WO2021047573A1 - 一种mek抑制剂与cdk4/6抑制剂联合在制备治疗肿瘤的药物中的用途 - Google Patents

一种mek抑制剂与cdk4/6抑制剂联合在制备治疗肿瘤的药物中的用途 Download PDF

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WO2021047573A1
WO2021047573A1 PCT/CN2020/114385 CN2020114385W WO2021047573A1 WO 2021047573 A1 WO2021047573 A1 WO 2021047573A1 CN 2020114385 W CN2020114385 W CN 2020114385W WO 2021047573 A1 WO2021047573 A1 WO 2021047573A1
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cancer
drug
inhibitor
tumor
formula
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French (fr)
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廖成
施松
袁吉民
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江苏恒瑞医药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to the use of a combination of a MEK inhibitor and a CDK4/6 inhibitor in the preparation of drugs for treating tumors, and belongs to the field of pharmacy.
  • Mitogen-activated protein kinase Mitogen-Activated Protein Kinase, MAPK
  • MAPK Mitogen-activated Protein Kinase
  • MAPK pathways regulate multiple important physiological processes of cells.
  • MAPK pathways There are four MAPK pathways in vertebrates and all multicellular organisms. Among them, the ERK pathway (RAS -RAF-MEK1/2-ERK1/2) is a classic MAPK signaling pathway where cascade signal dysregulation most often occurs in human tumors.
  • Abnormal activation of the ERK pathway is usually caused by acquired mutations in RAS and RAF gene family members, such as 33% of cholangiocarcinoma, 36% of colorectal cancer, 19% of lung cancer, 18% of bladder cancer, and 63% of pancreatic cancer. 15% of prostate cancers have mutations in RAS encoding genes (mainly KRAS, NRAS and HRAS), but the FDA has not yet approved an effective method for the treatment of RAS mutations.
  • MEK (MEK1 and MEK2) is a serine/threonine and tyrosine dual-function kinase on the ERK pathway. It can be phosphorylated by the upstream RAS and RAF kinases. After activation, the signal is transmitted to the downstream, and finally it can be phosphorylated.
  • the core transcription factor participates in the regulation of cell proliferation and differentiation. Therefore, inhibiting the phosphorylation of MEK can prevent further signal conduction, thereby achieving the effect of inhibiting the continuous activation of signal pathways and inhibiting tumor growth.
  • CN106795116A discloses the p-toluenesulfonate salt and crystal form of the compound represented by formula (I).
  • Cyclin-dependent kinase is a type of serine/threonine kinase that forms a dimer with the corresponding cyclin (Cyclin) and then phosphorylates downstream protein molecules to promote the cell cycle Orderly progress in each phase to achieve cell growth and proliferation.
  • CDK4/6 selective inhibitors have been in clinical trials or have been approved for listing in foreign countries, including Pfizer’s Palbociclib, Novartis’s Ribociclib and Eli Lilly’s Abemaciclib.
  • WO2014183520 discloses a chemical named 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2 ,3-d]pyrimidin-7(8H)-one, a CDK4/6 inhibitor with the structural formula shown in formula (II), which has significant CDK4/6 inhibitory activity and high selectivity,
  • WO2016124067A discloses the isethionate of the compound represented by the above formula (I) and a preparation method thereof.
  • the present disclosure provides a use of a combination of a MEK inhibitor and a CDK4/6 inhibitor in the preparation of drugs for treating tumors.
  • the tumor described in the present disclosure is selected from colorectal cancer, biliary tract cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, thyroid cancer, testicular cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, prostate cancer, melanoma, lymphoma , Lung cancer, angiosarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, myxoma, malignant fibrous histiocytoma, hematopoietic malignancies, neuroblastoma, head and neck cancer, endometrial cancer, colorectal cancer, esophageal cancer, Ovarian cancer, salivary gland cancer, small intestine cancer, thymus cancer, central nervous system tumor, bone cancer, adrenal adenoma, renal cell carcinoma, neuroblastoma.
  • the bile duct cancer in the present disclosure may specifically be intrahepatic cholangiocarcinoma, extrahepatic bile duct cancer or gallbladder cancer; the thyroid cancer may specifically be thyroid follicular carcinoma, anaplastic thyroid carcinoma, thyroid papillary carcinoma, thyroid Hurthle cell carcinoma
  • the lymphoma may specifically be Burkitt’s lymphoma, Hodgkin’s lymphoma, plasma cell myeloma, mantle cell lymphoma, non-Hodgkin’s lymphoma, acute lymphoblastic leukemia;
  • the lung cancer may be non- Small cell lung cancer, small cell lung cancer, said non-small cell lung cancer may be adenocarcinoma, squamous cell carcinoma or large cell carcinoma; said hematopoietic system malignant tumor may be acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic Cell leukemia, juvenile myelomonocytic leukemia.
  • the tumor is a Ras gene mutation tumor, specifically, it may be a KRAS gene and/or NRAS gene and/or HRAS gene mutation.
  • the tumor is an advanced or metastatic Ras gene mutation tumor.
  • the MEK inhibitor is selected from AZD-8330, GDC-0623, CI-1040, WX-554, TAK-733, SL-327, APS-2-79, BI-847325, HL-085, BI-847325, CEP-1347, U-0126, Binimetinib, Pimasertib, Cobimetinib, PD-0325901, PD-318088, RO-5126766, BIX-02189, BIX-02188, PD-98059, Trametinib, Refametinib, AS-703988, E-6201, Selumetinib, or the compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the daily dose range of the MEK inhibitor is selected from 0.01-500 mg, and the frequency of administration is 2 times a day, once a day, once every 2 days, and once every 3 days.
  • the daily dose of the MEK inhibitor described in the present disclosure is selected from 0.1 mg, 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg , 9mg, 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 400mg, 500mg, preferably 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg, 10mg, 15mg, 20mg, 30mg, 45mg, 50mg, 60mg, 75mg, 100mg; dos
  • the daily dose range of the MEK inhibitor is selected from 0.125 mg-10 mg, and the frequency of administration is once a day.
  • the daily dose range of the MEK inhibitor is selected from 0.125 mg to 4 mg, and the frequency of administration is once a day.
  • the daily dose of the MEK inhibitor is selected from 0.100mg, 0.125mg, 0.250mg, 0.375mg, 0.500mg, 0.625mg, 0.750mg, 0.875mg, 1.000mg, 1.125mg, 1.250mg, 1.375mg, 1.500mg, 1.625mg, 1.750mg, 1.875mg, 2.000mg, 2.125mg, 2.250mg, 2.375mg, 2.500mg, 2.625mg, 2.750mg, 2.875mg, 3.000mg, 3.125mg, 3.250mg, 3.375mg , 3.500mg, 3.625mg, 3.750mg, 3.875mg, 4.000mg, 4.125mg, 4.250mg, 4.375mg, 4.500mg, 4.625mg, 4.750mg, 4.875mg, 5.000mg, 5.125mg, 5.250mg, 5.375mg, 5.500 mg, 5.625m
  • the daily dose of the MEK inhibitor is 0.25 mg, 0.375 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.50 mg, 1.75 mg, 2 mg, 2.25 mg, 2.50 mg, 2.75mg, 3mg, 3.25mg, 3.50mg, 3.75mg, 4mg, the frequency of administration is once a day.
  • the daily dosage of the MEK inhibitor is 0.25 mg, and the frequency of administration is once a day.
  • the daily dosage of the MEK inhibitor is 0.375 mg, and the frequency of administration is once a day.
  • the daily dosage of the MEK inhibitor is 0.5 mg, and the frequency of administration is once a day.
  • the daily dosage of the MEK inhibitor is 0.75 mg, and the frequency of administration is once a day.
  • the CDK4/6 inhibitor described in the present disclosure may be selected from palbociclib, FCN-437c, abemaciclib, ribociclib, Alvocidib, trilaciclib, lerociclib, birociclib, PF-06873600, or a compound represented by formula (II) or Its pharmaceutically acceptable salt, preferably the compound represented by formula (II) or its pharmaceutically acceptable salt,
  • the daily dose of the CDK4/6 inhibitor is 1-500 mg, and the frequency of administration is once a day or twice a day.
  • the daily dose of the CDK4/6 inhibitor is selected from 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 2
  • the daily dose of the CDK4/6 inhibitor is selected from 50-200 mg, and the frequency of administration is once a day.
  • the daily dose of the CDK4/6 inhibitor is selected from 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, and the frequency of administration is once a day.
  • the daily dose of the CDK4/6 inhibitor is selected from 75 mg, and the frequency of administration is once a day.
  • the daily dose of the CDK4/6 inhibitor is selected from 100 mg, and the frequency of administration is once a day.
  • the daily dose of the CDK4/6 inhibitor is selected from 125 mg, and the frequency of administration is once a day.
  • the daily dose of the CDK4/6 inhibitor is selected from 150 mg, and the frequency of administration is once a day.
  • the daily dose of the CDK4/6 inhibitor is selected from 175 mg, and the frequency of administration is once a day.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) or the compound represented by formula (II) in this application can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite , Acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, Methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinic acid Salt, gluconate, lactobionate or lauryl sulfonate, etc.
  • the MEK inhibitor is a pharmaceutically acceptable salt of the compound represented by formula (I)
  • the CDK4/6 inhibitor is a pharmaceutically acceptable salt of the compound represented by formula (II).
  • the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is a tosylate salt.
  • the pharmaceutically acceptable salt of the compound represented by formula (II) in the present disclosure is isethionate.
  • the CDK4/6 inhibitor is administered once a day for three weeks and the drug is stopped for one week; the MEK inhibitor is administered once a day for three weeks and the drug is stopped for one week.
  • the CDK4/6 inhibitor is administered once a day for three weeks and the drug is stopped for one week; the MEK inhibitor is administered once a day for four weeks.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, 0.50 mg, and 0.75 mg; CDK4
  • the /6 inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 75 mg, 100 mg, 125 mg, 150 mg or 175 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is 0.25 mg;
  • the CDK4/6 inhibitor is a compound represented by formula (II) The compound is shown or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 75 mg, 100 mg, 125 mg, 150 mg, or 175 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is 0.375 mg;
  • the CDK4/6 inhibitor is a compound represented by formula (II) The compound is shown or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 75 mg, 100 mg, 125 mg, 150 mg, or 175 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is 0.5 mg;
  • the CDK4/6 inhibitor is a compound represented by formula (II) The compound is shown or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 75 mg, 100 mg, 125 mg, 150 mg, or 175 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is 0.75;
  • the CDK4/6 inhibitor is represented by formula (II)
  • the daily dose of the compound or a pharmaceutically acceptable salt thereof is selected from 75 mg, 100 mg, 125 mg, 150 mg or 175 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, 0.50 mg, and 0.75 mg; CDK4
  • the /6 inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is 75 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, 0.50 mg, and 0.75 mg; CDK4
  • the /6 inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is 100 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, 0.50 mg, and 0.75 mg; CDK4
  • the /6 inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is 125 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, 0.50 mg, and 0.75 mg; CDK4
  • the /6 inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is 150 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, 0.50 mg, and 0.75 mg; CDK4
  • the /6 inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is 175 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, and 0.50 mg; CDK4/6 inhibition
  • the agent is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is 100 mg or 175 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, and 0.50 mg; CDK4/6 inhibition
  • the agent is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is 100 mg.
  • the MEK inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and the daily dose is selected from 0.25 mg, 0.375 mg, and 0.50 mg; CDK4/6 inhibition
  • the agent is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and the daily dose is 175 mg.
  • the route of administration is selected from oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes but not Limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • both the MEK inhibitor and the CDK4/6 inhibitor are administered orally.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned MEK inhibitor and CDK4/6 inhibitor.
  • the pharmaceutical composition also contains one or more Pharmaceutical excipients, diluents or carriers.
  • the composition described in the present invention can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), Suppositories, inhalants or sprays.
  • the above-mentioned pharmaceutical composition containing MEK inhibitor and CDK4/6 inhibitor provided in the present disclosure can be used for the treatment of tumors.
  • the present disclosure provides a method for treating tumors, which includes administering to a patient a therapeutically effective amount of the above-mentioned MEK inhibitor and CDK4/6 inhibitor.
  • Another aspect of the present disclosure provides a MEK inhibitor for treating tumors, which is used in combination with a CDK4/6 inhibitor.
  • Another aspect of the present disclosure provides a CDK4/6 inhibitor for treating tumors, the CDK4/6 inhibitor being used in combination with an MEK inhibitor.
  • the route of administration is optionally the same or different, and the route of administration is selected from the group consisting of oral administration and parenteral administration.
  • Drugs and percutaneous administration include but is not limited to intravenous injection, subcutaneous injection, intramuscular injection, and both are preferably administered orally.
  • the "combination" described in the present disclosure is a mode of administration, which refers to the administration of at least one dose of MEK inhibitor and CDK4/6 inhibitor within a certain period of time, in which both drugs show pharmacological effects.
  • the time limit may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • the MEK inhibitor and CDK4/6 inhibitor can be administered simultaneously or sequentially. This period includes treatments in which the MEK inhibitor and the CDK4/6 inhibitor are administered by the same route of administration or different routes of administration.
  • Figure 4B The weight of the tumor tissue after the test compound acts on the HCT116 human colon cancer CDX mouse model transplanted in vivo;
  • FIG. 6A Tumor growth curve after the test compound acts on A549 human lung cancer CDX mice transplanted in vivo;
  • Figure 6B The effect of test compound on the weight of tumor tissue after transplantation of tumor model in A549 human colon cancer CDX mice;
  • FIG. 7A Tumor growth curve after the test compound acts on PAN#039 tumor PDX mice transplanted with tumor model in vivo;
  • Figure 7B The effect of the test compound on the tumor tissue weight after transplanting a tumor model in PAN#039 tumor PDX mice.
  • Example 1 Detecting the anti-proliferative effects of drug A and drug B alone and in combination on three Ras mutant tumor cell lines A549, MIA PaCa-2 and HCT116 in an in vitro drug susceptibility test.
  • Drugs the compound represented by formula (I) tosylate (drug A); the compound represented by formula (II) isethionate (drug B).
  • mice 90 BALB/c nude mice, female, 4-8 weeks old, weighing 18-22g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. (production license: SCXK ( ⁇ ) 2018-0008), qualified License number: 201902032, animal use license number: SYXK (Shanghai) 2015-0015.
  • Drugs the compound represented by formula (I) tosylate (drug A); the compound represented by formula (II) isethionate (drug B).
  • HCT116 cells were cultured in McCoy's 5A medium containing 10% fetal bovine serum (FBS). Collect HCT116 cells in the exponential growth phase, resuspend HBSS to 5 ⁇ 10 7 /mL, and transplant them into BALB/c nude mice subcutaneously under aseptic conditions. Each mouse is inoculated with 0.1mL cell suspension, which is 5 ⁇ 10 6 cells. cell. Observe the mice after inoculation and monitor the growth of tumors.
  • FBS fetal bovine serum
  • the average tumor volume of the tumor-bearing mice in groups reached 123.47mm 3 on the 12th day of inoculation, that is, the grouping and administration observation of the drug efficacy experiment were performed.
  • the specific grouping information is shown in Table 4 below.
  • the main purpose is to detect the growth inhibitory effect or complete cure ability of the tested drug on the subcutaneous transplanted tumor of HCT116 human colon cancer CDX mice.
  • TGI(%) [1-(Ti-T 0 )/(Vi-V 0 )] ⁇ 100
  • T i is the average tumor volume after initiation of the administration group of compounds, T 0 when the mean tumor volume for the first group of compounds administered, V 0 is the mean tumor volume at the first administration of vehicle control group, V i is a vehicle control group began Average tumor volume after administration.
  • T/C weight % T weight /V weight ⁇ 100%
  • T weight is the average tumor weight at the end of the experiment in the compound group
  • V weight is the average tumor weight at the end of the experiment in the vehicle control group.
  • the tumor volume changes, tumor weights and statistical analysis results of the tumor volume changes, tumor weights and statistical analysis results of each treatment group in the anti-tumor efficacy experiment of the HCT116 human colon cancer CDX animal model are shown in Figure 4, Table 6, Table 7 and Table 8.
  • mice in all treatment groups did not experience significant weight loss or other abnormal symptoms, indicating that tumor-bearing mice tolerated all treatments well.
  • Cell line human pancreatic cancer MIA PaCa-2 cells, resuscitated P7+3 generation to start expansion, derived from ATCC, cultured in DMEM medium containing 10% fetal bovine serum (FBS) and 2.5% horse serum.
  • FBS fetal bovine serum
  • mice 100 BALB/c nude mice, female, 4-8 weeks old, weighing 18-22g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. (production license: SCXK ( ⁇ ) 2018-0008), qualified License number: 201901853, animal use license number: SYXK (Shanghai) 2015-0015.
  • Drugs the compound represented by formula (I) tosylate (drug A); the compound represented by formula (II) isethionate (drug B).
  • MIA PaCa-2 human pancreatic cancer tumor cell culture tumor inoculation and group treatment MIA PaCa-2 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS) and 2.5% horse serum. MIA PaCa-2 cells in exponential growth phase were collected, HBSS was resuspended to 5 ⁇ 10 7 /mL, and transplanted into BALB/c nude mice subcutaneously under sterile conditions. Each mouse was inoculated with 0.1mL cell suspension, which is 5 ⁇ 10 6 cells. Observe the mice after inoculation and monitor the growth of tumors.
  • FBS fetal bovine serum
  • the average tumor volume of the tumor-bearing mice in groups reached 122.81 mm3 on the 17th day of inoculation, that is, the grouping of the drug efficacy experiment and the observation of the administration.
  • the specific grouping information is shown in Table 10.
  • N number of animals; administration volume is 10 ⁇ L/g; p.o.: intragastric administration.
  • the drug A 0.3 mg/kg administration group and the drug A 0.3 mg/kg + drug B 30 mg/kg combined administration group were both It showed a statistically significant inhibitory effect on tumor growth (P ⁇ 0.05).
  • the drug A 0.3 mg/kg + drug B 30 mg/kg combined administration group showed a statistically more significant inhibitory effect on tumor growth (P ⁇ 0.05) , And both have obvious synergistic effects (Q>1).
  • mice in each treatment group were euthanized and the tumors were stripped and weighed.
  • mice in all treatment groups did not experience significant weight loss or other abnormal symptoms, indicating that tumor-bearing mice tolerated all treatments well.
  • Example 4 The pharmacodynamic study of the tested drug on the subcutaneous transplanted tumor model of A549 human lung cancer CDX mice
  • Cell line human lung cancer A549 cells, resuscitated at generation P1 to start expansion, derived from ATCC, cultured in F-12K medium containing 10% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • mice 95 BALB/c nude mice, female, 4-8 weeks old, weighing 18-22g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. (production license: SCXK ( ⁇ ) 2018-0008), qualified License number: 201901374, animal use license number: SYXK (Shanghai) 2015-0015.
  • Drugs the compound represented by formula (I) tosylate (drug A); the compound represented by formula (II) isethionate (drug B).
  • A549 human lung cancer cells were cultured in F-12K medium containing 10% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • A549 cells in the exponential growth phase were collected, resuspended in HBSS to 5 ⁇ 107/mL, diluted with Matrigel at a ratio of 1:1, and then transplanted into BALB/c nude mice subcutaneously under aseptic conditions, and each mouse was inoculated with 0.2 mL
  • the cell suspension (containing 50% Matrigel) is 5 ⁇ 106 cells. Observe the mice after inoculation and monitor the growth of tumors.
  • the average tumor volume of the tumor-bearing mice reached 124.57 mm 3 in groups at 6 days of inoculation, that is, the grouping and administration observation of the drug efficacy experiment were performed.
  • the specific groups are as follows in Table 14.
  • N number of animals; administration volume is 10 ⁇ L/g; p.o.: intragastric administration.
  • the main purpose is to detect the growth inhibitory effect or complete cure ability of the tested drug on the subcutaneous transplanted tumor of A549 human lung cancer CDX mice.
  • the tumor volume changes, tumor weights and statistical analysis results of the tumor volume changes, tumor weights and statistical analysis results of each treatment group in the anti-tumor efficacy experiment of the A549 human lung cancer CDX animal model are shown in Figure 6, Table 15, Table 16, and Table 17.
  • T/C weight is basically the same as the overall trend of T/C.
  • mice in all treatment groups did not experience significant weight loss or other abnormal symptoms, indicating that tumor-bearing mice tolerated all treatments well.
  • CDK4/6 inhibitor drug B compound isethionate represented by formula (II)
  • MEK inhibitor drug A compound tosylate represented by formula (I)
  • the second phase of the study purpose to observe and evaluate the effectiveness and safety of CDK4/6 inhibitor drug B combined with MEK inhibitor drug A in the treatment of KRAS mutations in advanced or metastatic colorectal cancer/pancreatic cancer
  • the study is divided into two phases, the first phase is the combined dose exploration phase, and the second phase is the curative effect expansion phase.
  • the first stage Dose exploratory research
  • 4 weeks is a cycle.
  • set a fixed dose of drug B, 125mg qd, po take the drug for 3 weeks and stop the drug for 1 week/4 weeks, and drug A will follow the 0.25mg ⁇ 0375mg ⁇ 0.5mg gradient (qd, po, stop taking the drug for 3 weeks) Drug 1 week/4 weeks) to explore the dose.
  • drug B 125mg qd, po, taking the drug for 3 weeks and stopping the drug for 1 week/4 weeks + drug A 0.25mg qd, po, taking the drug for 3 weeks and stopping the drug for 1 week/4 weeks dose level is intolerable, adjust the drug B to 100mg qd, po, medication for 3 weeks and withdrawal for 1 week/4 weeks, drug A follows the 0.25mg ⁇ 0375mg ⁇ 0.5mg gradient (qd, po, medication for 3 weeks and withdrawal for 1 week/4 weeks) for the combined dose exploration.
  • the second stage Curative effect expansion stage: After the first stage of the trial is completed, the combined dose of the two will be determined. Enrolled 20 to 30 patients with advanced or metastatic KRAS mutation colorectal cancer/pancreatic cancer to initially explore the efficacy and safety of the combined regimen.
  • drug B will be stopped at the determined dose qd, po for 3 weeks for 1 week/4 weeks + drug A will be stopped for 3 weeks at the determined dose, qd, po
  • the medication is administered for 1 week/4 weeks, and the medication is continued until an event that meets the treatment termination criteria occurs.
  • the first phase of the study DLT observation period is the first cycle of the combination medication (4 weeks)
  • DLT definition Toxicity related to the study drug that occurred during the DLT observation period and meets any of the following conditions
  • Retinal vein occlusion RVO
  • uveitis uveitis
  • other serious ocular toxicities of grade 2 and above as determined by the investigator, such as central serous chorioretinopathy (CSR), retinal detachment, and retina Pigment epithelial detachment, optic nerve papillitis, etc. and including these ocular toxicities that cause macular edema, visual disturbances and blurred vision;
  • Drug B and/or Drug A stopped for more than 14 days due to related toxicity.
  • the subject is clinically diagnosed and pathologically confirmed KRAS mutant colorectal cancer/pancreatic cancer, advanced or metastatic tumors have failed standard treatment (disease progression or intolerance, such as chemotherapy, targeted therapy, immunotherapy, etc.), or Lack of effective treatments.
  • phase I plans to recruit 6-18 subjects to determine the MTD.
  • Phase II plans to recruit 20-30 subjects.
  • Test drug 1 Compound tosylate of formula (I) (drug A); manufacturer: Jiangsu Hengrui Pharmaceutical Co., Ltd.; dosage form: tablet; route of administration: oral; specification: 0.125 mg tablet, 0.5 mg /Tablet, 2mg/tablet.
  • Test drug 2 Isethionate of the compound represented by formula (II) (drug B); manufacturer: Jiangsu Hengrui Pharmaceutical Co., Ltd.; dosage form: tablet; route of administration: oral; specification: 25 mg/tablet, 50mg/tablet, 125mg/tablet.
  • Whether it is the first stage or the second stage, to screen suitable subjects is to receive drug B and drug A treatment.
  • Drug B oral, once a day for 21 consecutive days, stop for 7 days, 28 days as a treatment cycle.
  • Drug A taken orally 2 hours after a meal, once a day for 21 consecutive days, stopping for 7 days, 28 days as a treatment cycle.
  • the first cycle of the first phase of the study in principle, it is not allowed to adjust the dose of drug A and drug B, and the dose can be adjusted according to toxicity in subsequent cycles.
  • the second phase of the study allows for dose adjustments during the course of the study.
  • the dose is suspended first.
  • the investigator judges that drug A or drug B can continue to take the drug at the original dose or down by one dose level.
  • the downward gradient of drug B dose was 100 and 75 mg qd. If the toxicity of drug B or drug A cannot be restored to grade ⁇ 1 more than 21 days after the drug is stopped, the subject needs to terminate drug B or drug A treatment, and observe the recovery of toxicity.
  • the investigator judges that the subject can benefit from drug A single drug or drug B single drug treatment, and the subject can still receive the above-mentioned corresponding treatment.
  • Drug B dose reduction 1) When the dose is 125mg or 100mg, the dose reduction/dose suspension or termination is allowed; 2) The down-regulation gradient is 100 and 75mg qd. 75mg is the lowest dose, and it is not allowed to continue to decrease, but the dose is allowed to be suspended or terminated.
  • Drug A dose reduction 1) When the dose is 0.5 mg or 0.375 mg, the dose is allowed to be reduced, and the dose is suspended or terminated; 2) The downward gradient is 0.375 mg and 0.25 mg qd. 0.25mg is the lowest dose, and it is not allowed to continue to decrease, but the dose is allowed to be suspended or terminated.
  • Phase I study MTD of drug A in combination therapy
  • Phase II study Objective response rate (ORR)
  • DCR Disease Control Rate
  • PFS Progression-free survival
  • AE adverse events
  • SAE serious adverse events
  • Example 6 Evaluation and comparison of the therapeutic effects of drug A and drug B administered alone or in combination in the human pancreatic cancer PDX model PAN#039 nude mouse xenograft tumor model
  • mice mice, species: BALB/c nude mice; sex: female; age: 7-8 weeks; body weight: 20 g ⁇ 20%.
  • the mice are divided into groups by random block method, 8 mice in each group
  • PAN#039 is a 69-year-old male patient with pancreatic ductal adenocarcinoma (use P6).
  • Drug configuration 1% Tween-80+0.5% CMC-Na; drug A configuration solvent: 0.05% DMSO and 0.5% CMC-Na; drug B configuration solvent: 0.05M citric acid+0.5% CMC+0.5% Tween-80.
  • the dosage regimen is shown in Table 20.
  • PAN#039 tumors with a size of 600-800mm 3 , remove necrotic tissue and connective tissue, and cut them into tumor tissue pieces with a size of 15-30mm 3 ; 2) anesthetize the mouse; 3) transplant the tumor; 4) PAN# 039 37 days after tumor transplantation, 72 mice with a tumor volume of 150-255 mm3 were selected, and the animals were grouped according to the random block method, so that the tumor volume difference in each group was less than 5% of the average, with 8 mice in each group.
  • T/C The relative tumor proliferation rate T/C (%) is used to calculate the criteria for the inhibitory effect of drugs on tumor growth as follows: drugs have a significant inhibitory effect on tumors: T/C (%) ⁇ 40%, and P ⁇ 0.05; drugs have no effect on tumors Significant inhibition: T/C(%)>40%.
  • Table 23 Relative tumor proliferation rate and tumor growth inhibition rate (TGI%) of the tested drugs on the human pancreatic cancer PDX model PAN#039

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Abstract

一种MEK抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤的药物中的用途。具体地，所述MEK抑制剂选自式(I)所示化合物或其可药用盐，所述CDK4/6抑制剂选自式(II)所示化合物或其可药用盐。

Description

一种MEK抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤的药物中的用途
本申请要求申请日为2019年9月11日的中国专利申请CN201910859697.0的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种MEK抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤的药物中的用途，属于制药领域。
背景技术
恶性肿瘤的发生和发展与细胞内信号传导通路的异常持续激活密切相关。有丝分裂原活化的蛋白激酶(Mitogen-Activated Protein Kinase,MAPK)组成的信号通路调控着细胞的多个重要生理过程，在脊椎动物以及所有的多细胞生物中共有4条MAPK通路，其中ERK途径(RAS-RAF-MEK1/2-ERK1/2)是在人类肿瘤中最常发生级联信号失调的一条经典的MAPK信号通路。ERK通路的异常激活通常是由RAS和RAF基因家族成员的获得性突变导致，比如33％的胆管癌，36％的大肠癌，19％的肺癌，18％的膀胱癌，63％的胰腺癌，15％的前列腺癌存在RAS编码基因(主要是KRAS,NRAS和HRAS)的突变，但是目前FDA尚未批准有效的用于治疗RAS突变的方法。
MEK(MEK1和MEK2)是ERK通路上的一种丝/苏氨酸和酪氨酸双功能激酶，可被上游的RAS和RAF激酶磷酸化，激活后将信号传导至下游，最终可以磷酸化一些核心的转录因子，从而参与细胞增殖与分化的调控。所以抑制MEK的磷酸化可以阻止信号的进一步传导，从而达到抑制信号通路持续活化、抑制肿瘤生长的作用。
目前已公开了一系列MEK抑制剂，其中WO2015058589公开了其结构和制备方法，体外研究显示其具有较好的肿瘤抑制活性，具体结构如式(I)所示，
Figure PCTCN2020114385-appb-000001
CN106795116A公开了式(I)所示化合物的对甲苯磺酸盐及晶型。
细胞周期蛋白依赖性激酶(Cyclin-dependent kinase，CDK)是一类丝氨酸/苏氨酸激酶，通过与相应的细胞周期蛋白(Cyclin)形成二聚体，进而磷酸化下游蛋白分子，从而推动细胞周期各时相的有序行进，实现细胞生长和增殖。目前，国外已有多种CDK4/6选择性抑制剂在临床试验阶段或已获批上市，其中包括辉瑞公司的Palbociclib、诺华公司的Ribociclib及礼来公司的Abemaciclib等。
WO2014183520公开了一种化学名为6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮，结构式如式(II)所示的CDK4/6抑制剂，其具有显著的CDK4/6的抑制活性和高度选择性，
Figure PCTCN2020114385-appb-000002
WO2016124067A公开了上述式(I)所示化合物的羟乙基磺酸盐及其制备方法。
发明内容
本公开提供一种MEK抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤的药物中的用途。
本公开所述的肿瘤选自结直肠癌、胆道癌、膀胱癌、乳腺癌、宫颈癌、结肠癌、甲状腺癌、睾丸癌、胃癌、肝细胞癌、胰腺癌、前列腺癌、黑色素瘤、淋巴瘤、肺癌、血管肉瘤、平滑肌肉瘤、脂肪肉瘤、横纹肌肉瘤、粘液瘤、恶性纤维组织细胞瘤、造血系统恶性肿瘤、神经母细胞瘤、头颈部癌、子宫内膜癌、大肠癌、食管癌、卵巢癌、唾液腺癌、小肠癌、胸腺癌、中枢神经系统肿瘤、骨癌、肾上腺腺瘤、肾细胞癌、神经母细胞瘤。
本公开中所述胆道癌具体可以是肝内胆管癌、肝外胆管癌或胆囊癌；所述的甲状腺癌具体可以是甲状腺滤泡癌、甲状腺未分化癌、甲状腺乳头状癌、甲状腺Hurthle细胞癌；所述的淋巴瘤具体可以是伯基特氏淋巴瘤、霍奇金淋巴瘤、浆细胞骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、急性淋巴细胞白血病；所述的肺癌可以是非小细胞肺癌、小细胞肺癌、所述的非小细胞肺癌可以是腺癌、鳞癌或大细胞癌；所述的造血系统恶性肿瘤可以是急性髓性白血病、慢性粒细胞白血病、慢性粒单核细胞白血病、幼年型髓单核细胞白血病。
本公开可选的实施方案中，所述肿瘤为Ras基因突变肿瘤，具体可以为KRAS基因和/或NRAS基因和/或HRAS基因突变。
本公开中可选的实施方案中，所述肿瘤为晚期或者转移性的Ras基因突变肿瘤。
本公开可选的实施方案中，所述MEK抑制剂选自AZD-8330、GDC-0623、CI-1040、WX-554、TAK-733、SL-327、APS-2-79、BI-847325、HL-085、BI-847325、CEP-1347、U-0126、Binimetinib、Pimasertib、Cobimetinib、PD-0325901、PD-318088、RO-5126766、BIX-02189、BIX-02188、PD-98059、Trametinib、Refametinib、AS-703988、E-6201、Selumetinib、或式(I)所示化合物或其可药用盐，
Figure PCTCN2020114385-appb-000003
本公开的一些实施方案中，所述MEK抑制剂为式(I)所示化合物或其可药用盐。
在一些实施方案中，所述MEK抑制剂的每日剂量范围选自0.01-500mg，给药频次为每日2次、每日1次、每2天1次、每3天一次。
在一些实施方案中，本公开中所述MEK抑制剂的每日剂量选自0.1mg、0.125mg、0.25mg、0.5mg、0.75mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、30mg、45mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、400mg、500mg，优选0.25mg、0.5mg、1mg、2mg、3mg、4mg、10mg、15mg、20mg、30mg、45mg、50mg、60mg、75mg、100mg；给药频次为每日2次、每日1次、每2天1次、每3天一次，优选每日2次或每日1次，最优选每日1次。
在一些实施方案中，所述MEK抑制剂的每日剂量范围选自0.125mg-10mg，给药频次为每日1次。
在一些实施方案中，所述MEK抑制剂的每日剂量范围选自0.125mg-4mg，给药频次为每日1次。
在一些实施方案中，所述MEK抑制剂的每日剂量选自0.100mg、0.125mg、0.250mg、0.375mg、0.500mg、0.625mg、0.750mg、0.875mg、1.000mg、1.125mg、1.250mg、1.375mg、1.500mg、1.625mg、1.750mg、1.875mg、2.000mg、2.125mg、2.250mg、2.375mg、2.500mg、2.625mg、2.750mg、2.875mg、3.000mg、3.125mg、3.250mg、3.375mg、3.500mg、3.625mg、3.750mg、3.875mg、4.000mg、4.125mg、4.250mg、 4.375mg、4.500mg、4.625mg、4.750mg、4.875mg、5.000mg、5.125mg、5.250mg、5.375mg、5.500mg、5.625mg、5.750mg、5.875mg、6.000mg、6.125mg、6.250mg、6.375mg、6.500mg、6.625mg、6.750mg、6.875mg、7.000mg、7.125mg、7.250mg、7.375mg、7.500mg、7.625mg、7.750mg、7.875mg、8.000mg、8.125mg、8.250mg、8.375mg、8.500mg、8.625mg、8.750mg、8.875mg、9.000mg、9.125mg、9.250mg、9.375mg、9.500mg、9.625mg、9.750mg、9.875mg、10.000mg，给药频次为每日1次。
可选的实施方案中，所述的MEK抑制剂每日给药剂量为0.25mg、0.375mg、0.5mg、0.75mg、1mg、1.25mg、1.50mg、1.75mg、2mg、2.25mg、2.50mg、2.75mg、3mg、3.25mg、3.50mg、3.75mg、4mg，给药频次为每日1次。
在一些实施方案中，所述的MEK抑制剂每日给药剂量为0.25mg，给药频次为每日1次。
在一些实施方案中，所述的MEK抑制剂每日给药剂量为0.375mg，给药频次为每日1次。
在一些实施方案中，所述的MEK抑制剂每日给药剂量为0.5mg，给药频次为每日1次。
在一些实施方案中，所述的MEK抑制剂每日给药剂量为0.75mg，给药频次为每日1次。
在一些实施方案中，本公开所述的CDK4/6抑制剂可选自palbociclib、FCN-437c、abemaciclib、ribociclib、Alvocidib、trilaciclib、lerociclib、birociclib、PF-06873600，或式(II)所示化合物或其可药用盐，优选式(II)所示化合物或其可药用盐，
Figure PCTCN2020114385-appb-000004
一些实施方案中，所述的CDK4/6抑制剂每日剂量为1-500mg，给药频次为每日一次或每日两次。
可选的实施方案中，所述的CDK4/6抑制剂每日剂量选自5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、 195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg，给药频次为每日一次或每日两次。
可选的实施方案中，所述的CDK4/6抑制剂每日剂量选自50-200mg，给药频次为每日一次。
可选的实施方案中，所述的CDK4/6抑制剂每日剂量选自50mg、75mg、100mg、125mg、150mg、175mg、200mg，给药频率为每日一次。
可选的实施方案中，所述的CDK4/6抑制剂每日剂量选自75mg，给药频率为每日一次。
可选的实施方案中，所述的CDK4/6抑制剂每日剂量选自100mg，给药频率为每日一次。
可选的实施方案中，所述的CDK4/6抑制剂每日剂量选自125mg，给药频率为每日一次。
可选的实施方案中，所述的CDK4/6抑制剂每日剂量选自150mg，给药频率为每日一次。
可选的实施方案中，所述的CDK4/6抑制剂每日剂量选自175mg，给药频率为每日一次。
本申请中所述式(I)所示化合物或式(II)所示化合物的药学上可接受的盐可以是盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。
在一些实施方案中所述MEK抑制剂为式(I)所示化合物的药学上可接受的盐，所述CDK4/6抑制剂为式(II)所示化合物的药学上可接受的盐。
在一些实施方案中，本公开中式(I)所示化合物的药学上可接受的盐为甲苯磺酸盐。
在一些实施方案中，本公开中式(II)所示化合物的药学上可接受的盐为羟乙基磺酸盐。
可选的实施方案中，CDK4/6抑制剂每日一次给药，给药三周，停药一周；MEK抑制剂每日一次给药，给药三周，停药一周。
可选的实施方案中，CDK4/6抑制剂每日一次给药，给药三周，停药一周；MEK抑制剂每日一次给药，给药四周。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg、0.75mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量选自75mg、100mg、125mg、150mg或175mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量为0.25mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量选自75mg、100mg、125mg、150mg或175mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量为0.375mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量选自75mg、100mg、125mg、150mg或175mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量为0.5mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量选自75mg、100mg、125mg、150mg或175mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量为0.75；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量选自75mg、100mg、125mg、150mg或175mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg、0.75mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量为75mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg、0.75mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量为100mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg、0.75mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量为125mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg、0.75mg；CDK4/6抑制剂为式 (II)所示化合物或其药学上可接受的盐，每日剂量为150mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg、0.75mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量为175mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量为100mg或175mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量为100mg。
在一些实施方案中，本公开提供的用途，MEK抑制剂为式(I)所示化合物或其药学上可接受的盐，每日剂量选自0.25mg、0.375mg、0.50mg；CDK4/6抑制剂为式(II)所示化合物或其药学上可接受的盐，每日剂量为175mg。
本公开中所述MEK抑制剂与CDK4/6抑制剂联合给药时，给药途径选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
可选的实施方案中，MEK抑制剂与CDK4/6抑制剂均口服给药。
本公开提供一种包含上述MEK抑制剂与CDK4/6抑制剂的药物组合物，所述药物组合物除含有MEK抑制剂与CDK4/6抑制剂作为活性成分外，另含有一种或多种可药用的赋型剂、稀释剂或载体。本发明中所述的组合物可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本公开提供的上述含MEK抑制剂与CDK4/6抑制剂的药物组合物可用于治疗肿瘤。
本公开提供一种治疗肿瘤的方法，包括给与患者治疗有效量的上述MEK抑制剂与CDK4/6抑制剂。
本公开另一方面提供一种用于治疗肿瘤的MEK抑制剂，所述MEK抑制剂与CDK4/6抑制剂联合使用。
本公开另一方面提供一种用于治疗肿瘤的CDK4/6抑制剂，所述CDK4/6抑制剂与MEK抑制剂联用。
本公开提供的治疗肿瘤的方法，所述MEK抑制剂与CDK4/6抑制剂联合给药时，给药途径任选相同或者不同，所述给药途径选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射，优选二者均经口给药。
本公开中所述的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的MEK抑制剂和CDK4/6抑制剂，其中两种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内。可以同时或依次给予MEK抑制剂和CDK4/6抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予给予MEK抑制剂和CDK4/6抑制剂。
附图说明
图1.细胞系A549抑制曲线图；
图2.细胞系MIA PaCa-2抑制曲线图；
图3.细胞系HCT116抑制曲线图；
图4A.受试化合物作用于HCT116人源结肠癌CDX小鼠体内移植肿瘤模型后的肿瘤生长曲线(n＝8)；
图4B.受试化合物作用于HCT116人源结肠癌CDX小鼠体内移植肿瘤模型后肿瘤组织重量；
图5.受试化合物作用于MIA PaCa-2人源胰腺癌CDX小鼠体内移植肿瘤模型后的肿瘤生长曲线；
图6A.受试化合物作用于A549人源肺癌CDX小鼠体内移植肿瘤模型后的肿瘤生长曲线；
图6B.受试化合物作用A549人源结肠癌CDX小鼠体内移植肿瘤模型后肿瘤组织重量；
图7A.受试化合物作用于PAN#039肿瘤PDX小鼠体内移植肿瘤模型后的肿瘤生长曲线；
图7B.受试化合物作用PAN#039肿瘤PDX小鼠体内移植肿瘤模型后肿瘤组织重量。
具体实施方式
以下结合实施例用于进一步描述本申请，但这些实施例并非限制本申请的范围。
实施例1、检测药物药物A和药物B单独用药以及联合用药在体外药敏实验中对3株Ras突变肿瘤细胞系A549，MIA PaCa-2和HCT116的抗增殖作用。
1、实验材料
细胞株：A549,MIA PaCa-2,HCT116
药物：式(I)所示化合物甲苯磺酸盐(药物A)；式(II)所示化合物羟乙基磺酸盐(药物B)。
2、实验方法
复苏细胞并传代2次后，待细胞生长铺展面积达80％-90％时，使用胰酶将肿瘤细胞系A549，MIA PaCa-2和HCT116消化成单个细胞，依据细胞生长特点接种合适的细胞数到96孔板中，并放入37℃，5％二氧化碳培养箱中培养过夜，次日分别混合不同浓度的药物(药物A和药物B)，将96孔板放置于二氧化碳培养箱中培养3或4天，用CTG测定每个板孔中的细胞ATP含量，计算不同药物浓度的抑制率并绘制抑制曲线。
3、实验结果
3.1细胞抑制实验
在Ras突变肺癌A549，胰腺癌MIA PaCa-2，结直肠癌HCT116上进行药效实验，如图1-3，两药联用抑制细胞的生长，效果显著优于单药。
3.2协同抑制实验(CI，Combination Index)
表1.A549细胞株CI结果
Figure PCTCN2020114385-appb-000005
表2.MIA PaCa-2细胞株CI结果
Figure PCTCN2020114385-appb-000006
Figure PCTCN2020114385-appb-000007
表3.HCT116细胞株CI结果
Figure PCTCN2020114385-appb-000008
根据表1-3，CI计算结果表明在临床稳态药物浓度Css(药物A:0.03μM),Css(药物B:0.16μM)范围的协同效果明显，有一定抑制效果。
实施例2、受试药物对HCT116人源结肠癌CDX小鼠皮下移植瘤模型的药效学研究
1、实验材料
细胞株：人源结肠癌HCT116细胞，复苏P4+1代开始扩增，来源于ATCC，培养于含10％胎牛血清(FBS)的McCoy’s 5A培养液中。
实验动物：90只BALB/c nude小鼠，雌性，周龄4-8周，体重18-22g，购买于江苏集萃药康生物科技有限公司(生产许可：SCXK(苏)2018-0008)，合格证号：201902032，动物使用许可证号：SYXK(沪)2015-0015。
药物：式(I)所示化合物甲苯磺酸盐(药物A)；式(II)所示化合物羟乙基磺酸盐(药物B)。
2、实验步骤及方法
2.1 HCT116人源结肠癌肿瘤细胞的培养、肿瘤接种和分组治疗
将HCT116细胞培养在含10％胎牛血清(FBS)的McCoy’s 5A培养液中。收集指数生长期的HCT116细胞，HBSS重悬至5×10 7/mL，无菌条件下，移植于BALB/c nude 小鼠皮下，每只小鼠接种0.1mL细胞悬液即5×10 6个细胞。观察接种后小鼠并监测肿瘤的生长。
药效实验，在接种12天时分组用荷瘤小鼠平均肿瘤体积达到123.47mm 3，即进行药效实验的分组和给药观察，具体分组信息如下表4。
表4.药效实验给药和治疗
Figure PCTCN2020114385-appb-000009
注：N：动物只数；给药体积为10μL/g；p.o.：灌胃给药。
2.2受试药物的溶剂和配制(见表5)
表5.受试药物配制
Figure PCTCN2020114385-appb-000010
2.3评估指标及数据分析
主要是检测受试药物对HCT116人源结肠癌CDX小鼠皮下移植瘤的生长抑制作用或完全治愈能力。
2.3.1肿瘤体积和荷瘤鼠体重测量：使用游标卡尺每周两次测量，肿瘤体积计算公式为V＝0.5a×b 2，a，b分别代表肿瘤的长径和宽径；
2.3.2肿瘤生长抑制率TGI(％)＝[1-(Ti-T 0)/(Vi-V 0)]×100
T i为化合物组开始给药后的平均肿瘤体积，T 0为化合物组首次给药时的平均肿瘤体积，V 0为溶媒对照组首次给药时的平均肿瘤体积，V i为溶媒对照组开始给药后的平均肿瘤体积。
2.3.3相对肿瘤增殖率T/C(％)：计算公式如下：T/C％＝100-[1-(Ti-T 0)/(Vi-V 0)]×100，其中Ti为化合物组开始给药后的平均肿瘤体积，T0为化合物组首次给药时的平均肿瘤体积，V0为溶媒对照组首次给药时的平均肿瘤体积，Vi为溶媒对照组开始给药后的平均肿瘤体积。
2.3.4联合给药组增效效应：金氏公式Q＝E(a+b)/[Ea+Eb-Ea×Eb]，Ea为单药TGI，Q值>1反映药物联用具有增效效应。
2.3.5所有荷瘤鼠体重每周测量两次。同时计算给药后小鼠体重相对变化比率：RCBW(％)＝(BW i–BW 0)/BW 0×100，BW i为开始给药后的平均体重，BW 0为首次给药时的平均体重；
2.3.6实验结束后肿瘤照片和肿瘤块的重量。T/C weight％＝T weight/V weight×100％，T weight为化合物组实验结束时的平均肿瘤重量，V weight为溶媒对照组实验结束时的平均肿瘤重量。
所有数据均采用Mean±SEM表示，用One-way ANOVA LSD test比较治疗组肿瘤体积和瘤重与对照组相比有无显著性差异；用Student’s t test比较单药治疗组和联合治疗组两组之间有无显著性差异。所有的数据均用Graphpad进行分析。p<0.05即认为具有显著性差异。
3、实验结果
3.1肿瘤体积
受试药物作用于HCT116人源结肠癌CDX动物模型的抗肿瘤药效实验中的各治疗组肿瘤体积变化、肿瘤重量以及统计分析结果见图4、表6、表7和表8。
表6.肿瘤体积(mm 3)(Mean±SEM)
Figure PCTCN2020114385-appb-000011
Figure PCTCN2020114385-appb-000012
注：用One-way ANOVA LSD test比较治疗组肿瘤体积与对照组相比有无显著性差异，*P<0.05，**P<0.01，***P<0.001，与空白比较。
表7.联合给药组与单药组相比较的统计学分析结果(第21天)
Figure PCTCN2020114385-appb-000013
注：用Student’s t test比较相应单药治疗组和联合治疗组两组之间有无显著性差异，▲P<0.05，▲▲P<0.01，▲▲▲P<0.001，与药物B 30mg/kg单药组比较；▼P<0.05，▼▼P<0.01，与药物A 0.3mg/kg单药组比较。
表8.肿瘤块重量(g)(Mean±SEM)
Figure PCTCN2020114385-appb-000014
注：用One-way ANOVA LSD test比较治疗组肿瘤瘤重与对照组相比有无显著性差异，*P<0.05，**P<0.01，***P<0.001，与空白比较。
在第一次给药开始后第21天，肿瘤体积方面，与空白l组比较，药物B 30mg/kg给药组、药物A 0.3mg/kg给药组、药物A 0.3mg/kg+药物B 30mg/kg联合给药组均表现出统计学上明显的抑制肿瘤生长的作用(P<0.05)。此外，相比于相应各单药组的抗肿瘤药效学结果，药物A 0.3mg/kg+药物B 30mg/kg联合给药组表现出统计学上更加明显的抑制肿瘤生长作用(P<0.05)，并且均具有明显的增效效应(Q>1)。
实验结束后(第22天)，所有治疗小鼠被安乐死处理，剥离荷瘤鼠皮下移植瘤块并进行称量，肿瘤块平均重量方面，与空白组相比较，药物B 30mg/kg给药组、药物A  0.3mg/kg给药组、药物A 0.3mg/kg+药物B 30mg/kg联合给药组显示出统计学上明显抑制肿瘤生长的作用。T/Cweight与T/C总体趋势一致。
3.2小鼠体重
各治疗组的相对体重变化的结果见表9。本次实验过程中，所有治疗组小鼠均没有出现体重明显下降和其他异常症状，表明荷瘤小鼠对所有治疗均耐受性良好。
表9.治疗小鼠体重变化(Mean±SEM)
Figure PCTCN2020114385-appb-000015
实施例3、受试药物对MIA PaCa-2人源胰腺癌CDX小鼠皮下移植瘤模型的药效学研究
1、实验材料
细胞株：人源胰腺癌MIA PaCa-2细胞，复苏P7+3代开始扩增，来源于ATCC，培养于含10％胎牛血清(FBS)及2.5％马血清的DMEM培养液中。
实验动物：100只BALB/c nude小鼠，雌性，周龄4-8周，体重18-22g，购买于江苏集萃药康生物科技有限公司(生产许可：SCXK(苏)2018-0008)，合格证号：201901853，动物使用许可证号：SYXK(沪)2015-0015。
药物：式(I)所示化合物甲苯磺酸盐(药物A)；式(II)所示化合物羟乙基磺酸盐(药物B)。
2、实验步骤及方法
2.1 MIA PaCa-2人源胰腺癌肿瘤细胞的培养、肿瘤接种和分组治疗将MIA PaCa-2细胞培养在含10％胎牛血清(FBS)及2.5％马血清的DMEM培养液中。收集指数生长期的MIA PaCa-2细胞，HBSS重悬至5×10 7/mL，无菌条件下，移植于BALB/c nude小鼠皮下，每只小鼠接种0.1mL细胞悬液即5×10 6个细胞。观察接种后小鼠并监测肿瘤的生长。
药效实验，在接种17天时分组用荷瘤小鼠平均肿瘤体积达到122.81mm3，即进行药效实验的分组和给药观察，具体分组信息如下表10。
表10.药效实验给药和治疗
Figure PCTCN2020114385-appb-000016
注：N：动物只数；给药体积为10μL/g；p.o.：灌胃给药。
2.2受试药物的溶剂和配制如实施例1。
2.3评估指标及数据分析
主要是检测受试药物对MIA PaCa-2人源胰腺癌CDX小鼠皮下移植瘤的生长抑制作用或完全治愈能力。
评估指标及数据分析同实施例1。
3、实验结果
3.1肿瘤体积
受试药物作用于MIA PaCa-2人源胰腺癌CDX动物模型的抗肿瘤药效实验中的各治疗组肿瘤体积变化、以及统计分析结果见图5、表11、表12和表13。
表11.肿瘤体积(mm 3)(Mean±SEM)
Figure PCTCN2020114385-appb-000017
注：用One-way ANOVA LSD test比较治疗组肿瘤体积与对照组相比有无显著性差异，*P<0.05，**P<0.01，***P<0.001，与空白比较。
表12.联合给药组与单药组相比较的统计学分析结果(第55天)
Figure PCTCN2020114385-appb-000018
Figure PCTCN2020114385-appb-000019
注：用Student’s t test比较相应单药治疗组和联合治疗组两组之间有无显著性差异，▲P<0.05，▲▲P<0.01，▲▲▲P<0.001，与药物B 30mg/kg单药组比较；▼P<0.05，▼▼P<0.01，与药物A 0.3mg/kg单药组比较。
在第一次给药开始后第55天，就平均肿瘤体积而言，与空白组比较，药物A 0.3mg/kg给药组、药物A 0.3mg/kg+药物B 30mg/kg联合给药组均表现出统计学上明显地抑制肿瘤生长的作用(P<0.05)。此外，相比于相应各单药组的抗肿瘤药效学结果，药物A 0.3mg/kg+药物B 30mg/kg联合给药组表现出统计学上更加明显的抑制肿瘤生长作用(P<0.05)，并且均具有明显的增效效应(Q>1)。
实验结束后，各治疗组小鼠分别被实施安乐死并剥离肿瘤称重。
3.2小鼠体重
各治疗组的相对体重变化的结果见表13。本次实验过程中，所有治疗组小鼠均没有出现体重明显下降和其他异常症状，表明荷瘤小鼠对所有治疗均耐受性良好。
表13.治疗小鼠体重变化(Mean±SEM)
Figure PCTCN2020114385-appb-000020
实施例4、受试药物对A549人源肺癌CDX小鼠皮下移植瘤模型的药效学研究
1、实验材料
细胞株：人源肺癌A549细胞，复苏P1代开始扩增，来源于ATCC，培养于含10％胎牛血清(FBS)的F-12K培养液中。
实验动物：95只BALB/c nude小鼠，雌性，周龄4-8周，体重18-22g，购买于江苏集萃药康生物科技有限公司(生产许可：SCXK(苏)2018-0008)，合格证号：201901374，动物使用许可证号：SYXK(沪)2015-0015。
药物：式(I)所示化合物甲苯磺酸盐(药物A)；式(II)所示化合物羟乙基磺酸盐(药物B)。
2、实验步骤及方法
2.1人源肺癌肿瘤细胞的培养、肿瘤接种和分组治疗
将A549人源肺癌细胞培养在含10％胎牛血清(FBS)的F-12K培养液中。收集指数生长期的A549细胞，HBSS重悬至5×107/mL，按照1:1比例用Matrigel进行稀释，随后无菌条件下移植于BALB/c nude小鼠皮下，每只小鼠接种0.2mL细胞悬液(含50％Matrigel)即5×106个细胞。观察接种后小鼠并监测肿瘤的生长。
药效实验，在接种6天时分组用荷瘤小鼠平均肿瘤体积达到124.57mm 3，即进行药效实验的分组和给药观察，具体分组如下表14。
表14.药效实验给药和治疗
Figure PCTCN2020114385-appb-000021
注：N：动物只数；给药体积为10μL/g；p.o.：灌胃给药。
2.2受试药物的溶剂和配制
从药物A 0.03mg/mL溶液中吸出14mL，再使用28mL溶媒对照1进行稀释，最终得到42mL药物A 0.01mg/mL澄清透明溶液，其余同实施例1。
2.3评估指标及数据分析
主要是检测受试药物对A549人源肺癌CDX小鼠皮下移植瘤的生长抑制作用或完全治愈能力。
评估指标及数据分析同实施例1。
3、实验结果
3.1肿瘤体积
受试药物作用于A549人源肺癌CDX动物模型的抗肿瘤药效实验中的各治疗组肿瘤体积变化、肿瘤重量以及统计分析结果见图6、表15、表16和表17。
表15.肿瘤体积(mm 3)(Mean±SEM)
Figure PCTCN2020114385-appb-000022
注：用One-way ANOVA LSD test比较治疗组肿瘤体积与对照组相比有无显著性差异，*P<0.05，**P<0.01，***P<0.001，与空白比较。
表16.联合给药组与单药组相比较的统计学分析结果(第55天)
Figure PCTCN2020114385-appb-000023
注：用Student’s t test比较相应单药治疗组和联合治疗组两组之间有无显著性差异，▲P<0.05，▲▲P<0.01，与药物B 30mg/kg单药组比较；▼P<0.05，与药物A 0.3mg/kg单药组比较；ΔP<0.05，与药物A 0.1mg/kg单药组比较。
表17.肿瘤块重量(g)(Mean±SEM)
Figure PCTCN2020114385-appb-000024
Figure PCTCN2020114385-appb-000025
注：用One-way ANOVA LSD test比较治疗组肿瘤瘤重与对照组相比有无显著性差异，*P<0.05，**P<0.01，***P<0.001，与空白比较。
在第一次给药开始后第44天，就肿瘤体积而言，与空白组比较，药物A 0.3mg/kg给药组、药物A 0.3mg/kg+药物B 30mg/kg联合给药组均表现出统计学上明显的抑制肿瘤生长的作用(P<0.05)。此外，相比于相应各单药组的抗肿瘤药效学结果，药物A 0.3mg/kg+药物B 30mg/kg联合给药组表现出统计学上更加明显的抑制肿瘤生长作用(P<0.05)，并且具有明显的增效效应(Q>1)。
实验结束后(第44天)，所有治疗小鼠被安乐死处理，剥离荷瘤鼠皮下移植瘤块并进行称量，就肿瘤块平均重量而言，与空白组相比较，药物A 0.3mg/kg给药组、药物A 0.3mg/kg+药物B 30mg/kg联合给药组、药物A 0.1mg/kg+药物B 30mg/kg联合给药组显示出统计学上明显抑制肿瘤生长的作用。T/C weight与T/C总体趋势基本一致。
3.2小鼠体重
各治疗组的相对体重变化的结果见表18。本次实验过程中，所有治疗组小鼠均没有出现体重明显下降和其他异常症状，表明荷瘤小鼠对所有治疗均耐受性良好。
表18.治疗小鼠体重变化(Mean±SEM)
Figure PCTCN2020114385-appb-000026
实施例5、CDK4/6抑制剂药物B(式(II)所示化合物羟乙基磺酸盐)联合MEK抑制剂药物A(式(I)所示化合物甲苯磺酸盐)治疗KRAS突变晚期或转移性结直肠癌/胰腺癌的I/Ⅱ期临床研究
1、研究目的：初步评估CDK4/6抑制剂药物B联合MEK抑制剂药物A治疗KRAS突变晚期或转移性结直肠癌/胰腺癌的耐受性、安全性和疗效。第一阶段研究目的：评价CDK4/6抑制剂药物B联合MEK抑制剂药物A治疗KRAS突变晚期或转移性结直肠癌/胰腺癌的耐受性、安全性
第二阶段研究目的：观察和评价CDK4/6抑制剂药物B联合MEK抑制剂药物A治疗KRAS突变晚期或转移性结直肠癌/胰腺癌的有效性和安全性
2、研究设计
2.1总体设计
研究分为两阶段，第一阶段为联用剂量探索阶段，第二阶段为疗效拓展阶段。
第一阶段：剂量探索研究
招募6-18例晚期或转移性KRAS突变结直肠癌/胰腺癌受试者，探索药物B与药物A联用剂量。在选定剂量先入组3例受试者，如果3例受试者在用药第一周期内均未出现DLT，则认为该剂量水平可以耐受。如果在用药第一周期内，有1例受试者出现DLT，增加3名受试者。如果这3位受试者中再出现≥1例DLT，则认为该剂量水平不能耐受；如果未再出现DLT，则认为该剂量水平为可以耐受。如果在用药第一周期内，有≥2例DLT，则该剂量水平为不耐受。药物A与药物B联合探索剂量见下表19。
表19.药物A与药物B联合剂量探索设置
Figure PCTCN2020114385-appb-000027
4周为1个周期，首先设置药物B固定剂量，125mg qd，po，服药3周停药1周/4周，药物A按照0.25mg→0375mg→0.5mg梯度(qd，po，服药3周停药1周/4周)进行剂量探索。
如“药物B 125mg qd，po，服药3周停药1周/4周+药物A 0.25mg qd，po，服药3周停药1周/4周”剂量水平不耐受，调整药物B为100mg qd，po，服药3周停药1周/4周，药物A按照0.25mg→0375mg→0.5mg梯度(qd，po，服药3周停药1周/4周)进行联用方案的剂量探索。
如药物B 100mg qd，po，服药3周停药1周/4周+药物A 0.25mg qd，po，服药3周停药1周/4周剂量水平不耐受，则研究终止。
第二阶段：疗效拓展阶段：待第一阶段试验完成，确定两者联用的剂量之后开展。入组20～30例晚期或转移性KRAS突变结直肠癌/胰腺癌受试者，初步探索联用方案的疗效与安全性。
根据第一阶段确定的可耐受联合给药剂量，药物B按确定的剂量qd，po，服药3周停药1周/4周+药物A按确定的剂量,qd，po，服药3周停药1周/4周，连续用药至出现符合治疗终止标准的事件发生。
2.2剂量限制性毒性(DLT)
第一阶段研究DLT观察期为联合用药的第一周期(4周)
DLT定义：在DLT观察期内发生的与研究药物相关且满足以下任一条件的毒性
1.持续>3天的4级血液学毒性或伴有出血的≥3级血小板降低、伴有发热、感染的≥3级中性粒细胞降低；
2. 3级及以上的非血液毒性(实验室检查指标异常除外)，腹泻、恶心及呕吐须经过对症治疗仍不能控制者；
3.≥2级的视网膜静脉阻塞(RVO)、葡萄膜炎和研究者判定的其他较严重的2级及以上眼部毒性，例如：中心性浆液性脉络膜视网膜病变(CSR)、视网膜脱离、视网膜色素上皮脱离、视神经乳头炎等及包括这些眼部毒性引起黄斑水肿、视觉障碍和视力模糊等症状；
4. 3级及以上的实验室检查指标异常，须进行住院治疗或持续>7天；
5.由于相关毒性导致的药物B和/或药物A停药>14天。
2.3 MTD的定义
剂量探索阶段，在第一周期(28天)的给药观察期内，发生DLT的病例数<总例数1/3的最大剂量。
3、受试者信息
受试者为临床诊断和病理学确诊的KRAS突变结直肠癌/胰腺癌，晚期或转移性肿瘤经标准治疗失败(疾病进展或无法耐受，如化疗、靶向治疗以及免疫治疗等)，或缺乏有效的治疗方法。
小样本量研究，I期计划招募6-18例受试者，确定MTD。II期计划招募20-30例受试者。
4、研究药品
4.1药品信息
试验药物1：式(I)所示化合物甲苯磺酸盐(药物A)；生产厂家：江苏恒瑞医药股份有限公司；剂型：片剂；给药途径：口服；规格：0.125mg片，0.5mg/片，2mg/片。
试验药物2：式(II)所示化合物羟乙基磺酸盐(药物B)；生产厂家：江苏恒瑞医药股份有限公司；剂型：片剂；给药途径：口服；规格：25mg/片，50mg/片，125mg/片。
4.2给药方法
无论是第一阶段还是第二阶段，筛选合适的受试者即接受药物B与药物A的治疗。
药物B，口服，每日1次连续给药21天，停药7天，28天为一个治疗周期。
药物A，餐后2小时口服，每日1次连续给药21天，停药7天，28天为一个治疗周期。
联合治疗直至疾病进展、毒性不耐受、受试者主动撤销知情同意或研究者判断受试者不再适合继续接受治疗。
4.3剂量暂停与调整
第一阶段研究的第一周期，原则上不允许进行药物A和药物B的剂量调整，后续周期才能根据毒性进行剂量调整。第二阶段研究，允许在研究过程中进行剂量调整。
为保证整个研究中剂量调整的一致性，在进行与AE相关剂量下调时，首先进行剂量暂停。
研究期间出现3级(CTCAE4.03)及以上的与研究药物相关的AE或发生DLT时，须予以停药。根据具体发生3级AE或DLT的性质，可以同时停止二药，或分别单独停止药物A或药物B用药，并采取最佳支持治疗。联合用药的周期随着药物暂停无需重新计算。
待毒性恢复到≤1级后，经研究者判断药物A或药物B可将原剂量或下调1个剂量水平继续服药。药物B剂量下调梯度为100和75mg qd。若药物B或药物A停药后超过21天毒性仍不能恢复至≤1级，则该受试者需终止药物B或药物A治疗，并观察至毒性恢复。
如果受试者终止联合治疗，经研究者判断，受试者能够从药物A单药或药物B单药治疗获益，受试者仍可以接受上述相应的治疗。
研究期间原则上只允许进行剂量下调。发生剂量下调后，经研究者判断认为有必要时，可以进行剂量上调。
剂量下调的规定：
药物B剂量下调：1)剂量为125mg或100mg时，允许剂量下调/剂量暂停或终止；2)下调梯度为100和75mg qd。75mg为最低剂量，不允许继续下调，但允许剂量暂停或终止。
药物A剂量下调：1)剂量为0.5mg或0.375mg时，允许剂量下调，剂量暂停或终止；2)下调梯度为0.375mg和0.25mg qd。0.25mg为最低剂量，不允许继续下调，但允许剂量暂停或终止。
5、有效性评价
主要终点指标：第一阶段研究：联合用药中药物A的MTD；第二阶段研究：客观缓解率(ORR)
次要终点指标：
1)有效性指标：
1.客观缓解率(ORR)(第一阶段研究)
2.疾病控制率(DCR)
3.缓解持续时间(DoR)
4.至缓解发生时间(Time to response，TTR)
5.无进展生存期(PFS)基于RECIST1.1
6.总生存期(OS)基于RECIST1.1
2)安全性指标：
包括生命体征、实验室指标、不良事件(AE)、严重不良事件(SAE)、药物相关性AE及SAE。
实施例6、评价并比较药物A及药物B单独或联合给药在人胰腺癌PDX模型PAN#039裸小鼠异种移植瘤模型中的治疗作用
实验动物：小鼠，品种：BALB/c裸鼠；性别：雌性；年龄：7-8周；体重：20g±20％。当肿瘤体积接近150-250mm 3时用随机区组法分组，每组8只小鼠
PAN#039为69岁男性患者，胰导管腺癌(所用代数P6)。
药物配置：1％Tween-80+0.5％CMC-Na；药物A配置溶剂：0.05％DMSO和0.5％CMC-Na；药物B配置溶剂：0.05M柠檬酸+0.5％CMC+0.5％Tween-80。
给药方案见表20。
表20.给药方案设置
Figure PCTCN2020114385-appb-000028
实验过程：
1.建议模型
选取若干600-800mm 3大小的PAN#039肿瘤，除去坏死组织及结缔组织，将其切成大小为15-30mm 3的肿瘤组织块；2)麻醉小鼠；3)移植肿瘤；4)PAN#039肿瘤移植37天后，选取72只肿瘤体积为150-255mm3的小鼠，将动物按随机区组法进行分组，使各组肿瘤体积差异小于均值的5％，每组8只。
2.数据分析
以时间点为X轴，肿瘤体积为Y轴绘制肿瘤生长曲线；以时间点为X轴，动物体重为Y轴绘制体重增长变化曲线。肿瘤体积及小鼠体重变化百分比的数据使用Two Way Analysis of Variance(Two Way ANOVA)方法进行方差分析，再用Bonferroni post-hoc multiple pair-wise comparisons方法进行显著性检验(p≤0.05)。相对肿瘤增殖率T/C(％)用于计算药物对肿瘤生长抑制作用的标准如下：药物对肿瘤有显著抑制作用：T/C(％)≤40％，且P<0.05；药物对肿瘤无显著抑制作用：T/C(％)>40％。
实验结果：
1)受试物对人胰腺癌PDX模型PAN#039动物体重的影响
在整个实验周期内，动物生长行为正常，受试药物有较好的耐受性。与0天相比，25天时各组的动物平均体重没有显著变化(<5％)。具体数据见表21。
表21.各组的动物平均体重
Figure PCTCN2020114385-appb-000029
2)受试药物对人胰腺癌PDX模型PAN#039肿瘤体积的影响
在整个实验周期内，各组的肿瘤体积出现不同程度的变化。详细结果见表22和图7。
表22.受试药物对人胰腺癌PDX模型PAN#039肿瘤体积的影响
Figure PCTCN2020114385-appb-000030
3)受试药物对人胰腺癌PDX模型PAN#039肿瘤生长抑制率
以上结果显示，除第1组(溶剂对照)外，其它给药组均有显著抑制肿瘤生长作用。详细结果见表23。
表23：受试药物对人胰腺癌PDX模型PAN#039的相对肿瘤增殖率和肿瘤生长抑制率(TGI％)
组别 T/C(％) TGI(％) p值
   30 25天  
1 100％ 0 ＜0.05
2 55.8％ 44.2％ ＜0.05
3 18.48％ 81.52％ ＜0.05
4 34.59％ 65.41％ ＜0.05
5 16.16％ 83.84％ ＜0.05
6 18.55％ 81.45％ ＜0.05
P<0.05表示有统计学意义。

Claims (13)

  1. 一种MEK抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤的药物中的用途。
  2. 根据权利要求1所述的用途，所述肿瘤选自结直肠癌、胆道癌、膀胱癌、乳腺癌、宫颈癌、结肠癌、甲状腺癌、睾丸癌、胃癌、肝细胞癌、胰腺癌、前列腺癌、黑色素瘤、淋巴瘤、肺癌、血管肉瘤、平滑肌肉瘤、脂肪肉瘤、横纹肌肉瘤、粘液瘤、恶性纤维组织细胞瘤、造血系统恶性肿瘤、神经母细胞瘤、头颈部癌、子宫内膜癌、大肠癌、食管癌、卵巢癌、唾液腺癌、小肠癌、胸腺癌、中枢神经系统肿瘤、骨癌、肾上腺腺瘤、肾细胞癌、神经母细胞瘤，优选结肠癌、胰腺癌或肺癌。
  3. 根据权利要求2所述的用途，所述肿瘤为Ras基因突变肿瘤。
  4. 根据权利要求3所述的用途，所述Ras基因选自KRas基因和/或NRas基因和/或HRas基因突变。
  5. 根据权利要求1-4任一项所述的用途，所述MEK抑制剂选自AZD-8330、GDC-0623、CI-1040、WX-554、TAK-733、SL-327、APS-2-79、BI-847325、HL-085、BI-847325、CEP-1347、U-0126、Binimetinib、Pimasertib、Cobimetinib、PD-0325901、PD-318088、RO-5126766、BIX-02189、BIX-02188、PD-98059、Trametinib、Refametinib、AS-703988、E-6201、Selumetinib、或式(I)所示化合物或其可药用盐中的至少一种，优选式(I)所示化合物或其可药用盐
    Figure PCTCN2020114385-appb-100001
  6. 根据权利要求5所述的用途，所述MEK抑制剂的每日剂量范围选自0.01-500mg，给药频次为每日2次、每日1次、每2天1次、每3天一次，优选每日一次。
  7. 根据权利要求1-6任一项所述的用途，所述CDK4/6抑制剂选自palbociclib、FCN-437c、abemaciclib、ribociclib、Alvocidib、trilaciclib、lerociclib、birociclib、PF-06873600，或式(II)所示化合物或其可药用盐中的至少一种，优选式(II)所示化合物或其可药用盐，
    Figure PCTCN2020114385-appb-100002
  8. 根据权利要求7所述的用途，所述CDK4/6抑制剂每日剂量为1-500mg，给药频次为每日一次或每日两次，优选每日一次。
  9. 根据权利要求7-8任一项所述的用途，所述MEK抑制剂为式(I)所示化合物或其可药用盐，所述CDK4/6抑制剂为式(II)所示化合物或其可药用盐。
  10. 根据权利要求9所述的用途，所述式(I)所示化合物可药用盐为甲苯磺酸盐。
  11. 根据权利要求9所述的用途，所述式(II)所示化合物可药用盐为羟乙基磺酸盐。
  12. 根据权利要求9所述的用途，所述MEK抑制剂每日剂量选自0.25mg、0.375mg、0.50mg、0.75mg，所述CDK4/6抑制剂每日剂量选自75mg、100mg、125mg、150mg或175mg。
  13. 一种药物组合物，所述药物组合物含权利要求1-12任一项所述的MEK抑制剂和CDK4/6抑制剂，进一步含有一种或多种可药用的赋型剂、稀释剂或载体。
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