WO2021190546A1 - 包含蛋白激酶抑制剂和化疗药物的药物组合物及其用途 - Google Patents

包含蛋白激酶抑制剂和化疗药物的药物组合物及其用途 Download PDF

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WO2021190546A1
WO2021190546A1 PCT/CN2021/082656 CN2021082656W WO2021190546A1 WO 2021190546 A1 WO2021190546 A1 WO 2021190546A1 CN 2021082656 W CN2021082656 W CN 2021082656W WO 2021190546 A1 WO2021190546 A1 WO 2021190546A1
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platinum
ovarian cancer
cancer
paclitaxel
refractory
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PCT/CN2021/082656
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English (en)
French (fr)
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鲁先平
宁志强
王晓宁
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深圳微芯生物科技股份有限公司
成都微芯药业有限公司
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Priority to AU2021244744A priority Critical patent/AU2021244744A1/en
Priority to MX2022011837A priority patent/MX2022011837A/es
Priority to KR1020227035920A priority patent/KR20220157996A/ko
Priority to BR112022019127A priority patent/BR112022019127A2/pt
Priority to CA3176459A priority patent/CA3176459A1/en
Priority to EP21774279.0A priority patent/EP4129288A4/en
Priority to JP2022558549A priority patent/JP2023520383A/ja
Priority to US17/914,324 priority patent/US20230117545A1/en
Publication of WO2021190546A1 publication Critical patent/WO2021190546A1/zh
Priority to ZA2022/11304A priority patent/ZA202211304B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to the field of biotechnology, in particular to a pharmaceutical composition containing a protein kinase inhibitor and a chemotherapeutic drug and its use.
  • Protein B kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins. They are broadly classified into tyrosine and serine/threonine kinases. They represent a major role in regulating various cellular processes and maintaining cell functions. Family of proteins. Protein kinases are the enzymatic components of the signal transduction pathway, which catalyze the transfer of the terminal phosphate of ATP to the hydroxyl groups of the tyrosine, serine and/or threonine residues of the protein. Overexpression or improper expression of normal or mutant protein kinases in mammals has been the subject of extensive research and has been shown to play an important role in the development of many diseases, including cancer.
  • a partial non-limiting list of these kinases includes: non-receptor tyrosine kinases, such as the Janus kinase family (Jak1, Jak2, Jak3, and Tyk2); receptor tyrosine kinases, such as platelet-derived growth factor receptor kinase (PDGFR) ; And serine/threonine kinases, such as b-RAF.
  • non-receptor tyrosine kinases such as the Janus kinase family (Jak1, Jak2, Jak3, and Tyk2)
  • receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGFR)
  • PDGFR platelet-derived growth factor receptor kinase
  • serine/threonine kinases such as b-RAF.
  • Abnormal kinase activity is observed in many disease states, including benign and malignant proliferative disorders and diseases caused by inappropriate activation of the immune and
  • protein kinases are responsible for controlling various signal transduction processes in cells (see, for example, Hardie and Hanks, The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif., 1995) . Protein kinases are considered to have evolved from a common ancestor gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar catalytic domain with 250-300 amino acids. Kinases can be classified into families according to their phosphorylation receptors (eg protein-tyrosine, protein-serine/threonine, lipid, etc.).
  • phosphorylation receptors eg protein-tyrosine, protein-serine/threonine, lipid, etc.
  • Inappropriate kinase activity caused by mutation, overexpression or inappropriate regulation, abnormal or dysregulation, and overproduction or insufficient production of growth factors or cytokines can involve many diseases, including but not limited to cancer and other diseases .
  • Protein kinases have become an important class of enzymes as targets for therapeutic intervention.
  • overactivation of the tyrosine kinase cKit is associated with hematological malignancies and is a target of cancer therapy (Heinrich, Griffith et al., Blood 2000, 96(3): 925-32).
  • JAK3 signaling is involved in leukemia and lymphoma and is currently used as a potential therapeutic target (Heinrich, Griffith et al., 2000)).
  • Protein kinases also play a central role in cell cycle regulation. It has been found that defects in various components of the signal transduction pathway can cause a variety of diseases, including various forms of cancer (Gaestel et al., Current Medicinal Chemistry, (2007) 14: 2214-2234). In recent years, protein kinases related to oncogenic signal transduction pathways have become important drug targets in the treatment of various diseases including various types of cancers. There are also a variety of protein kinase inhibitors used as anti-tumor drugs.
  • Sioroni is a brand new protein kinase inhibitor with complete intellectual property rights independently developed by Shenzhen Microchip Biotechnology Co., Ltd.
  • Cioroni is a small molecule anti-tumor targeted drug targeting multiple protein kinases. It has high selective inhibitory activity on VEGFR/PDGFR/c-Kit, Aurora B and CSF-1R targets, and has anti-tumor vascularity. The three-way anti-tumor synergistic mechanism of generating, inhibiting tumor cell mitosis, regulating tumor inflammatory microenvironment, and playing a comprehensive anti-tumor effect.
  • the inhibitory activity of this product on the key mitotic enzyme Aurora B is unique and has potential reduction Genome instability of tumor tissues and inhibition of tumor cell metastasis.
  • Theoroni exerts anti-tumor activity through three complementary mechanisms of inhibition of tumor angiogenesis, cell mitosis and tumor inflammatory microenvironment.
  • its high target selectivity also reduces the risk of side effects caused by off-target effects.
  • DNA topoisomerase is an important ribozyme in the cell, which changes the topological structure of DNA mainly through catalysis.
  • the topoisomerases of eukaryotic cells are mainly divided into topoisomerase I (Topo I) and topoisomerase II (Topo II).
  • Topo II the intermediate product formed during the catalysis process causes a short break of DNA double-strand is called Topo II.
  • Topo II plays an important role in important life processes such as cell DNA replication, transcription and mitosis.
  • DNA Topo II The role of DNA Topo II is to mediate DNA double-strand unwinding (fracture and reconnection). Under normal circumstances, DNA Topo II forms a fragile complex with DNA. Topo II inhibitors are a class of anti-tumor drugs that target Topo II. Their anti-cancer effect is not to inhibit the activity of the enzyme itself, but to promote the formation of enzyme DNA fragmentation complexes, so that the equilibrium reaction tends to enzymatic DNA fragmentation The complex extends its half-life and stabilizes it, interfering with DNA Topo II-mediated DNA reconnection reaction, causing DNA single-strand or double-strand breaks, affecting DNA replication, and exerting cell killing effects. The formation and stable existence of the cleavable complex promotes the abnormal recombination of DNA, thereby initiating the apoptosis program and leading to cell death.
  • Topoisomerase II currently on the market includes etoposide and teniposide.
  • Paclitaxel is the most excellent natural anti-cancer drug discovered, and it has been widely used clinically in the treatment of breast cancer, ovarian cancer, and some head and neck cancers and lung cancers.
  • Paclitaxel is a diterpene alkaloid compound with anticancer activity. Its novel and complex chemical structure, extensive and significant biological activity, new and unique mechanism of action, and scarce natural resources have made it popular among botanists and chemists. The great favor of pharmacologists and molecular biologists has made it a world-renowned anti-cancer star and research focus in the second half of the 20th century. Derivatives such as docetaxel and albumin paclitaxel have similar effects to paclitaxel.
  • Ovarian malignant tumors include a variety of pathological types. The most common is epithelial cancer, which accounts for about 70% of ovarian malignant tumors, followed by malignant germ cell tumors and sex cord-stromal tumors, which account for about 20% and 5% respectively.
  • Platinum-refractory/platinum-resistant relapsed advanced ovarian cancer is the most difficult problem in clinical treatment. It provides new treatment ideas for platinum-refractory/platinum-resistant relapsed advanced ovarian cancer, and explores to find an effective treatment for platinum-refractory/platinum-resistant. The regimen for drug recurrence of advanced ovarian cancer is of great significance.
  • the present invention has discovered that a pharmaceutical composition containing a protein kinase inhibitor and a chemotherapeutic drug has an unexpected therapeutic effect on cancer, especially advanced ovarian cancer that is platinum-refractory/platinum-resistant and relapsed.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a protein kinase inhibitor and a chemotherapeutic drug, wherein the protein kinase inhibitor includes the compound described in CN200910223861.5, the entire content of which is incorporated herein by reference
  • the protein kinase inhibitor is preferably a compound having a structure represented by the general formula (I),
  • Z is CH or N
  • R 1 , R 2 and R 3 are each hydrogen, halogen, methyl, methoxy or trifluoromethyl
  • X is a benzene ring or a pyridine ring
  • R 5 is one or more substituents selected from hydrogen, halogen, methyl, methoxy or trifluoromethyl;
  • the protein kinase inhibitor is a compound having a structure represented by formula (II), and its chemical name is N-(2-aminophenyl)-6-(7-methoxyquinoline- 4-oxo)-1-naphthamide, the common Chinese name is Sioroni.
  • the chemotherapeutic drugs include topoisomerase II inhibitors or paclitaxel and its derivatives; the topoisomerase II inhibitors include etoposide or teniposide; the paclitaxel and its derivatives include paclitaxel, doxel Paclitaxel, paclitaxel albumin.
  • the dosage of the protein kinase inhibitor is 1-100 mg, preferably 20-80 mg, most preferably 50 mg; the dosage of the topoisomerase II inhibitor is 1-100 mg, preferably 20-80 mg, most preferably 50 mg;
  • the dosage of the paclitaxel and its derivatives is 10-200 mg/m 2 , preferably 50-100 mg/m 2 , and most preferably 60 mg/m 2 .
  • the pharmaceutical composition may also include a pharmaceutically acceptable carrier.
  • the present invention provides the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for the prevention and/or treatment of cancer, wherein the cancer is ovarian cancer, and the ovarian cancer includes malignant epithelial ovarian cancer, fallopian tube cancer and Primary peritoneal cancer.
  • the cancer is platinum-refractory/platinum-resistant recurrent ovarian cancer
  • the platinum-refractory refers to tumor progression during treatment with a platinum-containing regimen
  • the platinum-resistant treatment refers to a platinum-containing treatment regimen. Progress or relapse within 6 months after the end of treatment.
  • the cancer is platinum-refractory/platinum-resistant relapsed advanced ovarian cancer
  • the advanced stage includes stage III and stage IV according to stages.
  • Stage III The tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, accompanied by cytological or histological confirmation of extrapelvic peritoneal dissemination, and/or metastasis to retroperitoneal lymph nodes;
  • Stage IV Abdominal cavity Far away.
  • the present invention provides a method for treating and/or preventing cancer, which comprises the step of administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to a patient in need, and the cancer is ovarian cancer, preferably platinum Refractory/platinum-resistant relapsed ovarian cancer, most preferably platinum-refractory/platinum-resistant relapsed advanced ovarian cancer.
  • the amount of the protein kinase inhibitor is 1-100 mg, preferably 20-80 mg, and most preferably 50 mg; the protein kinase inhibitor is preferably an oral administration form, most preferably a capsule, preferably Take orally on an empty stomach every morning, once a day.
  • the dosage of the topoisomerase II inhibitor is 1-100 mg, preferably 20-80 mg, and most preferably 50 mg; the topoisomerase II inhibitor is preferably an oral dosage form, It is most preferably a capsule, preferably taken orally on an empty stomach every morning, taking the medicine continuously for 21 days and rest for 7 days, every 28 days is a treatment cycle, up to 6 treatment cycles.
  • the amount of paclitaxel and its derivatives is 10-200 mg/m 2 , preferably 50-100 mg/m 2 , and most preferably 60 mg/m 2 ; the paclitaxel and its derivatives are preferably It is a parenteral dosage form, more preferably an intravenous dosage form, preferably once a week (d1, d8, d15), and every 3 weeks is a treatment cycle, with a maximum of 6 treatment cycles.
  • the protein kinase inhibitor and the chemotherapeutic agent can be administered separately, simultaneously or sequentially.
  • the protein kinase inhibitor can be continuously administered for treatment.
  • the present invention provides a kit containing an effective amount of the above-mentioned pharmaceutical composition.
  • the protein kinase inhibitor, and topoisomerase II inhibitor or paclitaxel and its derivatives are unit preparations with the same or different specifications, respectively.
  • the protein kinase inhibitor is preferably an oral preparation
  • the topoisomerase II inhibitor is preferably an oral preparation
  • the paclitaxel and its derivatives are preferably an intravenous drip preparation.
  • the protein kinase inhibitor and the chemotherapeutic drug are separately provided in separate containers, and the protein kinase inhibitor and the chemotherapeutic drug can be administered simultaneously, sequentially or sequentially.
  • the kit contains in the same package:
  • a second container containing chemotherapy drugs A second container containing chemotherapy drugs.
  • the present invention also provides the use of a compound having a structure represented by formula (II) in the preparation of a drug for treating platinum-refractory/platinum-resistant recurrence of advanced ovarian cancer.
  • the present invention found that the "single-arm, multi-center, non-random, open clinical trial exploring efficacy and safety of Cioroni capsules for the treatment of relapsed and refractory advanced ovarian cancer" proved that after multiple chemotherapy, platinum refractory /In patients with advanced ovarian cancer with drug-resistant relapse, Cioroni single-drug showed the initial effect of tumor remission.
  • platinum refractory /In patients with advanced ovarian cancer with drug-resistant relapse, Cioroni single-drug showed the initial effect of tumor remission.
  • etoposide and paclitaxel were compared with platinum-refractory/platinum-resistant relapsed advanced ovarian cancer.
  • the objective remission rate was improved after the combined administration of Sioroni.
  • the remission rate of etoposide alone was about 27%, and that of paclitaxel alone was about 21%.
  • the objective remission rates of the two chemotherapeutic drugs combined with Cioronil reached 40% and 50%, respectively, indicating Cioro
  • the combination of Etoposide or Paclitaxel in the treatment of platinum-refractory/drug-resistant advanced ovarian cancer has achieved an unexpected synergistic effect.
  • the combination of Cioroni and etoposide or paclitaxel is effective in the treatment of platinum-refractory/drug-resistant relapsed advanced (stage III and IV) malignant epithelial ovarian cancer, especially for metastatic III Stage and IV malignant epithelial ovarian cancer.
  • the term “comprising”, “including” or “including” means to include the stated elements, integers or steps, but does not exclude any other elements, integers or steps.
  • the terms “comprising”, “comprising” or “including” are used, unless otherwise specified, it also covers the situation consisting of the stated elements, integers or steps.
  • prevention includes the suppression or delay of the occurrence or frequency of the occurrence or occurrence of a disease or disorder or its symptoms, and it generally refers to the administration of drugs before the occurrence or occurrence of the symptoms or symptoms, especially before the occurrence of the symptoms or symptoms in individuals at risk.
  • treatment refers to the slowing, prevention or reversal of the progression of a subject's cancer as evidenced by the reduction or elimination of the clinical or diagnostic symptoms of the disease. Treatment may include, for example, reducing the severity of symptoms, the number of symptoms, or the frequency of recurrence, for example, tumor growth inhibition, tumor growth arrest, or regression of existing tumors.
  • pharmaceutical composition refers to a non-fixed combination product or a fixed combination product.
  • non-fixed combination means that the active ingredients, such as protein kinase inhibitors and chemotherapeutic drugs, are administered to a patient simultaneously, without a specific time limit, or at the same or different time intervals, in separate entities, wherein such administration is in the patient
  • the two active agents are provided in the body at a preventive or therapeutically effective level.
  • the two molecules of protein kinase inhibitor and chemotherapeutic agent used in the pharmaceutical composition are administered at a level not exceeding the level when they are used alone.
  • fixed combination means that the two active agents are simultaneously administered to the patient in the form of a single entity.
  • the dosage and/or time interval of the two active agents are selected, so that the combined use of each part can produce an effect greater than that achieved by using either component alone in the treatment of diseases or conditions.
  • Each component may be in the form of a separate preparation, and the preparation form may be the same or different.
  • the term “therapeutically effective amount” as used herein refers to the combined effect that triggers the desired biological or medical response when administered in combination, that is, one or more cancers that are inhibited or ameliorated include relapsed and refractory ovarian cancer clinically or The combined dose for the diagnosis of symptoms.
  • therapeutically effective amount refers to the amount that produces a therapeutically effective and/or synergistic combined effect when administered together (sequentially or simultaneously) on the same day or on different days in the treatment cycle .
  • administration refers to the physical introduction of each active ingredient of the pharmaceutical combination of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art.
  • the route of administration of each active ingredient in the pharmaceutical combination of the present invention includes oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other parenteral routes of administration .
  • parenteral administration refers to methods of administration other than gastrointestinal and topical administration, usually via intravenous, and without limitation includes intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrasaccular , Intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injection and infusion, and in vivo electroporation.
  • each active ingredient in the pharmaceutical combination of the present invention can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, etc.
  • dose is the amount of a drug that induces a therapeutic effect. Unless otherwise stated, the dosage is related to the amount of the free form of the drug. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased in proportion to the amount of the drug in the free form. For example, the dosage will be stated on the product packaging or product information sheet.
  • pharmaceutically acceptable refers to those compounds that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and are commensurate with a reasonable benefit/risk ratio, Materials, compositions and/or dosage forms.
  • the present invention discloses a pharmaceutical composition containing a protein kinase inhibitor and a chemotherapeutic drug and its use.
  • AE adverse event
  • Example 1 A single-arm, multi-center, non-random, open clinical trial of Cioroni Capsules for the treatment of relapsed and refractory ovarian cancer to explore the efficacy and safety
  • ⁇ Main inclusion criteria epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer confirmed histologically; need to have received platinum-containing chemotherapy regimens, platinum-resistant patients should receive ⁇ 2 different chemotherapy regimens after disease progression or Recurrence; platinum-sensitive patients should receive ⁇ 2 different chemotherapy regimens after disease progression or recurrence, or refuse to receive chemotherapy again.
  • ⁇ Medication plan Cioroni, 50mg, taken orally on an empty stomach every morning, once a day, every 28 days is a treatment cycle, and there is no stopping interval between treatment weeks. Continue treatment until any of the following occurs (whichever occurs first): disease progression, intolerable toxicity, death, withdrawal of informed consent, or loss to follow-up.
  • PFS Progression-free survival
  • TTP time to disease progression
  • DOR disease control rate at week 16 (16W-DCR)
  • OS overall survival
  • the full analysis set (FAS) and safety data set (SS) were used for analysis, and 25 subjects entered each data set.
  • Cioroni single-drug showed the initial effect of tumor remission.
  • Safety indicators include adverse events, vital signs, ECG and abnormal laboratory results, judged according to CTCAE V4.03.
  • the 25 subjects with relapsed and refractory ovarian cancer enrolled in the study were all included in the safety data set (SS) for analysis. The results are shown in Table 2.
  • Cioronib single-agent therapy is similar to those reported for VEGFR target drugs (sorafenib, sunitinib, etc.), which can be tolerated by most subjects and the safety is controllable.
  • Example 2 Phase II multicenter clinical trial of Cioroni combined with chemotherapy in the treatment of platinum-refractory/platinum-resistant relapsed advanced ovarian cancer
  • the test is divided into two stages: pre-test and formal test.
  • pre-test 3 subjects were enrolled in each group for pre-tests to initially evaluate the safety of the combination of Cioroni and chemotherapeutics, and analyze the potential effects of chemotherapeutics on the pharmacokinetics of Cioroni. After all pre-test subjects have completed the first cycle of safety and pharmacokinetics assessment, they will be enrolled in the formal trial.
  • ⁇ Main selection criteria Malignant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer diagnosed by histology or cytology; platinum-refractory or platinum-resistant recurrent ovarian cancer; previous ⁇ 1 line of platinum-containing chemotherapy (including platinum Treatment for at least 4 treatment cycles), for platinum refractory or platinum resistance treatment ⁇ 2 lines.
  • ⁇ Medication regimen It includes two treatment phases, the combined chemotherapy phase and the single-agent maintenance phase of Cioroni. All subjects were treated until disease progression, intolerable toxicity, withdrawal of knowledge or death (whichever occurs first).
  • CE group Cioroni Capsule: Pre-test stage, 25mg orally, once a day, after completing the pharmacokinetic study sampling at the specified time point of the plan, the investigator will determine whether to observe comprehensive tolerance and preliminary efficacy Increase to 50mg orally, once a day; in the formal test phase, 50mg, orally on an empty stomach every morning, once a day, continuous medication; Etoposide soft capsule: 50mg, orally on an empty stomach every morning, and rest for 21 consecutive days 7 Days, every 28 days is a treatment cycle, up to 6 treatment cycles.
  • Cioroni's pre-experimental and formal trial phases are the same as the CE group; paclitaxel injection: 60mg/m2, intravenous drip, once a week (d1, d8, d15), one every 3 weeks Treatment cycles, up to 6 treatment cycles.
  • ⁇ Single-drug maintenance stage Both the CE group and CP group received sioroni single-drug maintenance treatment.
  • ⁇ Efficacy indicators The efficacy evaluation is carried out according to the RECIST 1.1 (2009) standard for solid tumors.
  • ORR objective response rate
  • OS overall survival
  • TTP time to disease progression
  • DOR duration of disease response
  • the combination of Cioroni and etoposide or paclitaxel is effective in the treatment of platinum-refractory/drug-resistant relapsed advanced (stage III and IV) malignant epithelial ovarian cancer, especially for metastatic III Stage and IV malignant epithelial ovarian cancer.
  • Safety indicators include safety evaluation through testing or observing various vital signs, adverse events and laboratory inspection indicators. The severity of adverse events is judged according to the CTCAE V4.03 standard.

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Abstract

涉及生物技术领域，具体涉及包含蛋白激酶抑制剂和化疗药物的药物组合物及其用途。发现治疗铂难治/耐药复发的晚期卵巢癌，依托泊苷和紫杉醇分别与西奥罗尼联合用药后，缓解率分别为40％和50％，而依托泊苷单用的缓解率约27％，紫杉醇单用的缓解率约2l％，说明西奥罗尼联合依托泊苷或紫杉醇治疗铂难治/耐药复发的晚期卵巢癌取得了预料不到的协同增效作用。

Description

包含蛋白激酶抑制剂和化疗药物的药物组合物及其用途 技术领域
本发明涉及生物技术领域，具体涉及包含蛋白激酶抑制剂和化疗药物的药物组合物及其用途。
背景技术
B蛋白激酶是催化蛋白质中特定残基磷酸化的酶家族，广义地分为酪氨酸和丝氨酸/苏氨酸激酶，代表了在调节多种细胞过程和维持细胞功能中发挥重要作用的一大家族的蛋白质。蛋白激酶是信号转导途径的酶组分，其催化ATP的末端磷酸酯转移到蛋白质的酪氨酸、丝氨酸和/或苏氨酸残基的羟基上。在哺乳动物中正常或突变的蛋白激酶的超量表达或不当表达已经成为广泛研究的主题，并且已经证明在许多疾病包括癌症的发展中起到重要作用。这些激酶的部分非限制性清单包括：非受体酪氨酸激酶，如Janus激酶家族(Jak1、Jak2、Jak3和Tyk2)；受体酪氨酸激酶，如血小板衍生生长因子受体激酶(PDGFR)；以及丝氨酸/苏氨酸激酶，如b-RAF。在许多疾病状态中观察到异常的激酶活性，包括良性和恶性增殖性障碍以及免疫和神经系统的不适当激活导致的疾病。
蛋白激酶作为一大家族结构上相关的酶，负责控制细胞内多种信号转导过程(参见例如Hardie及Hanks，The Protein Kinase Facts Book，I and II，Academic Press，San Diego，Calif.，1995)。蛋白激酶因其结构及催化功能的保守性而被认为自共同祖先基因进化而来。几乎所有激酶均含有类似的具有250-300个氨基酸的催化结构域。激酶可根据其磷酸化受体(例如蛋白-酪氨酸、蛋白-丝氨酸/苏氨酸、脂质等)分类为各家族。已鉴别出通常对应于这些家族中每一个的序列基序(参见例如Hanks及Hunter，(1995)，FASEB J.9：576-596；Knighton等，Science，(1991)253：407-414；Hiles等，Cell，(1992)，70：419-429；Kunz等，Cell(1993)，73：585-596；Garcia-Bustos等，EMBO J.，(1994)，13：2352-2361)。
由于突变、过度表达或不适当调节、调节异常或失调，以及生长因子或细胞因子的过度产生或产生不足所导致的不适当的激酶活性可涉及许多疾病，其包括但不限于癌症等多种疾病。蛋白激酶已成为一类重要的作为治疗性介入的靶标的酶。特别地，酪氨酸激酶cKit过度活化与血液学恶性病相关，且为癌症疗法的标靶(Heinrich，Griffith等，Blood 2000，96(3)：925-32)。同样，JAK3信号传导涉及白血病及淋巴瘤且目前用作潜在治疗标靶(Heinrich，Griffith等人，2000))。蛋白激酶在细胞周期调控中同样发挥着核心作用。已发现在信号转导途径的各个组成部分中的缺陷可引起多种疾病，包括多种形式的癌症(Gaestel等，Current Medicinal Chemistry，(2007)14：2214-2234)。近年来，与致癌信号传导途径有关的蛋白激酶已在治疗包括多种类型癌症在内的多种疾病方面成为重要的药物靶标。也有多种蛋白激酶抑制剂用作抗肿瘤药物。
西奥罗尼是深圳微芯生物科技股份有限公司自主研发的具有完全知识产权的全新蛋白激酶抑制剂。西奥罗尼是一个以多蛋白激酶为靶点的小分子抗肿瘤靶向药物，通过对VEGFR/PDGFR/c-Kit、Aurora B、CSF-1R靶点的高选择抑制活性，具有抗肿瘤血管生成、抑制肿瘤细胞有丝分裂、调控肿瘤炎性微环境等三通路抗肿瘤协同作用机制，发挥综合抗肿瘤作用。与传统的VEGFR类靶向抑制剂(如舒尼替尼/Sunitinib、索拉菲尼/Sorafenib等)相比，本品对有丝分裂关键酶Aurora B的抑制活性是其所特有的，具有潜在的降低肿瘤组织基因组不稳定性及抑制肿瘤细胞转移的作用。西奥罗尼通过抑制肿瘤血管生成、细胞有丝分裂和肿瘤炎性微环境三种互补的作用机制发挥抗肿瘤活性，同时其高靶标选择性也降低了因脱靶效应带来的副作用风险。
DNA拓扑异构酶是细胞内重要的核酶，主要通过催化作用改变DNA的拓扑结构。真核细胞的拓扑异构酶主要分为拓扑异构酶I(Topo I)和拓扑异构酶II(Topo II)。其中，在催化过程中形成的中间产物造成DNA双链短暂断裂的称为Topo II。在细胞DNA复制、转录和有丝分裂等重要的生命过程中，Topo II都发挥重要作用。
DNA Topo II的作用在于介导DNA双链解螺旋(断裂和再连接)，在通常情况下，DNA Topo II与DNA形成一种易断裂复合物。Topo II抑制剂是一类以Topo II为靶点的抗肿瘤药物，其抗癌作用并不在于抑制酶本身的活性， 而在于促使酶DNA断裂复合物的形成，使平衡反应趋向于酶DNA断裂复合物，延长其半衰期并使其稳定，干扰DNA Topo II介导的DNA再连接反应，导致DNA单链或双链断裂，影响DNA复制，发挥细胞杀伤作用。可断裂复合物的形成及稳定存在促进了DNA的异常重组，从而启动细胞凋亡程序而导致细胞死亡。
基于对Topo II在细胞中关键作用的认识，对该类化合物的研究一直是抗肿瘤药物研发的热点之一。目前已上市的拓扑异构酶II包括依托泊苷和替尼泊苷等。
紫杉醇是已发现的最优秀的天然抗癌药物，在临床上已经广泛用于乳腺癌、卵巢癌和部分头颈癌和肺癌的治疗。紫杉醇作为一个具有抗癌活性的二萜生物碱类化合物，其新颖复杂的化学结构、广泛而显著的生物活性、全新独特的作用机制、奇缺的自然资源使其受到了植物学家、化学家、药理学家、分子生物学家的极大青睐，使其成为20世纪下半叶举世瞩目的抗癌明星和研究重点。多西紫杉醇和白蛋白紫杉醇等衍生物具有与紫杉醇相似的功效。
在我国，卵巢癌年发病率居女性生殖系统肿瘤第3位，位于子宫颈癌和子宫体恶性肿瘤之后，呈逐年上升的趋势，而死亡率位于女性生殖道恶性肿瘤之首，是严重威胁女性健康的恶性肿瘤。卵巢恶性肿瘤包括多种病理类型，其中最常见的是上皮性癌，约占卵巢恶性肿瘤的70％，其次是恶性生殖细胞肿瘤和性索间质肿瘤，各约占20％和5％。
卵巢癌的治疗一直是妇科肿瘤面临的最艰巨的挑战，理想的细胞减灭术是治疗的基石，以铂类为主的联合化疗方案是卵巢癌化疗的主要方案，但晚期患者即使经过上述治疗获得完全缓解，仍有70％～80％出现复发。
铂难治/铂耐药复发的晚期卵巢癌是临床治疗最棘手的难题，为铂难治/铂耐药复发的晚期卵巢癌提供新的治疗思路、探索寻找能够有效治疗铂难治/铂耐药复发的晚期卵巢癌的方案具有重要意义。
发明内容
本发明发现，包含蛋白激酶抑制剂和化疗药物的药物组合物对于癌症尤其是铂难治/铂耐药复发的晚期卵巢癌具有意想不到的治疗作用。
第一方面，本发明提供了一种药物组合物，其包含蛋白激酶抑制剂和化疗药物，其中，所述蛋白激酶抑制剂包括描述于CN200910223861.5中的化合物，其全部内容被引入本文作为参考，所述蛋白激酶抑制剂优选为具有通式(I)所示结构的化合物，
Figure PCTCN2021082656-appb-000001
其中，Z为CH或N；
R 1、R 2和R 3分别为氢、卤素、甲基、甲氧基或三氟甲基；
R 4为
Figure PCTCN2021082656-appb-000002
X为苯环或吡啶环；
R 5为一个或多个取代基，选自氢、卤素、甲基、甲氧基或三氟甲基；
包括其游离形式、盐的形式、对映异构体或非对映异构体。
在一个优选的方案中，所述蛋白激酶抑制剂为具有式(II)所示结构的化合物，其化学名为N-(2-氨基苯基)-6-(7-甲氧基喹啉-4-氧)-1-萘酰胺，中文通用名为西奥罗尼。
Figure PCTCN2021082656-appb-000003
所述化疗药物包括拓扑异构酶II抑制剂或紫杉醇及其衍生物；所述拓扑异构酶II抑制剂包括依托泊苷或替尼泊苷；所述紫杉醇及其衍生物包括紫杉醇，多西紫杉醇，白蛋白紫杉醇。
所述蛋白激酶抑制剂的用量为1-100mg，优选为20-80mg，最优选为50mg；所述拓扑异构酶II抑制剂的用量为1-100mg，优选为20-80mg，最优选为50mg；所述紫杉醇及其衍生物的用量为10-200mg/m 2，优选为50-100mg/m 2，最优选为60mg/m 2。
所述药物组合物还可以包含药学上可以接受的载体。
第二方面，本发明提供了上述药物组合物在制备用于预防和/或治疗癌症的药物中的用途，其中所述癌症为卵巢癌，所述卵巢癌包括恶性上皮性卵巢癌，输卵管癌和原发性腹膜癌。
在一个优选的实施方案中，所述癌症为铂难治/铂耐药复发卵巢癌，所述铂难治是指含铂方案治疗过程中肿瘤进展，所述铂耐药是指含铂治疗方案在治疗结束后6个月内进展或复发。
在一个优选的实施方案中，所述癌症为铂难治/铂耐药复发的晚期卵巢癌，所述晚期根据分期包括III期和IV期。III期：肿瘤累及一侧或双侧卵巢或输卵管，或原发性腹膜癌，伴有细胞学或组织学确认的盆腔外腹膜播散，和(或)转移至腹膜后淋巴结；IV期：腹腔之外的远处转移。
第三方面，本发明提供了一种用于治疗和/或预防癌症的方法，其包括向有需要的患者施用治疗有效量的上述药物组合物的步骤，所述癌症为卵巢癌，优选为铂难治/铂耐药复发卵巢癌，最优选为铂难治/铂耐药复发的晚期卵巢癌。
在一个优选的实施方案中，所述蛋白激酶抑制剂的用量为1-100mg，优选为20-80mg，最优选为50mg；所述蛋白激酶抑制剂优选为口服施用剂型，最优选为胶囊，优选每日早晨空腹口服，每日1次。
在一个优选的实施方案中，所述拓扑异构酶II抑制剂的用量为1-100mg，优选为20-80mg，最优选为50mg；所述拓扑异构酶II抑制剂优选为口服施用剂型，最优选为胶囊，优选每日早晨空腹口服，连续服药21天休息7天，每28天为一个治疗周期，最多6个治疗周期。
在一个优选的实施方案中，所述紫杉醇及其衍生物的用量为10-200mg/m 2，优选为50-100mg/m 2，最优选为60mg/m 2；所述紫杉醇及其衍生物优选为胃肠外施用剂型，更优选静脉内施用剂型，优选每周给药1次(d1、d8、d15)，每3周为一个治疗周期，最多6个治疗周期。
在一个优选的实施方案中，所述蛋白激酶抑制剂和化疗药物可分开、同时或依次施用。
在一个优选的实施方案中，所述蛋白激酶抑制剂和化疗物质联合治疗周期结束后，可继续给予蛋白激酶抑制剂给予治疗。
第四方面，本发明提供了一种药盒，其包含有效量的上述药物组合物。
在一个优选的实施方案中宏，所述药盒中，所述蛋白激酶抑制剂，以及拓扑异构酶II抑制剂或紫杉醇及其衍生物分别是具有相同或不同规格的单位制剂。所述蛋白激酶抑制剂优选为口服制剂，所述拓扑异构酶II抑制剂优选为口服制剂，所述紫杉醇及其衍生物优选为静脉滴注制剂。
在一个优选的实施方案中，所述蛋白激酶抑制剂和化疗药物分别置于单独容器中提供，所述蛋白激酶抑制剂和化疗药物可同时、先后或依次施用。
在一个优选的实施方案中，所述药盒在同一包装内包含：
含有蛋白激酶抑制剂的第一容器；以及
含有化疗药物的第二容器。
最后，本发明还提供了具有式(II)所示结构的化合物在制备治疗铂难治/铂耐药复发的晚期卵巢癌药物中的用途。
Figure PCTCN2021082656-appb-000004
本发明发现，通过“西奥罗尼胶囊治疗复发难治晚期卵巢癌的单臂、多中心、非随机、开放性探索疗效和安全性的临床试验”，证实在经过多次化疗、铂难治/耐药复发的晚期卵巢癌受试者中，西奥罗尼单药显示了肿瘤缓解的初步疗效。通过“西奥罗尼联合化疗治疗铂难治/铂耐药复发卵巢癌的II期多中心临床试验”，初步提示治疗铂难治/耐药复发的晚期卵巢癌，依托泊苷和紫杉醇分别与西奥罗尼联合用药后，客观缓解率均得到提高。依托泊苷单药的缓解率约27％，紫杉醇单药的缓解率约21％，而两种化疗药物分别联合西奥罗尼后的客观缓解率分别达到40％和50％，说明西奥罗尼联合依托泊苷或紫杉醇治疗铂难治/耐药复发的晚期卵巢癌取得了预料不到的协同增效作用。根据入组病例的实际情况，说明西奥罗尼联合依托泊苷或紫杉醇治疗铂难治/耐药复发的晚期(III期和IV期)恶性上皮性卵巢癌效果优异，尤其是发生转移的III期和IV期恶性上皮性卵巢癌。
如本文中所用，术语“含有”、“包含”或“包括”意指包括所述的要素、整数或步骤，但是不排除任意其他要素、整数或步骤。在本文中，当使用术语“含有”、“包含”或“包括”时，除非另有指明，否则也涵盖由所述及的要素、整数或步骤组成的情形。
术语“预防”包括对疾病或病症或其症状的发生或发生频率的抑制或推迟，其通常是指在病征或症状发生前，特别是在具有风险个体的病征或症状发生前的药物施用。
本文所用术语“治疗”指通过疾病的临床或诊断症状的减轻或消除来证明的对象癌症进展的减缓、阻止或逆转。治疗可包括例如，降低症状严重程度、症状数量或复发频率，例如，肿瘤生长抑制、肿瘤生长阻滞或已有肿瘤的消退。
术语“药物组合物”是指非固定组合产品或固定组合产品。术语“非固定组合”意指活性成分例如蛋白激酶抑制剂和化疗药物以分开的实体被同时、无特定时间限制或以相同或不同的时间间隔、依次地施用于患者，其中这类施用在患者体内提供预防或治疗有效水平的所述两种活性剂。在一些实施方案中，药物组合物中使用的蛋白激酶抑制剂和化疗药物这两种分子以不超过它们单独使用时的水平施用。术语“固定组合”意指两种活性剂以单个实体的形式被同时施用于患者。优选对两种活性剂的剂量和/或时间间隔进行选择，从而使各部分的联合使用能够在治疗疾病或病症时产生大于单独使用任何一种成分所能达到的效果。各成分可以各自呈单独的制剂形式，其制剂形式可以相同也可以不同。
涉及联合治疗时，本文所用术语“治疗有效量”指联合给药时联合作用引发所需的生物学或医学反应，即，抑制或改善的一种或多种癌症包括复发难治卵巢癌临床或诊断症状的联合给药量。例如，提到联合治疗时，本文所用 术语“治疗有效量”是在治疗周期中的同一天或不同天一起给药(依次或同时)时，产生治疗有效和/或协同性的联合作用的用量。
术语“施用”指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将本发明的药物组合中的各活性成分物理导入至个体。本发明的药物组合中的各活性成分的施用途径包括口服、静脉内(例如输注(又称滴注)或注射)、肌内、皮下、腹膜内、脊髓、局部或其他胃肠外施用途径。本文所用的短语“胃肠外施用”指胃肠和局部施用之外的施用方式，通常通过静脉内，且非限制性地包括肌内、动脉内、鞘内、淋巴内、病灶内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注，以及体内电穿孔。相应地，本发明的药物组合中的各活性成分可以被配制成胶囊剂、片剂、注射剂(包括输液或注射液)、糖浆、喷雾剂、锭剂、脂质体或栓剂等。
术语“剂量”是引发治疗效果的药物的量。除非另有说明，否则剂量与游离形式的药物的量有关。如果药物是可药用盐形式，药物的量与游离形式的药物的量相比成比例地增加。例如，剂量将在产品包装或产品信息单中声明。
术语“药学上可以接受的”是指那些适合用于与人类和动物组织接触使用而没有过多的毒性、刺激、过敏反应或其他问题或并发症，与合理的益处/风险比相称的化合物、材料、组合物和/或剂型。
具体实施方式
本发明公开了包含蛋白激酶抑制剂和化疗药物的药物组合物及其用途，本领域技术人员可以借鉴本文内容，适当改进实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用进行改动或适当变更与组合，来实现和应用本发明技术。
以下进一步通过非限制性实例来说明本发明，其不旨在限制本发明所涵盖的范围。
除非另有定义，否则本文中使用的所有技术和科学术语均具有与本领域一般技术人员通常所理解的含义相同的含义。为了本发明的目的，下文定义了以下术语。
术语“约”在与数字数值联合使用时意为涵盖具有比指定数字数值小5％的下限和比指定数字数值大5％的上限的范围内的数字数值。
术语“不良事件”(AE)是指病人或临床试验受试者接受一种药品(物)后出现的不良医学事件，但不一定与治疗有因果关系。包括在临床研究过程中发生的原有其他疾病复发，不管它的发生是否与治疗有关。临床进行有创性检查本身不作为不良事件，但导致这些检查的原因应作为不良事件。
实施例1西奥罗尼胶囊治疗复发难治卵巢癌的单臂、多中心、非随机、开放性探索疗效和安全性的临床试验
1、试验设计
●单臂、多中心、非随机、开放性Ib期试验。
●主要入选标准：经组织学确诊的上皮性卵巢癌、输卵管癌或原发性腹膜癌；需接受过含铂类化疗方案，铂类耐药者应接受≥2个不同化疗方案后疾病进展或复发；铂类敏感者应接受≥2个不同化疗方案后疾病进展或复发，或者拒绝接受再次化疗。
●用药方案：西奥罗尼，50mg，每日早晨空腹口服，每日1次，每28天为一个治疗周期，治疗周期间无停药间隔期。持续治疗直至出现以下任一情况(以先发生者为准)：疾病进展、不能耐受的毒性反应、死亡、撤回知情同意或失访。
●疗效指标：由研究者和影像学专家根据RECIST1.1标准进行评价。
√主要：客观缓解率(ORR)
√次要：无进展生存期(PFS)、至疾病进展时间(TTP)、第16周疾病控制率(16W-DCR)、疾病缓解持续时间(DOR)、总生存期(OS)
2、受试者人群
研究入组25例复发难治卵巢癌受试者，既往治疗方案数均≥3个。末次含铂化疗敏感的3例(12.0％)，末次含铂化疗难治或耐药的22例(88.0％)。截至试验数据截止日(2019年3月20日)，因疾病进展结束治疗16例(64.0％)，因不良事件结束治疗3例(12.0％)，其他结束治疗的原因包括受试者自愿退出、试验结束及失访。
采用全分析集(FAS)和安全性数据集(SS)进行分析，25例受试者均进入各数据集。
3、疗效结果
各项疗效指标评价情况，如表1所示。25例受试者中，经确认的最佳疗效分别为部分缓解(PR)1例(4.0％)，疾病稳定(SD)14例(56.0％)，疾病进展(PD)7例(28.0％)，不可评价(NE)3例(12.0％)。ORR为4.0％。
截至试验数据截止日(2019年3月20日)，已获得PFS的研究事件(疾病进展或死亡)数12例，中位PFS为3.7(95％Cl，1.8～NE)个月。中位TTP为3.7(95％Cl，1.8～NE)个月，16W-DCR为32.0％，中位DOR和OS尚无法估计。
表1西奥罗尼胶囊治疗复发难治卵巢癌的疗效结果
  N＝25
最佳疗效评估，n(％)  
CR 0
PR 1(4.0)
SD 14(56.0)
PD 7(28.0)
NE 3(12.0)
客观缓解率，％(95％Cl) 4.0(0.10％，20.35％)
16周疾病控制率，％(95％Cl) 32.0(15.0％，53.5％)
无进展生存期，Median(95％Cl)，月 3.7(1.8，NE)
事件 12
删失 13
至疾病进展时间，Median(95％Cl)，月 3.7(1.8，NE)
事件 11
删失 14
缓解持续时间，Median(95％Cl)，月 NE(NE，NE)
事件 0
删失 2
总生存期，Median(95％Cl)，月 NE(6.0，NE)
事件 11
删失 14
4、疗效结论
在经过多次化疗、铂难治/耐药复发的卵巢癌受试者中，西奥罗尼单药显示了肿瘤缓解的初步疗效。
5、安全性评价
安全性指标包括不良事件、生命体征、ECG和实验室结果异常，根据CTCAE V4.03判断。研究入组25例复发难治卵巢癌受试者均进入安全性数据集(SS)进行分析，结果如表2所示。
表2西奥罗尼胶囊治疗复发难治卵巢癌的安全性评价结果
Figure PCTCN2021082656-appb-000005
Figure PCTCN2021082656-appb-000006
Figure PCTCN2021082656-appb-000007
当前数据提示，西奥罗尼单药治疗毒性反应特点与VEGFR靶点药物(索拉菲尼、舒尼替尼等)报道相似，大部分受试者可以耐受，安全性可控。
实施例2西奥罗尼联合化疗治疗铂难治/铂耐药复发的晚期卵巢癌的II期多中心临床试验
1、试验设计
●多中心、随机、开放设计，II期试验。
●根据筛选时无治疗间期(TFI)是否大于等于3个月分层，按1∶1的比例随机分配到西奥罗尼联合依托泊苷组(CE组)或西奥罗尼联合紫杉醇组(CP组)
●试验分为两阶段：预实验和正式试验。正式试验开始前，每组各入3例受试者做预试验，初步评估西奥罗尼与化疗药物联合用药的安全性、分析化疗药物对西奥罗尼药代动力学的潜在影响。所有预试验受试者完成第一周期安全性和药代评估后，开始正式试验的入组。
●主要入选标准：经组织学或细胞学确诊恶性上皮性卵巢癌、输卵管癌或原发性腹膜癌；铂难治或铂耐药复发卵巢癌；既往接受过≥1线含铂化疗(含铂治疗至少4个治疗周期)，针对铂难治或铂耐药治疗≤2线。
●用药方案：包括两个治疗阶段，联合化疗阶段与西奥罗尼单药维持阶段。所有受试者均治疗至疾病进展、不可耐受毒性、撤回知情或死亡(以先发生为准)。
√联合化疗阶段：CE组：西奥罗尼胶囊：预试验阶段，25mg口服，每日1次，完成方案规定时间点的药代研究采样后，研究者综合耐受性和初步疗效观察决定是否增加到50mg口服，每日1次；正式试验阶段，50mg，每日早晨空腹口服，每日1次，连续用药；依托泊苷软胶囊：50mg，每日早晨空腹口服，连续服药21天休息7天，每28天为一个治疗周期，最多6个治疗周期。CP组：西奥罗尼预实验及正式试验阶段服药方案同CE组；紫杉醇注射液：60mg/m2，静脉滴注，每周给药1次(d1、d8、d15)，每3周为一个治疗周期，最多6个治疗周期。
√单药维持阶段：CE组和CP组均接受西奥罗尼单药维持治疗。
●疗效指标：采用实体瘤RECIST 1.1版(2009年)标准进行疗效评估。
√主要：无进展生存期(PFS)
√次要：客观缓解率(ORR)、总生存期(OS)、至疾病进展时间(TTP)、疾病缓解持续时间(DOR)
2、受试者人群
截止至2019年12月26日，共入组21例(CE组10例，CP组11例)。入组受试者治疗时间在0～5个周期之间，下述疗效结果基于截止日前的可评价数据。
3、疗效结果
各项疗效指标评价情况，如表3所示。21例受试者中有11例有疗效评估记录(CE组5例，CP组6例)。最佳疗效反应显示：CE组中有2例(40.0％)获得PR，3例SD；CP组中有3例(50.0％)获得PR，2例SD，1例PD。
表3西奥罗尼胶囊联合化疗治疗复发难治晚期卵巢癌的疗效结果
最佳疗效反应 CE(N＝10) CP(N＝11)
无疗效评估 5 5
有疗效评估 5 6
CR(完全缓解) 0 0
PR(部分缓解) 2(40.0) 3(50.0)
SD(疾病稳定) 3(60.0) 2(33.3)
PD(疾病进展) 0 1(16.7)
4、疗效结论
历史数据显示：治疗铂难治/耐药复发的晚期卵巢癌，依托泊苷单药的缓解率约27％，紫杉醇单药的缓解率约21％。当前数据提示，依托泊苷和紫杉醇分别与西奥罗尼联合用药后，缓解率分别为40％和50％，说明西奥罗尼联合依托泊苷或紫杉醇治疗铂难治/耐药复发的晚期卵巢癌取得了预料不到的协同增效作用。根据入组病例的实际情况，说明西奥罗尼联合依托泊苷或紫杉醇治疗铂难治/耐药复发的晚期(III期和IV期)恶性上皮性卵巢癌效果优异，尤其是发生转移的III期和IV期恶性上皮性卵巢癌。
5、安全性评价
安全性指标包括通过检测或观察各项生命体征、不良事件及实验室检查指标进行安全性评价。不良事件的严重程度按照CTCAE V4.03标准判断。
截止至2019年12月26日，共入组21例(CE组10例，CP组11例)。入组受试者治疗时间在0～5个周期之间，安全性结果均基于截止日前的可评价数据，结果如表4所示。
表4西奥罗尼胶囊联合化疗治疗复发难治晚期卵巢癌的安全性评价结果
Figure PCTCN2021082656-appb-000008
Figure PCTCN2021082656-appb-000009
当前数据提示，依托泊苷和紫杉醇分别与西奥罗尼联合用药后，与各化疗药物单药、西奥罗尼单药报道相比，不良事件类型相似，尚未发现新的安全性信号；不良事件发生率有所升高，但大部分患者可以耐受，尚无因不良事件结束治疗，安全性可控。
以上对本发明进行了详细的介绍，本文中应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想，包括最佳方式，并且也使得本领域的任何技术人员都能够实践本发明，包括制造和使用任何装置或系统，和实施任何结合的方法。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。本发明专利保护的范围通过权利要求来限定，并可包 括本领域技术人员能够想到的其他实施例。如果这些其他实施例具有不是不同于权利要求文字表述的结构要素，或者如果它们包括与权利要求的文字表述无实质差异的等同结构要素，那么这些其他实施例也应包含在权利要求的范围内。

Claims (11)

  1. 一种药物组合物，其包含蛋白激酶抑制剂和化疗药物，其中，所述蛋白激酶抑制剂为具有通式(I)所示结构的化合物，
    Figure PCTCN2021082656-appb-100001
    其中，Z为CH或N；
    R1、R2和R3分别为氢、卤素、甲基、甲氧基或三氟甲基；
    R4为
    Figure PCTCN2021082656-appb-100002
    X为苯环或吡啶环；
    R5为一个或多个取代基，选自氢、卤素、甲基、甲氧基或三氟甲基；
    包括其游离形式、盐的形式、对映异构体或非对映异构体。
  2. 根据权利要求1所述的药物组合物，其中，所述蛋白激酶抑制剂为具有式(II)所示结构的化合物。
    Figure PCTCN2021082656-appb-100003
  3. 根据权利要求1所述的药物组合物，其特征在于，所述化疗药物包括拓扑异构酶II抑制剂或紫杉醇及其衍生物；所述拓扑异构酶II抑制剂包括依托泊苷或替尼泊苷；所述紫杉醇及其衍生物包括紫杉醇，多西紫杉醇，白蛋白紫杉醇。
  4. 根据权利要求1-3任一项所述的药物组合物，其特征在于，所述药物组合物用于治疗和/或预防癌症，优选为卵巢癌，所述卵巢癌包括恶性上皮性卵巢癌，输卵管癌和原发性腹膜癌，更优选为铂难治/铂耐药复发卵巢癌，最优选为铂难治/铂耐药复发的晚期卵巢癌。
  5. 根据权利要求1-3任一项所述的药物组合物，其特征在于，所述蛋白激酶抑制剂的用量为1-100mg，所述拓扑异构酶II抑制剂的用量为1-100mg，所述紫杉醇及其衍生物的用量为10-200mg/m2。
  6. 根据权利要求1-5任一项所述的药物组合物在制备用于预防和/或治疗癌症的药物中的用途，其中所述癌症为卵巢癌，所述卵巢癌包括恶性上皮性卵巢癌，输卵管癌和原发性腹膜癌，优选为铂难治/铂耐药复发卵巢癌，最优选为铂难治/铂耐药复发的晚期卵巢癌。
  7. 用于治疗和/或预防癌症的方法，其特征在于向有需要的患者施用治疗有效量的权利要求1-5任一项所述的药物组合物，所述癌症为卵巢癌，所述卵巢癌包括恶性上皮性卵巢癌，输卵管癌和原发性腹膜癌，优选为铂难治/铂耐药复发卵巢癌，最优选为铂难治/铂耐药复发的晚期卵巢癌。
  8. 一种药盒，其特征在于包含权利要求1-5任一项所述的药物组合物。
  9. 根据权利要求8所述的药盒，其特征在于，所述蛋白激酶抑制剂，以及拓扑异构酶II抑制剂或紫杉醇及其衍生物分别是具有相同或不同规格的单位制剂，所述蛋白激酶抑制剂优选为口服制剂，所述拓扑异构酶II抑制剂优选为口服制剂，所述紫杉醇及其衍生物优选为静脉滴注制剂。
  10. 根据权利要求8或9所述的药盒，其特征在于，所述蛋白激酶抑制剂，以及拓扑异构酶II抑制剂或紫杉醇及其衍生物分别置于单独容器中提供。
  11. 具有式(II)所示结构的化合物在制备治疗铂难治/铂耐药复发的晚期卵巢癌药物中的用途。
    Figure PCTCN2021082656-appb-100004
PCT/CN2021/082656 2020-03-24 2021-03-24 包含蛋白激酶抑制剂和化疗药物的药物组合物及其用途 WO2021190546A1 (zh)

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BR112022019127A BR112022019127A2 (pt) 2020-03-24 2021-03-24 Composição farmacêutica que compreende inibidor de proteína quinase e fármaco quimioterápico e uso do mesmo
CA3176459A CA3176459A1 (en) 2020-03-24 2021-03-24 Pharmaceutical composition comprising protein kinase inhibitor and chemotherapeutic drug and use thereof
EP21774279.0A EP4129288A4 (en) 2020-03-24 2021-03-24 PHARMACEUTICAL COMPOSITION COMPRISING A PROTEIN KINASE INHIBITOR AND A CHEMOTHERAPEUTIC DRUG AND USE THEREOF
JP2022558549A JP2023520383A (ja) 2020-03-24 2021-03-24 プロテインキナーゼ阻害剤と化学療法薬とを含む医薬組成物及びその使用
US17/914,324 US20230117545A1 (en) 2020-03-24 2021-03-24 Pharmaceutical composition comprising protein kinase inhibitor and chemotherapeutic drug and use thereof
ZA2022/11304A ZA202211304B (en) 2020-03-24 2022-10-14 Pharmaceutical composition comprising protein kinase inhibitor and chemotherapeutic drug and use thereof

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