过伊立替康和铂类药物(例如包括但不限于奥沙利铂、顺铂、卡铂、奈达铂、双环铂、乐铂、四硝酸三铂、菲铂、吡铂、米铂、沙铂)治疗的难治性复发的小细胞肺癌。
第二治疗药物
本申请所述的第二治疗药物包括但不限于化疗药物、小分子靶向抗肿瘤药物、免疫治疗药物、大分子抗体药物。
在一些实施方案中，所述的第二治疗药物为化疗药物，包括但不限于铂类药物、氟嘧啶衍生物、喜树碱类、紫杉类、长春碱类、蒽环类、抗生素类、鬼臼类、抗代谢类抗肿瘤药物中的一种或多种，可以列举的实例包括但不限于铂类药物(例如奥沙利铂、顺铂、卡铂、奈达铂、双环铂(dicycloplatin)、乐铂(Lobaplatin)、四硝酸三铂、菲铂、吡铂、米铂、沙铂)、氟嘧啶衍生物(例如吉西他滨、卡培他滨、安西他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷、替吉奥)、紫杉烷类(例如紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇)、喜树碱类(例如喜树碱、羟基喜树碱、9-氨基喜树碱、7-乙基喜树碱、伊立替康、拓扑替康)、长春碱类(长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁(vinflunine))、蒽环类(表柔比星、阿霉素、柔红霉素、吡柔比星、氨柔比星、伊达柔比星、米托蒽醌、阿柔比星、戊柔比星、佐柔比星、匹杉琼)、培美曲塞、卡氮芥、美法仑、依托泊苷(足叶乙苷)、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、甲氨蝶呤、苯达莫司汀、脂质体阿霉素、放线菌素D(更生霉素)、博来霉素、平阳霉素、替莫唑胺、氨烯咪胺、培洛霉素、艾日布林、普那布林(plinabulin)、Sapacitabine、曲奥舒凡(treosulfan)、153Sm-EDTMP、和encequidar中的一种或多种。
在某些具体实施方案中，所述第二治疗药物是铂类药物中的一种或几种，所述铂类药物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂、四硝酸三铂、菲铂、吡铂、沙铂、米铂、乐铂等。
在一些实施方案中，所述化疗药物选自依托泊苷、伊立替康、顺铂、卡铂、乐铂、奈达铂、拓扑替康、紫杉醇、多西他赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星、替加氟、吉美嘧啶、奥替拉西、替吉奥的一种或多种。
视需要，所述的第二治疗药物配合化疗辅助药物使用，所述的化疗辅助药物包括但不限于甲酰四氢叶酸钙(CF)、醛氢叶酸、美司钠、双膦酸盐、氨磷汀、造血细胞集落刺激因子(CSFs)。在一些实施方案中，所述的化疗辅助药物为甲酰四氢叶酸钙(CF)、美司钠、醛氢叶酸。
在一些实施方案中，所述的第二治疗药物为免疫治疗药物，包括但不限于干扰素(干扰素α、干扰素α-1b、干扰素α-2b)、白介素、西罗莫司(temsirolimus)、依维莫司(everolimus)、地磷莫司(ridaforolimus)、替西罗莫司的一种或多种。
在一些实施方案中，所述的第二治疗药物为小分子靶向抗肿瘤药物，包括但不限于蛋白激酶抑制剂。其中，所述的蛋白激酶抑制剂包括但不限于酪氨酸激酶抑制剂、丝氨酸和/或苏氨酸激酶抑制剂、聚ADP核糖聚合酶(PARP，poly ADP-ribose polymerase)抑制剂，所述抑制剂针对的靶点包括但不限于Fascin-1蛋白、HDAC(组蛋白去乙酰化酶)、蛋白酶体(Proteasome)、CD38、SLAMF7(CS1/CD319/CRACC)、RANKL、EGFR(表皮生长因子受体)、间变性淋巴瘤(ALK)、MET基因、ROS1基因、HER2基因、RET基因、BRAF基因、PI3K信号通路、DDR2(盘状死亡受体2)基因、FGFR1(成纤维生长因子受体1)、NTRK1(神经营养酪氨酸激酶1型受体)基因、KRAS基因；所述小分子靶向抗肿瘤药物的靶点还包括COX-2(环氧酶-2)、APE1(脱嘌呤脱嘧啶核酸内切酶)、VEGFR(血管内皮生长因子受体)、CXCR-4(趋化因子受体-4)、MMP(基质金属蛋白酶)、IGF-1R(胰岛素样生长因子受体)、Ezrin、PEDF(色素上皮衍生因子)、AS、ES、OPG(骨保护因子)、Src、IFN、ALCAM(白细胞活化黏附因子)、HSP、JIP1、GSK-3化(糖原合成激酶3糖)、CyclinD1(细胞周期调节蛋白)、CDK4(细胞周期素依赖性激酶)、TIMP1(组织金属蛋白酶抑制物)、THBS3、PTHR1(甲状旁腺素相关蛋白受体1)、TEM7(人肿瘤血管内皮标志物7)、COPS3、组织蛋白酶K。可以列举的小分子靶向抗肿瘤药物包括但不限于伊马替尼(Imatinib)、舒尼替尼(Sunitinib)、尼罗替尼(Nilotinib)、波舒替尼(bosutinib)、塞卡替尼(Saracatinib)、帕唑帕尼(Pazopanib)、曲贝替定(Trabectedin)、瑞格非尼(Regorafenib)、西地尼布(Cediranib)、硼替佐米(Bortezomib)、帕比司他(Panobinostat)、卡非佐米(Carfilzomib)、伊沙佐米(Ixazomib)、阿帕替尼(apatinib)、厄洛替尼(Erlotinib)、阿法替尼(Afatinib)、克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、威罗菲尼(Vemurafenib)、达拉菲尼(Dabrafenib)、卡博替尼(Cabozantinib)、吉非替尼(Gefitinib)、达可替尼(Dacomitinib)、奥希替尼(Osimertinib)、奥美替尼、艾乐替尼(Alectinib)、布格替尼(Brigatinib)、劳拉替尼(Lorlatinib)、曲美替尼(Trametinib)、拉罗替尼(Larotrectinib)、埃克替尼(icotinib)、拉帕替尼(Lapatinib)、凡德他尼(Vandetanib)、司美替尼(Selumetinib)、索拉非尼(Sorafenib)、奥莫替尼(Olmutinib)、沃利替尼(Savolitinib)、呋喹替尼(Fruquintinib)、恩曲替尼(Entrectinib)、达沙替尼(Dasatinib)、恩沙替尼(Ensartinib)、乐伐替尼(Lenvatinib)、itacitinib、吡咯替尼(Pyrotinib)、比美替尼(Binimetinib)、厄达替尼(Erdafitinib)、阿西替尼(Axitinib)、来那替尼(Neratinib)、考比替尼(Cobimetinib)、阿卡替尼(Acalabrutinib)、法米替尼(Famitinib)、马赛替尼(Masitinib)、伊布替尼(Ibrutinib)、rociletinib、尼达尼布(nintedanib)、来那度胺、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、帕博西尼(palbociclib)、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、poziotinib、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesed pegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinib succinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparib tosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat、quisinostat、LCL-161、KML-001中的一种或者多种。在一些实施方案中，所述的小分子靶向抗肿瘤药物为索拉非尼、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、尼达尼布中的一种或者多种。
在一些实施方案中，所述的第二治疗药物为大分子抗体药物。其中，所述大分子抗体药物针对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)和/或抑制PD-1活性的抗体或其抗原结合部分，或者，是结合程序性死亡配体1(PD-L1)和/或抑制PD-L1活性的抗体或其抗原结合部分，例如是抗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)抗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；或(b)抗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。
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抗体可以选自纳武利尤单抗(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、Sintilimab)、卡瑞利株单抗(Camrelizumab)、替雷利株单抗(BGB-A317)、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抗体可以选自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抗体可以选自伊匹单抗(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)中的任意一种或多种。
在某些具体实施方案中，所述第二治疗药物是替吉奥。
在某些具体实施方案中，所述第二治疗药物是依托泊苷和至少一种的铂类药物。
在某些具体实施方案中，所述第二治疗药物是依托泊苷、顺铂中的一种或两种。在一种具体实施方案中，所述第二治疗药物是EP方案(依托泊苷+顺铂)。
在某些具体实施方案中，所述第二治疗药物是卡铂、依托泊苷中的一种或两种。在一种具体实施方案中，所述第二治疗药物是EC方案(卡铂+依托泊苷)。
在某些具体实施方案中，所述第二治疗药物是依托泊苷、乐铂中的一种或两种。
在某些具体实施方案中，所述第二治疗药物是环磷酰胺、长春新碱、甲氨蝶呤、依托泊苷中的一种、两种、三种或四种。在一种具体实施方案中，所述第二治疗药物是COME方案(环磷酰胺+长春新碱+甲氨蝶呤+依托泊苷)。
在某些具体实施方案中，所述第二治疗药物是环磷酰胺、阿霉素、长春新碱中的一种、两种或三种。在一种具体实施方案中，所述第二治疗药物是CAV方案(环磷酰胺+阿霉素+长春新碱)。
在某些具体实施方案中，所述第二治疗药物是环磷酰胺、阿霉素、依托泊苷中的一种、两种或三种。在一种具体实施方案中，所述第二治疗药物是CAE方案(环磷酰胺+阿霉素+依托泊苷)。
在某些具体实施方案中，所述第二治疗药物是异环磷酰胺、依托泊苷、顺铂中的一种、两种或三种。在一种具体实施方案中，所述第二治疗药物是IEP方案(异环磷酰胺+依托泊苷+顺铂)。
在某些具体实施方案中，所述第二治疗药物是卡铂、紫杉醇、依托泊苷中的一种、两种或三种。在一种具体实施方案中，所述第二治疗药物是CPE方案(卡铂+紫杉醇+依托泊苷)。
在某些具体实施方案中，所述第二治疗药物是顺铂、长春新碱、阿霉素、依托泊苷中的一种、两种、三种或四种。在一种具体实施方案中，所述第二治疗药物是CODE方案(顺铂+长春新碱+阿霉素+依托泊苷)。
在某些具体实施方案中，所述第二治疗药物是拓扑替康。
化合物I或其药学上可接受的盐
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 PCTCN2020091312-appb-000002
本申请中，凡是涉及安罗替尼，均是指化合物I。
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，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本申请的范围内可按照本领域公知的方法由不同的有机酸和无机酸产生。
在一些实施方案中，以化合物I盐酸盐的形式给药。在一些实施方案中，以化合物I一盐酸盐的形式给药。在一些实施方案中，以化合物I二盐酸盐的形式给药。在一些实施方案中，以化合物I盐酸盐的晶体形式给药。在特定的实施方案中，以化合物I二盐酸盐的晶体形式给药。
化合物I或其药学上可接受的盐、第二治疗药物可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内和鞘内。在一个特定的实施方案中，通过口服给药。
给予化合物I或其药学上可接受的盐、第二治疗药物的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、受试者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至16毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克至14毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为6毫克至12毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为6毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为12毫克。在本申请中，例如，对于片剂或胶囊剂而言，“以单位剂量为基础含有12mg的化合物I或其药学上可接受的盐”意味着最终制成的每片片剂或每颗胶囊剂中含有12mg的化合物I。
化合物I或其药学上可接受的盐、第二治疗药物可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一个实施方案中，以口服固体制剂每天给药一次。
上述治疗方法中，给药的方法可根据药物的活性、毒性以及受试者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。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化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学 上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，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2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。在一个具体的实施方案中，化合物I或其药学上可接受的盐在每个周期的第1-14天给药，每21天为一个给药周期。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
药物组合
在某些实施方案中，化合物I或其药学上可接受的盐与手术切除和/或放射疗法组合。
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，所述药物组合物的各组分分开配制，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，本申请的药物组合物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第二治疗药物和化合物I或其药学上可接受的盐各自呈药物组合物形式。
在本申请的一些实施方案中，化合物I或其药学上可接受的盐与一种或多种第二治疗药物同时或先后给予。在某些实施方案中，一种或多种第二治疗药物在给予化合物I或其药学上可接受的盐前或在与化合物I或其药学上可接受的盐组合前已给予受试者。在某些实施方案中，一种或多种第二治疗药物在给予化合物I或其药学上可接受的盐后或在与化合物I或其药学上可接受的盐组合后再给予受试者。在某些实施方案中，化合物I或其药学上可接受的盐在给予一种或多种第二治疗药物前或在与一种或多种第二治疗药物组合前已给予受试者。在某些实施方案中，化合物I或其药学上可接受的盐在给予一种或多种第二治疗药物后或在与一种或多种第二治疗药物组合后再给予受试者。在一些实施方案中，化合物I或其药学上可接受的盐与一种或多种第二治疗药物组合给予受试者时，序贯给予受试者化合物I或其药学上可接受的盐和一种或多种第二治疗药物。
在一些方案中，还提供一种用于治疗小细胞肺癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有化疗药物作为活性成分；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小细胞肺癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有小分子靶向抗肿瘤药物作为活性成分；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小细胞肺癌的药物 组合物的试剂盒，其中含有：(a)第一种药物组合物，含有免疫治疗药物作为活性成分；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小细胞肺癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有大分子抗体药物作为活性成分；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小细胞肺癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有替吉奥作为活性成分；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小细胞肺癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有依托泊苷和铂类药物作为活性成分；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小细胞肺癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有依托泊苷和顺铂作为活性成分；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小细胞肺癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有依托泊苷和乐铂作为活性成分；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。
定义和说明
本文中，除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
如本文所用，术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对受试者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
如本文所用，术语“治疗失败”是指毒副作用不可耐受、治疗过程中疾病进展或治疗结束后复发。
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”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。施用途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径，例如通过注射或输注。本文中使用的短语“胃肠外施用”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模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、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，药物通过非胃肠外途径施用，在某些实施方案中，口服施用。其它非胃肠外途径包括局部、表皮或粘膜施用途径，例如，鼻内地、阴道地、直肠地、舌下地或局部地。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
“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“受试者”在本文中的某些语境下可互换地使用。
作为例子，“抗癌药”促进主体中的癌症消退或阻止进一步的肿瘤生长。在某些实施方案中，药物将癌症消退促进至消除癌症的点。“促进癌症消退”是指单独地或与抗肿瘤剂联合施用药物，导致肿瘤生长或大小的减小、肿瘤的坏死、至少一种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。此外，关于治疗的术语“有效的”和“有效性”包括药理学有效性和生理学安全性。药理学有效性表示药物在受试者中促进癌症消退的能力。生理学安全性表示由药物施用引起的在细胞、器官和/或生物体水平的毒性水平或其它不利的生理效应(不良作用)。
作为用于治疗肿瘤的例子，相对于未治疗的主体，或者，在某些实施方案中，相对于用护理标准疗法治疗的受试者，抗癌药可以将细胞生长或肿瘤生长抑制至少约10％、至少约20％、至少约40％、至少约60％或至少约80％。在本申请的其它实施方案中，可以观察到肿瘤消退并持续至少约20天、至少约40天或至少约60天的时间段。尽管存在治疗有效性的这些最终测量，药物的评价还必须考虑“免疫相关的”应答模式。
“免疫相关的”应答模式表示在用免疫治疗剂治疗的癌症受试者中经常观察到的临床应答模式，所述免疫治疗剂通过诱导癌症特异性免疫应答或通过改变天然免疫过程而产生抗肿瘤作用。该应答模式的特征在于在肿瘤负荷的初始增加或新病变出现之后的有益的治疗效果，其在传统化学治疗剂的评价中将被分类为疾病进展并且将与药物失效同义。因此，免疫治疗剂的适当评价可以需要长期监测这些药剂对靶疾病的影响。
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)'2片段、Fv片段、分离的CDR区、单 链Fv分子(scFv)、Fd片段和本领域已知的其它抗体片段。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-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”)是指单一分子成的抗体分子。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 PCTCN2020091312-appb-000003
帕博利珠单抗(Pembrolizumab)
Figure PCTCN2020091312-appb-000004
Durvalumab、Avelumab、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)、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 PCTCN2020091312-appb-000005
罗氏)、Avelumab(
Figure PCTCN2020091312-appb-000006
默克/辉瑞)、Durvalumab(
Figure PCTCN2020091312-appb-000007
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。
“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。
“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。
“不能切除的”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”。
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、对甲基苯磺酸盐、钠盐、钾盐、铵盐或氨基酸盐，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1:0.5～1:5，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1:0.5～1:5，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(例如化疗药物或化合物I)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分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(例如第二治疗药物或化合物I)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。
本申请中的“临床有收益”，包括但不限于：临床患者无进展生存期(PFS)得到延长、总生存期(OS)得到延长、客观缓解率(ORR)得到提高、疾病控制率(DCR)得到提高、不良反应数量减少和/或程度降低。
本申请中的“约”是指在所给定的具体数值范围±5％范围内波动，优选在±2％范围内波动，更优选在±1％范围内波动。
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。
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
在患有可测量病灶的经病理学确诊为小细胞肺癌(包含广泛期、局限期)患者中，联合给药组分为两组，分别为采用EP或EC方案(依托泊苷+顺铂/卡铂)+安罗替尼的联合给药组，同时将单独的EP或EC(依托泊苷+顺铂/卡铂)作为对照给药组。具体给药方法如下：
联合给药组，患者接受依托泊苷：100mg/m 2，i.v.，持续120mins，每周期d1-3给药，21天为一个周期；顺铂：75mg/m 2或卡铂：AUC 5，i.v.，持续120mins，每周期d1给药，21天为一个周期；安罗替尼，12mg/日，晨起空腹口服，每周期d1-14，21天为一个周期，联合治疗4-6周期后，安罗替尼维持治疗，12mg/日，晨起空腹口服，每周期d1-14给药，21天为一个周期直至疾病进展。
对照给药组，患者接受依托泊苷：100mg/m 2，i.v.，持续120mins，每周期d1-3给药，21天为一个周期；顺铂：75mg/m 2或卡铂：AUC 5，i.v.，持续120mins，每周期d1给药，21天为一个周期。
观察指标：主要终点：无进展生存期(PFS)；次要终点：客观缓解率(ORR)、总生存期(OS)、疾病控制率(DCR)、安全性、耐受性。
实施了该临床试验研究，在2018年2月至2019年10月之间，纳入了31例患者，截止目前，联合给药组的疗效评价结果为中位PFS为8.9个月，完全缓解(CR)的患者3名(3/31)，部分缓解(PR)的患者20名(20/31)，病情(SD)稳定的患者9名(9/31)，尚未疾病进展(PD)的患者(0/31)，客观缓解率(ORR)为74.2％(21/31)，疾病控制率(DCR)为100％(31/31)，发现安罗替尼联合EP方案或EC方案的临床疗效好，具有良好的临床安全性。
实施例2
在经病理组织学或者细胞学检查确诊的小细胞肺癌、既往接受过1次系统化疗、且包含以铂类为基础的化疗方案，治疗后复发或失败的患者中，排除非小细胞肺癌、包括小细胞与非小细胞混合型的患者，分成两组，联用给药组和单药化疗对照组，具体给药方法如下：
联用给药组：盐酸安罗替尼胶囊:12mg qd po d1-14+伊立替康60～80mg/m 2i.v.d1和d8；q3w，化疗周期最多不超过6个周期；
单药化疗对照组：伊立替康60～80mg/m 2i.v.d1和d8；q3w，化疗周期最多不超过6个周期。
获得完全缓解(CR)、部分缓解(PR)和病情稳定(SD)的患者继续给药直至疾病进展(PD)、不可耐受毒性或患者要求停药或病情进展(PD)的患者则终止给药。疗效评估观察指标包括无进展生存期(PFS)、总生存期(OS)、客观缓解率(ORR)、疾病控制率(DCR)、缓解持续时间(DOR)、生存质量评分、药物安全性。
该研究表明，对于小细胞肺癌患者，安罗替尼联用伊立替康的治疗方案临床有收益。
实施例3
在经病理学确诊为小细胞肺癌、且二线化疗失败后(既往接受过两种化疗方案)的广泛期小细胞肺癌患者，联合给药安罗替尼和依托泊苷，具体给药方法如下：
依托泊苷软胶囊：每日一次，早餐前口服，每次100mg(以其中的依托泊苷的重量计)，每个周期的d1-10给药，21天为一个治疗周期；
盐酸安罗替尼胶囊：每日一次，早餐前口服，每次12mg，每个周期的d1-14给药，21天为一个治疗周期。
两药间隔时间半小时以上，如出现漏服，确认距下次用药时间不短于12小时，否则不再补服。用药过程中，根据患者出现的药物相关性毒性反应程度和可能的疗效受益情况，可进行剂量调整。对于安罗替尼可调整为以下2个水平的剂量：10mg和8mg。如果需要降低2个剂量水平以上，则终止治疗。依托泊苷剂量调整可减量至50mg。
疗效评估观察指标包括无进展生存期(PFS)、总生存期(OS)、客观缓解率(ORR＝CR+PR)、疾病控制率(DCR＝CR+PR+SD)、安全性指标。
该研究表明，对于小细胞肺癌患者，安罗替尼联用依托泊苷的治疗方案临床有收益。
实施例4
在经组织学或细胞学证实的小细胞肺癌(不限局限期还是广泛期)、既往接受过至少一线标准以铂类为基础针对SCLC治疗、且客观影像学进展，包括如下的患者：
[1]敏感复发：距离末次化疗≥90天进展、
[2]耐药复发：化疗期间进展或距离末次化疗＜90天进展；
每3周为1个给药周期进行持续6周期的联合给药安罗替尼和S-1(替吉奥)治疗，以及S-1维持治疗，每个周期第1天按顺序给予上述两种药物治疗，给药时间窗可±3天，但每次给药前3天内，除影像学检查外，受试者必须完成包括生命体征、体格检查、实验室检查、体能状态评分等各项检查。受试者还需要在首次给药后48周内以每6周1次(±7天)的频率，首次给药后48周之后以每9周1次(±7天)的频率，完成肿瘤影像学评价(评价方法前后一致，CT或MRI)。具体给药方法如下：
联合治疗(6周期)：
盐酸安罗替尼胶囊12mg 1次/天+S-1 60mg/m 2bid，连续用药2周停1周；
维持治疗：
完成诱导治疗后进入维持治疗阶段，受试者将继续接受S-1维持治疗(20mg/m2bid，连续用药2周停1周，21天为一个周期)受试者接受维持治疗，直至疾病进展、无法耐受的毒副作用、撤知情或研究者决定让受试者退出研究、不依从研究治疗或研究程序或方案规定的其它原因。
评价S-1联合盐酸安罗替尼治疗复发性小细胞肺癌的无进展生存期(PFS)和客观缓解率(ORR)、总生存期(OS)；疾病控制率(DCR)、在6个月和1年时的PFS率、在1年和2年时的OS率、安全性等疗效评估指标。
实施例5
经组织学或细胞学证实的病理学确诊的、既往至少接受过一种系统性化疗方案治疗复发的小细胞肺癌患者，联合给药安罗替尼和信迪利单抗，具体给药方法如下：
盐酸安罗替尼胶囊：每日一次，早餐前口服，每次12mg，每个周期的d1-14给药，连续服药2周，停药1周，21天为一个治疗周期；
信迪利单抗：200mg，静脉输注，每个周期d1给药，21天为一个治疗周期。
所有患者持续治疗时间最多为12个月，或直至疾病进展、发生不可耐受的毒性反应、撤回知情同意、死亡或发生其它案中规定需要终止治疗的情况，以先发生者为准。
疗效评估观察指标包括无进展生存期(PFS)、总生存期(OS)、客观缓解率(ORR＝CR+PR)、疾病控制率(DCR＝CR+PR+SD)、安全性指标。该研究表明，对于小细胞肺癌患者，安罗替尼联用信迪利单抗的治疗方案临床有收益，无进展生存期得到延长，截至目前已有患者无进展生存期延长达6个月。
在本申请的上述实施例中，盐酸安罗替尼胶囊的量以其中包含的安罗替尼游离碱的重量计。
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、程序上和其它的细节补充本文所述内容。

Claims (15)

  1. 用于治疗小细胞肺癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物，
    Figure PCTCN2020091312-appb-100001
  2. 根据权利要求1所述的药物组合物，其中，所述的小细胞肺癌为复发性的、和/或难治性的、和/或不可切除的、和/或晚期的、和/或转移性的小细胞肺癌，优选为化疗药物和/或靶向药物治疗失败的小细胞肺癌、接受过至少两种化疗方案的小细胞肺癌、难治性复发的小细胞肺癌、局部晚期和/或晚期转移性的小细胞肺癌。
  3. 根据权利要求1或2所述的药物组合物，其中，所述的第二治疗药物为化疗药物、小分子靶向抗肿瘤药物、免疫治疗药物、大分子抗体药物中的一种或多种。
  4. 根据权利要求3所述的药物组合物，其中，所述的化疗药物为奥沙利铂、顺铂、卡铂、奈达铂、双环铂、乐铂、四硝酸三铂、菲铂、吡铂、米铂、沙铂、吉西他滨、卡培他滨、安西他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷、紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇、喜树碱、羟基喜树碱、9-氨基喜树碱、7-乙基喜树碱、伊立替康、拓扑替康、长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁、表柔比星、阿霉素、柔红霉素、吡柔比星、氨柔比星、伊达柔比星、米托蒽醌、阿柔比星、戊柔比星、佐柔比星、匹杉琼、培美曲塞、卡氮芥、美法仑、依托泊苷、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、甲氨蝶呤、苯达莫司汀、脂质体阿霉素、放线菌素D、博来霉素、平阳霉素、替莫唑胺、氨烯咪胺、培洛霉素、艾日布林、普那布林、Sapacitabine、曲奥舒凡、153Sm-EDTMP、替吉奥和encequidar中的一种或多种。
  5. 根据权利要求3所述的药物组合物，其中，所述的免疫治疗药物为干扰素、白介素、西罗莫司、依维莫司、地磷莫司、替西罗莫司中的一种或多种。
  6. 根据权利要求3所述的药物组合物，其中，所述的小分子靶向抗肿瘤药物为伊马替尼、舒尼替尼、尼罗替尼、波舒替尼、塞卡替尼、帕唑帕尼、曲贝替定、瑞格非尼、西地尼布、硼替佐米、帕比司他、卡非佐米、伊沙佐米、阿帕替尼、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、奥美替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、索拉非尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、rociletinib、尼达尼布、来那度胺、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、帕博西尼、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、poziotinib、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesed pegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinib succinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparib tosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat、quisinostat、LCL-161、KML-001中的一种或者多种。
  7. 根据权利要求3所述的药物组合物，其中，所述的大分子抗体药物为抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、抗-PDGFRα抗体、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。
  8. 根据权利要求7所述的药物组合物，其中，所述抗PD-1抗体选自纳武利尤单抗、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、杰诺单抗、丽珠单抗、HLX-10、BAT-1306、AK103、AK104、CS1003、SCT-I10A、F520、SG001、GLS-010中的任意一种或多种；所述抗PD-L1抗体选自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；所述的抗CTLA-4抗体选自伊匹单抗、替西木单抗、AGEN-1884、BMS-986249、BMS-986218、AK-104、IBI310中的任意一种或多种。
  9. 根据权利要求3所述的药物组合物，其中，所述的第二治疗药物为氟嘧啶衍生物、鬼臼类药物、铂类药物、喜树碱类药物、抗PD-1抗体中的一种或多种。
  10. 根据权利要求1～8任一项所述的药物组合物，其中，所述第二治疗药物为以下(1)～(14)中的任意一种或多种：
    (1)替吉奥；
    (2)依托泊苷和至少一种的铂类药物；
    (3)环磷酰胺、长春新碱、甲氨蝶呤、依托泊苷中的一种、两种、三种或四种；
    (4)环磷酰胺、阿霉素、长春新碱中的一种、两种或三种；
    (5)环磷酰胺、阿霉素、依托泊苷中的一种、两种或三种；
    (6)异环磷酰胺、依托泊苷、顺铂中的一种、两种或三种；
    (7)卡铂、紫杉醇、依托泊苷中的一种、两种或三种；
    (8)顺铂、长春新碱、阿霉素、依托泊苷中的一种、两种、三种或四种；
    (9)拓扑替康；
    (10)依托泊苷和乐铂；
    (11)依托泊苷和顺铂；
    (12)依托泊苷和卡铂；
    (13)信迪利单抗；
    (14)伊立替康。
  11. 根据权利要求1～10任一项所述的药物组合物，其中，给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克，优选为5毫克至20毫克，更优选为8毫克至16毫克，进一步优选为8毫克至14毫克，最优选为8毫克、10毫克或12毫克。
  12. 根据权利要求1-11任一项所述的药物组合物，其中化合物I或其药学上可接受的盐在每个周期的第1-14天给药，每21天为一个给药周期。
  13. 权利要求1～12任一项所述的药物组合物在制备用于治疗小细胞肺癌的药物中的用途。
  14. 一种用于治疗小细胞肺癌的试剂盒，其中含有：(a)第一种药物组合物，含有化疗药物和/或小分子靶向抗肿瘤药物和/或免疫治疗药物和/或大分子抗体药物作为活性成分；和(b)第二种药物组合物，其中含有权利要求1～12任一项中所述的化合物I或其药学上可接受的盐作为活性成分。
  15. 一种用于治疗小细胞肺癌的方法，所述方法包括向需要治疗的受试者给予权利要求1～12任一项所述的药物组合物。
PCT/CN2020/091312 2019-05-20 2020-05-20 用于联合治疗小细胞肺癌的喹啉衍生物 Ceased WO2020233602A1 (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU2020279289A AU2020279289B2 (en) 2019-05-20 2020-05-20 Quinoline derivative used for combination treatment of small cell lung cancer
US17/595,519 US20220193066A1 (en) 2019-05-20 2020-05-20 Quinoline derivative used for combination treatment of small cell lung cancer
JP2021568907A JP7761490B2 (ja) 2019-05-20 2020-05-20 小細胞肺がんの併用療法用キノリン誘導体
CN202080034910.5A CN113811298B (zh) 2019-05-20 2020-05-20 用于联合治疗小细胞肺癌的喹啉衍生物
EP20810457.0A EP3973964A4 (en) 2019-05-20 2020-05-20 QUINOLINE DERIVATIVE USED FOR COMBINATION TREATMENT OF SMALL CELL LUNG CANCER
CA3141167A CA3141167A1 (en) 2019-05-20 2020-05-20 Quinoline derivative used for combination treatment of small cell lung cancer
KR1020217039271A KR102936318B1 (ko) 2019-05-20 2020-05-20 소세포폐암의 병용 치료용 퀴놀린 유도체

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910419546 2019-05-20
CN201910419546.3 2019-05-20

Publications (1)

Publication Number Publication Date
WO2020233602A1 true WO2020233602A1 (zh) 2020-11-26

Family

ID=73458290

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/091312 Ceased WO2020233602A1 (zh) 2019-05-20 2020-05-20 用于联合治疗小细胞肺癌的喹啉衍生物

Country Status (8)

Country Link
US (1) US20220193066A1 (zh)
EP (1) EP3973964A4 (zh)
JP (1) JP7761490B2 (zh)
KR (1) KR102936318B1 (zh)
CN (1) CN113811298B (zh)
AU (1) AU2020279289B2 (zh)
CA (1) CA3141167A1 (zh)
WO (1) WO2020233602A1 (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3842070A4 (en) * 2018-07-18 2022-04-20 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. DRUG COMBINATION OF QUINOLINE DERIVATIVE AND ANTIBODY
CN114642728A (zh) * 2021-06-02 2022-06-21 德琪(浙江)医药科技有限公司 mTOR抑制剂的制药用途及其药物组合物
EP3854396A4 (en) * 2018-09-18 2022-06-29 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Quinoline derivative used for treating small cell lung cancer
WO2023011631A1 (zh) * 2021-08-05 2023-02-09 正大天晴药业集团股份有限公司 治疗小细胞肺癌的药物组合

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015085847A1 (zh) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Pd-1抗体、其抗原结合片段及其医药用途
CN107771078A (zh) * 2015-05-04 2018-03-06 爱德程医药有限公司 用于制备抗癌剂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、其结晶形式和其盐的方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105311030B (zh) * 2014-06-06 2020-03-24 正大天晴药业集团股份有限公司 用于抗肿瘤的螺取代化合物
CN106999484A (zh) * 2014-12-09 2017-08-01 正大天晴药业集团股份有限公司 治疗非小细胞肺癌的喹啉衍生物
US11419862B2 (en) * 2018-03-14 2022-08-23 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Quinoline derivative for treatment of nasopharyngeal carcinoma
JP7455806B2 (ja) * 2018-07-18 2024-03-26 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド キノリン誘導体と抗体による薬物の組み合わせ
CN113518621A (zh) * 2019-03-07 2021-10-19 南京爱德程医药科技有限公司 按顺序使用卡奎替尼(安罗替尼)和标准化学疗法或免疫疗法的组合以治疗癌症
CA3133141A1 (en) * 2019-03-15 2020-09-24 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Combined pharmaceutical composition for treating small cell lung cancer
ES3049047T3 (en) * 2019-04-19 2025-12-12 Chia Tai Tianqing Pharmaceutical Group Co Ltd Quinoline compound or pharmaceutically acceptable salt thereof for treating ewing's sarcoma
CN113747898A (zh) * 2019-05-10 2021-12-03 正大天晴药业集团股份有限公司 用于联合治疗软组织肉瘤的喹啉衍生物
CN113747897B (zh) * 2019-05-10 2024-04-02 正大天晴药业集团股份有限公司 喹啉衍生物与抗体联合治疗软组织肉瘤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015085847A1 (zh) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Pd-1抗体、其抗原结合片段及其医药用途
CN105026428A (zh) 2013-12-12 2015-11-04 上海恒瑞医药有限公司 PD-l抗体、其抗原结合片段及其医药用途
CN107771078A (zh) * 2015-05-04 2018-03-06 爱德程医药有限公司 用于制备抗癌剂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、其结晶形式和其盐的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP3973964A4
WANG, YONGMING ET AL.: "Anlotinib Used in Patients with Small Cell Lung Cancer", JOURNAL OF INTERNATIONAL ONCOLOGY, vol. 46, no. 4, 8 April 2019 (2019-04-08), CN , pages 253 - 254, XP009532488, ISSN: 1673-422X, DOI: 10.3760/cma.j.issn.1673-422X.2019.04.013 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3842070A4 (en) * 2018-07-18 2022-04-20 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. DRUG COMBINATION OF QUINOLINE DERIVATIVE AND ANTIBODY
US12390458B2 (en) 2018-07-18 2025-08-19 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Therapeutic combination of quinoline derivative and antibody
EP3854396A4 (en) * 2018-09-18 2022-06-29 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Quinoline derivative used for treating small cell lung cancer
CN114642728A (zh) * 2021-06-02 2022-06-21 德琪(浙江)医药科技有限公司 mTOR抑制剂的制药用途及其药物组合物
WO2023011631A1 (zh) * 2021-08-05 2023-02-09 正大天晴药业集团股份有限公司 治疗小细胞肺癌的药物组合
CN116209443A (zh) * 2021-08-05 2023-06-02 正大天晴药业集团股份有限公司 治疗小细胞肺癌的药物组合

Also Published As

Publication number Publication date
EP3973964A4 (en) 2023-05-03
CA3141167A1 (en) 2020-11-26
KR20220011647A (ko) 2022-01-28
AU2020279289A1 (en) 2022-01-06
KR102936318B1 (ko) 2026-03-06
US20220193066A1 (en) 2022-06-23
JP7761490B2 (ja) 2025-10-30
EP3973964A1 (en) 2022-03-30
JP2022533211A (ja) 2022-07-21
AU2020279289B2 (en) 2026-03-19
CN113811298B (zh) 2023-08-01
CN113811298A (zh) 2021-12-17

Similar Documents

Publication Publication Date Title
US12527784B2 (en) Combined pharmaceutical composition for treating small cell lung cancer
TWI685341B (zh) 阿帕替尼和c-Met抑制劑聯合在製備治療腫瘤的藥物中的用途
CN113811298B (zh) 用于联合治疗小细胞肺癌的喹啉衍生物
CN112043702A (zh) 用于联合治疗结直肠癌的喹啉类化合物
WO2020249018A1 (zh) 治疗驱动基因阳性肺癌的联用药物组合物
EP4512421A1 (en) Drug combination of anti-tim-3 antibody and anti-pd-1 antibody
TR201908138T4 (tr) Bir anti-her2 antikoru ilaç konjügatı ve bir bcl-2 inhibitörü ile kombinasyon terapisi.
CN111973747A (zh) 用于联合治疗卵巢癌的喹啉衍生物
CN112043831A (zh) 用于联合治疗乳腺癌的喹啉类化合物
CN112121048A (zh) 用于联合治疗食管癌的喹啉类化合物
WO2021219138A1 (zh) 用于治疗肾癌的联用药物
WO2023093663A1 (en) Pharmaceutical composition and use thereof
AU2020278733B2 (en) Quinoline derivatives for treatment of head and neck cancer
CN112043832A (zh) 用于联合治疗胃癌的喹啉类化合物
TW202045175A (zh) Ｓｕｍｏ-活化酶抑制劑及檢查點抑制劑之投與
HK40072142A (zh) 用於联合治疗小细胞肺癌的喹啉衍生物
CN120346313A (zh) 治疗肿瘤的药物组合
WO2026077321A1 (zh) 抗her2抗体药物偶联物和免疫检查点抑制剂的药物组合
CN112294814A (zh) 用于治疗胶质母细胞瘤的喹啉衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20810457

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021568907

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3141167

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20217039271

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020279289

Country of ref document: AU

Date of ref document: 20200520

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020810457

Country of ref document: EP

Effective date: 20211220