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CN118576601A - Application of pharmaceutical combination product in preparation of medicine for treating colon cancer - Google Patents

Application of pharmaceutical combination product in preparation of medicine for treating colon cancer Download PDF

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Publication number
CN118576601A
CN118576601A CN202410669081.8A CN202410669081A CN118576601A CN 118576601 A CN118576601 A CN 118576601A CN 202410669081 A CN202410669081 A CN 202410669081A CN 118576601 A CN118576601 A CN 118576601A
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tumor
cancer
pharmaceutical combination
combination
tyrosine kinase
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Inventor
任永欣
范士明
周京红
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Hutchmed Ltd
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Hutchison Medipharma Ltd
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    • 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
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to an application of a pharmaceutical combination product in preparing a medicament for treating colon cancer. In particular, the invention relates to the use of a pharmaceutical combination of a chemotherapeutic agent and a multi-receptor tyrosine kinase inhibitor in the manufacture of a medicament for the treatment of colon cancer.

Description

Application of pharmaceutical combination product in preparation of medicine for treating colon cancer
The application is a divisional application of Chinese patent application with the application number 202111234778.5 and the application name of 'pharmaceutical combination of a multi-receptor tyrosine kinase inhibitor and a chemotherapeutic agent and a using method thereof' which are filed on 10 months 22 of 2021.
Technical Field
The present invention relates to pharmaceutical combinations comprising a chemotherapeutic agent and a multi-receptor tyrosine kinase (multi-RTK) inhibitor for use in the prevention or treatment of cancer. The invention also relates to uses and methods of using the combination products to prevent or treat cancer.
Background
The tumor has heterogeneity and complexity, so that single drug therapy is clinically applied, and the durable anti-tumor curative effect cannot be obtained by inhibiting a single signal path and the appearance of drug resistance is overcome, so that combined drug has become the trend of the current anti-tumor research.
A multi-receptor tyrosine kinase inhibitor is an agent that inhibits or reduces the tyrosine kinase activity of at least two or more receptors. As a representative of multi-receptor tyrosine kinase inhibitors, the small molecule compound, sovantinib, is a selective tumor angiogenesis inhibitor whose primary targets are Vascular Endothelial Growth Factor Receptor (VEGFR) family VEGFR1,2,3 and fibroblast growth factor receptor 1 (FGFR 1), and furthermore, sovantinib inhibits colony stimulating factor 1 receptor (CSF 1R) kinase activity.
The invention researches the anti-tumor activity of the combination drug of the small molecular compound sovantinib (which can regulate the microenvironment of the tumor and inhibit the growth of the tumor through inhibiting angiogenesis of the tumor and inhibiting multiple paths of FGFR1 and CSF1R signal paths) and the chemotherapeutic drug. Has important significance for improving clinical benefit and safety.
Disclosure of Invention
SUMMARY
The present invention provides pharmaceutical combinations comprising a multi-receptor tyrosine kinase (multi-RTK) inhibitor and a chemotherapeutic agent and uses and methods for the prevention or treatment of cancer.
Specifically, the present invention provides the following embodiments:
The present invention provides a pharmaceutical combination comprising (i) a multi-receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) a chemotherapeutic agent.
In one aspect, the invention provides a pharmaceutical combination as described above wherein the multi-receptor tyrosine kinase inhibitor inhibits at least the tyrosine kinase activity of two or more of the following receptors: (1) One, two, or three of VEGFR1, VEGFR2, and VEGFR3, (2) one, two, three, or four of FGFR1, FGFR2, FGFR3, and FGFR 4; and (3) CSF1R.
In some embodiments, the invention provides a pharmaceutical combination as described above, wherein the multi-receptor tyrosine kinase inhibitor can simultaneously inhibit the tyrosine kinase activity of the receptors VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF 1R.
In some embodiments, the invention provides a pharmaceutical combination as described above, wherein the multi-receptor tyrosine kinase inhibitor is suovatinib or a pharmaceutically acceptable salt thereof.
In one aspect, the invention provides a pharmaceutical combination as described above, wherein the chemotherapeutic agent is selected from one or more of an alkylating agent, a platinum drug, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, a topoisomerase inhibitor.
In some embodiments, the invention provides a pharmaceutical combination comprising a multi-receptor tyrosine kinase inhibitor as described above or a pharmaceutically acceptable salt thereof and wherein the chemotherapeutic agent comprises one or more antimetabolites (e.g., 5-fluorouracil, gemcitabine).
In some embodiments, the invention provides a pharmaceutical combination comprising a multi-receptor tyrosine kinase inhibitor as described above or a pharmaceutically acceptable salt thereof and wherein the chemotherapeutic agent comprises one or more mitotic inhibitors (e.g., paclitaxel, docetaxel).
In some embodiments, the invention provides a pharmaceutical combination comprising a multi-receptor tyrosine kinase inhibitor as described above, or a pharmaceutically acceptable salt thereof, and wherein the chemotherapeutic agent comprises one or more topoisomerase inhibitors (e.g., irinotecan).
In some embodiments, the invention provides a pharmaceutical combination as described above, wherein the chemotherapeutic agent comprises one or more selected from 5-fluorouracil, gemcitabine, paclitaxel, docetaxel, or irinotecan.
In some embodiments, the invention provides a pharmaceutical combination as described above, wherein (i) the multi-receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) the chemotherapeutic agent are administered separately, simultaneously or sequentially.
In some embodiments, the invention provides a pharmaceutical combination product, wherein the administration period of the pharmaceutical combination product may be one week, two weeks, three weeks, one month, two months, three months, four months, five months, half year or more, optionally, the time of each administration period may be the same or different, and the interval between each administration period may be the same or different.
In one aspect, the invention provides a pharmaceutical combination for use in preventing or treating cancer in a subject in need thereof, wherein the cancer is a solid tumor selected from sarcomas (e.g., fibrosarcoma, ewing's sarcoma), non-small cell lung cancer, colon cancer.
In one aspect, the invention provides a method of preventing or treating cancer, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical combination as defined in any one of the preceding embodiments, wherein the cancer is a solid tumor selected from sarcomas (e.g., fibrosarcoma, ewing's sarcoma), non-small cell lung cancer, colon cancer.
In one aspect, the present invention provides the use of a pharmaceutical combination as defined in any of the preceding embodiments for the prevention or treatment of cancer in a subject suffering from or at risk of suffering from cancer, or for the manufacture of a medicament for the prevention or treatment of cancer in a subject suffering from or at risk of suffering from cancer.
In another aspect, the present invention relates to a pharmaceutical composition comprising the pharmaceutical combination of the invention and at least one pharmaceutically acceptable carrier and/or excipient.
In one aspect, the present invention provides a kit comprising a pharmaceutical combination as defined in any of the preceding embodiments, preferably the kit comprises one or more single drug dosage units. In some embodiments, the invention provides a kit further comprising instructions for instructing the method of use of the pharmaceutical combination.
In the various embodiments described above, the individual is a mammal, such as a human. In some preferred embodiments, the individual is an individual having or at risk of having cancer, e.g., a cancer patient.
In some more preferred embodiments, the individual comprises an individual having a lower expected response to treatment with the chemotherapeutic agent alone, e.g., a cancer patient having a lower expected response to treatment with the chemotherapeutic agent alone.
The cancer being refractory to monotherapy with a chemotherapeutic agent refers to a cancer that has a lower expected response rate to treatment with the chemotherapeutic agent alone.
In still other more preferred embodiments, the individual comprises an individual whose expected response to treatment with the multi-receptor tyrosine kinase inhibitor alone is lower, such as a cancer patient whose expected response to treatment with the multi-receptor tyrosine kinase inhibitor alone is lower.
The cancer which is refractory to monotherapy with a multi-receptor tyrosine kinase inhibitor refers to a cancer which is expected to have a lower response rate to treatment with a multi-receptor tyrosine kinase inhibitor alone.
Surprisingly, the pharmaceutical combination or method of treatment of the present invention has significantly better anticancer efficacy, similar clinical safety and/or side effects than administration of a chemotherapeutic agent alone or a multi-receptor tyrosine kinase inhibitor alone.
Drawings
FIG. 1 inhibition of fibrosarcoma HT-1080 tumor growth by combination of sorafenib and gemcitabine.
FIG. 2 effects of Sofositinib in combination with gemcitabine on the relative body weight of fibrosarcoma HT-1080 tumor bearing mice.
FIG. 3 inhibition of Ewing sarcoma A-673 tumor growth by combination of Sofositinib and gemcitabine.
FIG. 4 effects of Sofositinib in combination with gemcitabine on relative body weight of Ewing sarcoma A-673 tumor bearing mice.
FIG. 5 inhibition of non-small cell lung cancer NCI-H460 tumor growth by combination of Sofositinib and paclitaxel.
FIG. 6 effects of Sofositinib in combination with paclitaxel on the relative body weight of non-small cell lung carcinoma NCI-H460 tumor bearing mice.
FIG. 7 inhibition of colorectal cancer HT-29 tumor growth by combination of sorafenib and irinotecan.
FIG. 8 effects of Sofositinib in combination with irinotecan on relative body weight of colon cancer HT-29 tumor bearing mice.
FIG. 9 inhibition of colorectal cancer HT-29 tumor growth by combination of soratinib and fluorouracil.
FIG. 10 effects of Sofositinib in combination with fluorouracil on relative body weight of colon cancer HT-29 tumor bearing mice.
Detailed Description
Before describing the present invention in detail, it is to be understood that this invention is not limited to particular methodology and experimental conditions described herein, as such methods and conditions may vary. In addition, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention in any way.
Definition of the definition
In order that the invention may be more readily understood, certain technical and scientific terms are defined as follows. Unless otherwise defined herein, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "about" refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, depending in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within 1 or greater than 1 standard deviation according to practice in the art. Or "about" may refer to a range of up to 10% or 20% (i.e., ±10% or ±20%). In this document, when a particular value or composition is provided, unless otherwise explicitly stated, the meaning of "about" shall be assumed to be within an acceptable error range for that particular value or composition.
All numerical ranges herein should be understood to disclose each and every number and subset of values within the range, whether or not they are specifically and additionally disclosed. For example, reference to any one range of values should be taken to mean reference to each value within that range of values, e.g., each integer within the range of values. The present invention relates to all values falling within these ranges, all smaller ranges, and the upper or lower limits of the ranges of values.
The term "and/or" when used to connect two or more selectable items is understood to mean any one of the selectable items or any two or more of the selectable items.
As used herein, the terms "comprises" or "comprising" are intended to include the stated elements, integers or steps but do not exclude any other elements, integers or steps. In this document, the terms "comprises" or "comprising" when used herein, unless otherwise indicated, also encompass the circumstance of consisting of the recited elements, integers or steps.
"Multi-receptor tyrosine kinase inhibitor", "tyrosine kinase inhibitor" or "Multi-RTK" refers to an agent that inhibits or reduces tyrosine kinase activity of at least two or more receptors. The activity of tyrosine kinases includes both direct and indirect activity. Exemplary direct activities include, but are not limited to, association with a target molecule or phosphorylation of a target substrate (i.e., kinase activity). Exemplary indirect activities include, but are not limited to, activation or inhibition of downstream biological events, such as NF-KB mediated activation of gene transcription.
The term "chemotherapeutic agent" or "chemotherapeutic agent" refers to a substance that induces apoptosis or necrotic cell death, examples of which include, but are not limited to:
a. Alkylating agents (e.g., nitrogen mustard, chlorambucil, cyclophosphamide, ifosfamide, streptozotocin, carmustine, robustamine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa, or altretamine);
b. Platinum drugs (e.g., cisplatin, carboplatin, or oxaliplatin);
c. Antimetabolites (e.g., 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, or pemetrexed);
d. Antitumor antibiotics (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, or mitoxantrone); and
E. Mitotic inhibitors (e.g., paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, or estramustine); and
F. Topoisomerase inhibitors (e.g. etoposide) teniposide (P) topotecan irinotecan, a process for preparing difluoro-or irinotecan).
The terms "cancer" and "cancer" refer to or describe physiological or pathological conditions in mammals that are generally characterized by unregulated cell growth. Included within this definition are benign and malignant cancers, and dormant tumors or micrometastases. Cancers include, but are not limited to, solid tumors and hematological cancers. Examples of various cancers include, but are not limited to, sarcomas (e.g., fibrosarcoma, ewing's sarcoma), non-small cell lung cancer, colon cancer.
The term "tumor" when applied to an individual diagnosed with or suspected of having cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms. Solid tumors are abnormal growths or masses of tissue that do not typically contain cysts or liquid areas. Different types of solid tumors are named for the cell type from which they are formed. Leukemia (hematological cancer) generally does not form a solid tumor (National Cancer Institute dictionary of CANCER TERMS).
The term "sarcoma" refers to cancers derived from mesenchymal tissue, sarcomas include, but are not limited to, osteosarcoma, chondrosarcoma, chordoma, connective tissue sarcoma, sarcomas mesothelioma, ewing's sarcoma, fibrosarcoma, synovial sarcoma, soft tissue sarcoma, vascular sarcoma, kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, rhabdomyosarcoma.
The term "patient", "subject" or "patient" refers to any individual in need of treatment or participation in a clinical trial, epidemiological study or as a control, including humans and mammals such as cattle, horses, dogs and cats.
A "therapeutically effective amount" of a drug or therapeutic agent refers to an amount of an active agent (e.g., an organic molecule or other drug) effective to "treat" a disease or condition in a patient or mammal. In the case of cancer, a therapeutically effective amount of the active agent may reduce the number of cancer cells; reducing tumor size; inhibiting or stopping infiltration of cancer cells into peripheral organs including, for example, cancer spread to soft tissues and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; alleviating one or more symptoms associated with the cancer to some extent; reducing morbidity and mortality; improving the quality of life; reducing the tumorigenicity, frequency of tumorigenesis or tumorigenicity of a tumor; reducing the number or frequency of cancer stem cells in a tumor; differentiating tumorigenic cells into a non-tumorigenic state; or a combination of these effects. The extent to which the agent prevents growth and/or kills existing cancer cells may be referred to as cell quiescence and/or cytotoxicity.
The term "dose" is the amount of drug that elicits a therapeutic effect. The dosage is related to the amount of drug in free form, unless otherwise indicated. If the drug is in the form of a pharmaceutically acceptable salt, the amount of drug increases proportionally to the amount of drug in free form. For example, the dosage will be stated in the product package, product information sheet, or instructions attached to the kit.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a non-toxic, biologically tolerable or other salt that is biologically suitable for administration in the treatment or prevention of a disease. Including but not limited to acid addition salts or base addition salts, such as: hydrochloride, hydrobromide, phosphate, sulfate, sulfite, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, salts with alkanedicarboxylic acids of the formula HOOC- (CH 2) n-COOH (where n is 0-4), and the like.
The term "carrier" or "pharmaceutically acceptable carrier" includes solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, absorption delaying agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof. Further details can be found, for example, in Remington 'sPharmaceutical Sciences [ Lemington's pharmaceutical science ], 18 th edition, MACK PRINTING Company,1990, pages 1289-1329.
The term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one therapeutic agent (i.e., a multi-receptor tyrosine kinase inhibitor and a chemotherapeutic agent) to be administered to an individual (e.g., a mammal such as a human). The pharmaceutical combinations of the invention may be formulated into pharmaceutical compositions suitable for various routes of administration, such as enteral or parenteral administration, for example those in unit dosage forms, such as capsules, tablets, injections (including infusions or injectable solutions), syrups, sprays, lozenges, liposomes or suppositories. If not otherwise indicated, these dosage forms are prepared in a manner known per se, for example by means of various conventional mixing, comminuting, direct compression, granulating, dragee-making, dissolving, lyophilizing processes or manufacturing techniques that are apparent to those skilled in the art. The pharmaceutical composition may contain from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of one or more therapeutic agents. One of ordinary skill in the art may select one or more of the foregoing vectors by routine experimentation.
The term "inhibit" refers to a decrease in certain parameters (e.g., VEGFR, FGFR1, CSF1R activity) of a given molecule (e.g., a multi-receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof). For example, the term includes inhibition of activity by at least 5%, 10%, 20%, 30%, 40% or more. Therefore, the inhibition need not be 100%.
The term "treatment" refers to 1) a therapeutic measure that cures, slows, alleviates, and/or stops the progression of a diagnosed pathological condition or disorder, and 2) a prophylactic or preventative measure that prevents and/or slows the development of a pathological condition or disorder in an individual. Thus, a need for treatment includes patients who have suffered from the disease, patients who are prone to suffer from the disease, and patients who want to prevent the disease. In certain embodiments, an individual is successfully "treated" for cancer via the methods of the invention, wherein the individual exhibits one or more of the following: the number of cancer cells is reduced or completely disappeared; tumor size reduction; inhibiting or lack of infiltration of cancer cells into peripheral organs including, for example, the spread of cancer to soft tissues and bone; inhibit or lack tumor metastasis; inhibit or lack tumor growth; alleviating one or more symptoms associated with the particular cancer; reducing morbidity and mortality; improving the quality of life; reducing the tumorigenicity, frequency of tumorigenesis or tumorigenicity of a tumor; reducing the number or frequency of cancer stem cells in a tumor; differentiating tumorigenic cells into a non-tumorigenic state; or a combination of the above effects.
The term "prevention" includes inhibition or delay of the occurrence or frequency of occurrence of a disease or disorder or symptom thereof, which generally refers to administration of a drug prior to the occurrence of a sign or symptom, particularly prior to the occurrence of a sign or symptom in an individual at risk.
The term "inhibit tumor growth" refers to any mechanism by which tumor cell growth can be inhibited. In certain embodiments, tumor cell growth is inhibited by delaying tumor cell proliferation. In certain embodiments, tumor cell growth is inhibited by stopping tumor cell proliferation. In certain embodiments, tumor cell growth is inhibited by killing tumor cells. In certain embodiments, tumor cell growth is inhibited by inducing apoptosis in the tumor cells. In certain embodiments, tumor cell growth is inhibited by inducing tumor cell differentiation. In certain embodiments, tumor cell growth is inhibited by depriving the tumor cells of nutrients. In certain embodiments, tumor cell growth is inhibited by preventing tumor cell migration. In certain embodiments, tumor cell growth is inhibited by preventing tumor cell invasion.
The term "administering" refers to physically introducing each active ingredient in the pharmaceutical combination of the present invention into an individual using any of a variety of methods and delivery systems known to those of skill in the art. Routes of administration of each active ingredient in the pharmaceutical combination of the invention include oral, intravenous (e.g. infusion (also called instillation) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, topical or other parenteral routes of administration. The phrase "parenteral administration" as used herein refers to modes of administration other than parenteral and topical administration, typically by intravenous, intra-arterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. Accordingly, each of the active ingredients in the pharmaceutical combination of the present invention may be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, and the like.
The term "continuous administration" refers to daily administration. In the case of continuous administration, the drug may be administered once or more times daily, for example, once daily, twice daily, three times daily, preferably once daily.
The terms "pharmaceutical combination" and "pharmaceutical combination product" are used interchangeably herein to refer to a non-fixed combination product or a fixed combination product, including but not limited to a kit, a pharmaceutical composition. The term "non-fixed combination" means that the active ingredients (e.g., chemotherapeutic agents, multi-receptor tyrosine kinase (multi-RTK) inhibitors) are administered to a patient simultaneously, without specific time constraints, or sequentially at the same or different time intervals, with such administration providing prophylactically or therapeutically effective levels of the two active agents in the patient. In some embodiments, the chemotherapeutic agent, multi-receptor tyrosine kinase (multi-RTK) inhibitor used in the pharmaceutical combination is administered at a level that does not exceed that at which they are used alone. The term "fixed combination" means that the two active agents are administered to a patient simultaneously in the form of a single entity. The dosages and/or time intervals of the two active agents are preferably selected so that the combined use of the parts will produce a greater effect in the treatment of the disease or condition than would be achieved by either component alone. The components can be in the form of separate preparations, and the preparations can be the same or different.
The term "individual" refers to both mammalian and non-mammalian animals. A mammal refers to any member of the mammal, including but not limited to: a person; non-human primates, bovine, equine, ovine, porcine, rabbit, canine, and feline, etc. The term "individual" is not limited to a particular age or sex. In some embodiments, the individual is a human.
The term "single-dose pharmaceutical unit" refers to a single pharmaceutical dosage form comprising a chemotherapeutic agent of the invention and/or a single pharmaceutical dosage form comprising a multiple receptor tyrosine kinase inhibitor of the invention for single administration to a patient. The single pharmaceutical dosage form may be a parenterally administered dosage form, such as a vial, ampoule, prefilled needle, or prefilled syringe for injection, wherein the drug is contained in a solution or lyophilized powder, or a parenterally administered dosage form, such as orally administered tablets, capsules, lozenges, powders, suspensions, and the like.
All numerical ranges herein should be understood to disclose each and every number and subset of values within the range, whether or not they are specifically and additionally disclosed. For example, reference to any one range of values should be taken to mean reference to each value within that range of values, e.g., each integer within the range of values. The present invention relates to all values falling within these ranges, all smaller ranges, and the upper or lower limits of the ranges of values.
Technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
Pharmaceutical combination
In some embodiments, the multi-receptor tyrosine kinase inhibitors in the pharmaceutical combinations of the invention inhibit at least the tyrosine kinase activity of two or more of the following receptors: (1) One, two or three of VEGFR1, VEGFR2 and VEGFR 3; (2) One, two, three or four of FGFR1, FGFR2, FGFR3 and FGFR 4; and (3) CSF1R.
In some embodiments, the multi-receptor tyrosine kinase inhibitors in the pharmaceutical combinations of the invention can simultaneously inhibit the tyrosine kinase activity of the receptors VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF 1R.
In some embodiments, the multi-receptor tyrosine kinase inhibitors in the pharmaceutical combinations of the present invention are described in WO2018090324A1 and other co-owned patent applications/patents, the entire contents of which, including the term definitions, are incorporated herein for all purposes.
In some embodiments, the multi-receptor tyrosine kinase inhibitor in the pharmaceutical combination of the present invention is "soratinib", also referred to herein as "Surufatinib", which has a strong inhibitory effect on the tyrosine kinases of the receptors VEGFR1, VEGFR2 (KDR), VEGFR3, FGFR1 and CSF1R, half inhibitory concentrations being 2, 24, 1, 15 and 4nM, respectively, and a weaker inhibition on the kinases of the remaining receptors, most half inhibitory concentrations being greater than 100nM, showing better selectivity. "Softitinib" is a compound having the structure of formula (I).
Sofositinib and pharmaceutically acceptable salts thereof are described herein in patent CN102070618, WO2011060746A1 and other co-owned patent applications/patents. In some embodiments, the soratinib is a crystal, such as form I or form II described in CN102070618, WO2011060746A1, and other co-owned patent applications/patents. The above-mentioned patent applications/patents are incorporated herein by reference for all purposes.
In some embodiments, the soratinib is present in the form of a composition comprising a micronized compound of formula (I), and/or at least one pharmaceutically acceptable salt of a compound of formula (I), and at least one pharmaceutically acceptable excipient, which composition is described in patent WO2016188399A1 and other co-owned patent applications/patents, which are incorporated herein by reference for all purposes.
In some embodiments, the chemotherapeutic agent in the pharmaceutical combination of the invention is selected from at least one of the following chemotherapeutic agents:
a. Antimetabolites (e.g., 5-fluorouracil, gemcitabine);
b. Mitotic inhibitors (e.g., paclitaxel, docetaxel);
c. topoisomerase inhibitors (e.g. irinotecan).
In some embodiments, the pharmaceutical combination of the invention comprises (i) suovatinib or a pharmaceutically acceptable salt thereof, and (ii) gemcitabine.
In some embodiments, the pharmaceutical combination of the invention comprises (i) sovietnib, or a pharmaceutically acceptable salt thereof, and (ii) paclitaxel.
In some embodiments, the pharmaceutical combination of the invention comprises (i) suovatinib or a pharmaceutically acceptable salt thereof, and (ii) 5-fluorouracil.
In some embodiments, the pharmaceutical combination of the invention comprises (i) soratinib, or a pharmaceutically acceptable salt thereof, and (ii) irinotecan.
The pharmaceutical combinations of the invention may also comprise one or more additional therapeutic agents. The additional therapeutic agent may be, for example, a biologic therapeutic, an immunogenic agent (e.g., an attenuated cancer cell, a tumor antigen, an antigen presenting cell such as a tumor derived antigen or a nucleic acid pulsed dendritic cell), an immunostimulatory cytokine (e.g., IL-2, IFN- α, GM-CSF), and a cell transfected with a gene encoding an immunostimulatory cytokine such as, but not limited to GM-CSF.
Dosage and dosing regimen
The choice of the dosing regimen (also referred to herein as the dosing regimen) for the pharmaceutical combination of the invention depends on several factors, including the solid serum or tissue turnover rate, the level of symptoms, the overall immunogenicity, and the accessibility of the target cells, tissues or organs of the subject. Preferably, the dosing regimen maximizes the amount of each therapeutic agent delivered to the patient, consistent with acceptable levels of side effects. Thus, the dosage and frequency of administration of each of the biologic and chemotherapeutic agents in a pharmaceutical combination depends in part on the particular therapeutic agent, the severity of the cancer being treated, and the patient's characterization. Guidance in selecting appropriate doses of antibodies, cytokines and small molecules can be obtained. The determination of the appropriate dosage regimen may be made by the clinician, for example with reference to parameters or factors known or suspected in the art to affect treatment or expected to affect treatment, and will depend, for example, on the clinical history of the patient (e.g., previous treatments), the type and stage of cancer being treated, and the biomarkers of one or more therapeutic agents in the response combination therapy.
Each therapeutic agent of the pharmaceutical combination of the invention may be administered simultaneously (i.e., in the same pharmaceutical composition), concurrently (i.e., in separate pharmaceutical formulations, administered one after the other in any order), or sequentially in any order. Sequential administration of therapeutic agents in a pharmaceutical combination may be particularly useful in different dosage forms (e.g., one drug is a tablet or capsule and the other drug is a sterile liquid formulation) and/or in different dosing schedules.
In some embodiments, the therapeutic agents in at least one pharmaceutical combination are administered using the same dosage regimen (therapeutic dose, frequency, and duration) that is typically used when the agents are used in monotherapy for the treatment of the same tumor. In other embodiments, the patient receives a lower total amount of at least one therapeutic agent in combination therapy, such as a smaller dose, less frequent dose, and/or a shorter duration of treatment than when the agent is used as monotherapy.
The dosing cycles of the chemotherapeutic agent and/or the multiple receptor tyrosine kinase inhibitor in the pharmaceutical combination of the invention may be the same or different, for one week, two weeks, three weeks, one month, two months, three months, four months, five months, half a year or more, optionally the time of each dosing cycle may be the same or different, and the interval between each dosing cycle may be the same or different.
Each therapeutic agent in the pharmaceutical combination of the present invention may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical, and transdermal routes, independently.
The multi-receptor tyrosine kinase (multi-RTK) inhibitors in the pharmaceutical combinations of the invention are administered in their approved or recommended doses and the treatment is continued until a clinical effect is observed or until unacceptable toxicity or disease progression occurs. In some embodiments, the multi-receptor tyrosine kinase (multi-RTK) inhibitor in the pharmaceutical combination of the invention is suovatinib, which is administered in a single dose selected from any fixed dose of about 50mg to about 350 mg. In some embodiments, the single administration dose of soratinib is selected from any fixed dose of about 50mg, 75mg, 100mg, 110mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, or 350 mg. A representative dosing regimen may be twice daily, once every two days, or once every three days. In some embodiments, the soratinib is administered to the individual once a day. In some embodiments, the soratinib is administered at a dose selected from about 125mg, about 150mg twice daily (BID). In other embodiments, the soratinib is administered once daily at a dose of about 250 mg.
The chemotherapeutic agent in the pharmaceutical combination of the invention is administered in its approved or recommended dose, and the treatment is continued until a clinical effect is observed or until unacceptable toxicity or disease progression occurs.
The chemotherapeutic agent in the pharmaceutical combination of the invention comprises at least gemcitabine, and the single administration dose of gemcitabine ranges from about 100mg/m 2 to about 1500mg/m 2, for example about 100mg/m2、200mg/m2、300mg/m2、400mg/m2、500mg/m2、600mg/m2、700mg/m2、800mg/m2、900mg/m2、1000mg/m2、1100mg/m2、1200mg/m2、1300mg/m2、1400mg/m2 or 1500mg/m 2. In some embodiments, the single dose of gemcitabine administered is about 1000mg/m 2, administered 1 time per week, rest 1 week after 3 weeks of treatment, and the 4 week treatment cycle described above is repeated. In some embodiments, the chemotherapeutic agent in the pharmaceutical combination of the invention comprises at least gemcitabine in combination with other chemotherapeutic agents, such as cisplatin, where the single administration dose of gemcitabine may be about 1250mg/m 2, administered on days 1, 8, and 15 of each 28-day treatment cycle. In some embodiments, the chemotherapeutic agent in the pharmaceutical combination of the invention comprises gemcitabine in combination with other chemotherapeutic agents, such as paclitaxel, administered at about 175mg/m 2 of paclitaxel on day 1 of the 21-day treatment cycle, followed by gemcitabine administered at about 1250mg/m 2 on days 1 and 8.
In some embodiments, the chemotherapeutic agent in the pharmaceutical combination of the invention comprises at least 5-fluorouracil, and the single administration dose of 5-fluorouracil is about 5-40 mg/kg (e.g., 10-20 mg/kg) or 200-800 mg/m 2 (e.g., 300-500 mg/m 2 or 500-600 mg/m 2). In some embodiments, the 5-fluorouracil is administered intravenously at a single dose of about 10-20 mg/kg daily for 5-10 days, 5-7 grams (even 10 grams) per course of treatment. In some embodiments, 5-fluorouracil is administered by intravenous drip, and a single administration may be administered at a dose of about 300-500 mg/m 2 daily for 3-5 days. In some embodiments, the 5-fluorouracil is administered intraperitoneally at a single dose of about 500-600 mg/m 2, 1 time per week, 2-4 times per week for 1 course of treatment.
In some embodiments, the chemotherapeutic agent in the pharmaceutical combination of the invention comprises at least paclitaxel, and the single administration dose of paclitaxel ranges from about 100mg/m 2 to 300mg/m 2, preferably about 135mg/m 2 or about 175mg/m 2, once every three weeks. In some embodiments, the chemotherapeutic agent in the pharmaceutical combination of the invention comprises paclitaxel in combination with at least one other chemotherapeutic agent, which may be selected from cisplatin and gemcitabine.
In some embodiments, the chemotherapeutic agent in the pharmaceutical combination of the invention comprises at least irinotecan, with a single dose of irinotecan ranging from about 100mg/m 2 to about 300mg/m 2, preferably about 180mg/m 2. In some embodiments, the chemotherapeutic agent in the pharmaceutical combination of the invention is irinotecan in combination with other chemotherapeutic agents selected from 5-fluorouracil or calcium folinate or a combination thereof.
Therapeutic methods or uses
The present invention provides the use of the aforementioned pharmaceutical combination of the invention for preventing and/or treating the severity of at least one symptom or indication of cancer or inhibiting the growth of cancer cells in an individual.
The present invention provides a method of preventing or treating cancer comprising administering to an individual in need thereof an effective amount of the aforementioned pharmaceutical combination of the invention. The effective amount includes a prophylactically effective amount and a therapeutically effective amount.
The invention provides the use of the aforementioned pharmaceutical combination of the invention for the manufacture of a medicament for the prevention or treatment of cancer. The pharmaceutical combination of the invention may be used before or after surgery to remove the tumor and may be used before, during or after radiation therapy. Wherein the cancer is a solid tumor selected from the group consisting of sarcoma (e.g., fibrosarcoma, ewing's sarcoma), non-small cell lung cancer, colon cancer.
In some embodiments, the present invention provides a method of preventing or treating sarcoma, particularly ewing's sarcoma and fibrosarcoma, comprising administering to a subject in need thereof an effective amount of a pharmaceutical combination as defined in any of the preceding embodiments. In some embodiments, wherein the pharmaceutical combination in the method comprises (i) suovatinib or a pharmaceutically acceptable salt thereof, and (ii) gemcitabine.
In some embodiments, the present invention provides a method of preventing or treating ewing's sarcoma, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical combination as defined in any of the preceding embodiments. In some embodiments, the pharmaceutical combination comprises (i) suovatinib or a pharmaceutically acceptable salt thereof, and (ii) gemcitabine.
In some embodiments, the present invention provides a method of preventing or treating fibrosarcoma, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical combination as defined in any of the preceding embodiments. In some embodiments, the pharmaceutical combination comprises (i) suovatinib or a pharmaceutically acceptable salt thereof, and (ii) gemcitabine.
In some embodiments, the present invention provides a method of preventing or treating non-small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical combination as defined in any of the preceding embodiments. In some embodiments, the pharmaceutical combination comprises (i) sovietnib or a pharmaceutically acceptable salt thereof, and (ii) paclitaxel.
In some embodiments, the present invention provides a method for preventing or treating colon cancer, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical combination as defined in any one of the preceding embodiments. In some embodiments, the pharmaceutical combination comprises (i) soratinib, or a pharmaceutically acceptable salt thereof, and (ii) irinotecan or 5-fluorouracil.
The pharmaceutical combinations described in the present invention may be used in the treatment of tumors found by palpation or by imaging techniques known in the art, such as MRI, ultrasound or CAT scan.
Medicine box
The chemotherapeutic agents described herein and the multi-receptor tyrosine kinase (multi-RTK) inhibitors described therein or pharmaceutically acceptable salts thereof may be provided as a kit comprising a first container and a second container and a package insert. The first container contains at least one dose of a formulation comprising a chemotherapeutic agent, the second container contains at least one dose of a formulation comprising a multi-receptor tyrosine kinase inhibitor described therein, or a pharmaceutically acceptable salt thereof, and the package insert or label contains instructions for using the formulation to treat cancer in a patient. The first and second containers may comprise the same or different shapes (e.g., vials, syringes, and bottles) and/or materials (e.g., plastic or glass). The kit may further contain other materials useful for administering the formulation, such as diluents, filters, IV bags and tubing, needles and syringes.
In the above embodiments, the single drug dosage unit refers to a single drug dosage form comprising a chemotherapeutic agent of the invention and/or a single drug dosage form comprising a multi-receptor tyrosine kinase inhibitor of the invention for single administration to a patient. The single pharmaceutical dosage form may be a parenterally administered dosage form, such as a vial, ampoule, prefilled needle, or prefilled syringe for injection, wherein the drug is contained in a solution or lyophilized powder, or a parenterally administered dosage form, such as orally administered tablets, capsules, lozenges, powders, suspensions, and the like.
These and other aspects of the invention, including the exemplary embodiments set forth below, will be apparent from the teachings contained herein.
Detailed Description
EXAMPLE 1 inhibition of fibrosarcoma HT-1080 tumor growth by combination of Sofositinib and gemcitabine
HT-1080(CCL-121 TM) cells were cultured in ATCC recommended medium and culture conditions. Subcutaneous tumor model construction: HT-1080 tumor cells were suspended in serum-free MEM medium and implanted subcutaneously in right flank of male BALB/c nude mice (Shanghai Ling Biotechnology Co., ltd.) at an inoculum size of 2X 10 6 cells/mouse.
Pharmacodynamics study: 1) HT-1080 model when the average tumor volume was grown to about 130mm 3, mice were randomized into 4 groups according to tumor volume, and dosed on the Day of the grouping (noted Day 1) for 20 days. Gemcitabine is diluted with 0.9% physiological saline for injection and administered intravenously at a dose of 10mg/kg once a week; sofositinib is added into 0.5% sodium carboxymethyl cellulose, and is prepared into suspension by an ultrasonic method, and the suspension is orally and gastro-orally administrated at a dosage of 80mg/kg twice a day.
The transplanted tumor diameter was measured with a vernier caliper at regular intervals, the tumor volume was calculated (tumor volume=0.5×long diameter×short diameter 2), and the weight of the mice was weighed. Tumor growth inhibition (tumor growth inhibition, TGI) was calculated for each treatment group after the last measurement using the tumor growth inhibition calculation formula.
The tumor growth inhibition rate calculation formula is: TGI (%) = [1- (TV Dt( treatment group )-TVD1( treatment group ))/(TVDt( Control group )-TVD1( Control group )) ]x100%. Where TV D1 represents the tumor volume obtained by grouping the first measurements and TV Dt represents the tumor volume at a later measurement. Statistical analysis of tumor volume changes was performed using the Student t test method.
The calculation formula of the relative weight of mice (RBW%) is that rbw=bw Dt/BWD1×100％.BWD1 represents the weight of the animals obtained when the group is first weighed, and BW Dt represents the weight of the animals at each subsequent weighing.
Experimental results:
The results of the HT-1080 model experiments are shown in Table 1 and FIGS. 1-2. In the experiment, the inhibition rates (TGI) of the small molecular compound sovantinib and the chemotherapeutic gemcitabine on tumor growth are 64.0% and 61.9% respectively, the TGI of the combined administration group is 90.2%, and the tumor volume change of the combined administration group has obvious statistical difference (P < 0.01) compared with that of the two single administration groups. The experimental data suggest that the combined use of the soratinib and the chemotherapeutic drug gemcitabine can obviously enhance the inhibition effect on the growth of fibrosarcoma HT-1080 model tumor.
In addition, the weight of animals in the vehicle-treated group was reduced by about 10% at the end of the experiment, i.e., the relative weight was about 90%, and the gemcitabine alone group slightly delayed the reduction in weight of tumor-bearing mice compared to the vehicle-treated group, while both the soratinib alone group and the combination group significantly improved the effect of HT-1080 cachexia on the relative weight of animals.
TABLE 1 inhibition of fibrosarcoma HT-1080 tumor growth and Effect of Sofositinib in combination with gemcitabine on the relative body weight of mice
Example 2 inhibition of Ewing sarcoma A-673 tumor growth by Sofositinib and gemcitabine combination
A-673(CRL-1598 TM) cells were cultured in the medium and culture conditions recommended by ATCC. Subcutaneous tumor model construction: the A-673 tumor cells were suspended in serum-free DMEM medium and implanted subcutaneously in the right flank of female BALB/c nude mice (Shanghai Ling Biotechnology Co., ltd.) at an inoculum size of 2X 10 6 cells/mouse.
Pharmacodynamics study: when the average tumor volume grew to approximately 180mm 3, the mice were randomly divided into 4 groups by tumor volume and dosed the next Day after the grouping (grouping diary was Day 0) for 18 days. Gemcitabine is diluted with 0.9% physiological saline for injection and administered by intraperitoneal injection at a dose of 50mg/kg twice a week; sofositinib is added into 0.5% sodium carboxymethyl cellulose, and is prepared into suspension by an ultrasonic method, and the suspension is orally and gastro-orally administrated at a dosage of 40mg/kg twice a day.
The transplanted tumor diameter was measured with a vernier caliper at regular intervals, the tumor volume was calculated (tumor volume=0.5×long diameter×short diameter 2), and the weight of the mice was weighed. Tumor growth inhibition (tumor growth inhibition, TGI) was calculated for each treatment group after the last measurement using the tumor growth inhibition calculation formula.
The tumor growth inhibition rate calculation formula is: TGI (%) = [1- (TV Dt( treatment group )-TVD0( treatment group ))/(TVDt( Control group )-TVD0( Control group )) ]x100%. Where TV D0 represents the tumor volume obtained by grouping the first measurements and TV Dt represents the tumor volume at a later measurement. Statistical analysis of tumor volume changes was performed using the Student t test method.
The calculation formula of the relative weight of mice (RBW%) is that rbw=bw Dt/BW D0×100％.BWD0 represents the weight of the animals obtained when the group is first weighed, and BW Dt represents the weight of the animals at each subsequent weighing.
Experimental results:
The results of the A-673 model experiments are shown in Table 2 and FIGS. 3-4. In the experiment, the inhibition rates of the small molecular compound sovantinib and the chemotherapeutic gemcitabine on the tumor growth are 39.9% and 36.1% respectively, the inhibition rate of the combined administration group is 66.4%, and compared with the two single administration groups, the tumor volume of the combined administration group has obvious statistical difference (P <0.05 or P < 0.01). The experimental data suggest that the combined administration of the soratinib and the chemotherapeutic drug gemcitabine can obviously enhance the inhibition effect on the tumor growth of the Ewing sarcoma A-673 model.
In addition, mice in each group developed rapidly in weight during the observation period and behaved normally, suggesting that the animals were well tolerated.
TABLE 2 inhibition of Ewing sarcoma A-673 tumor growth and Effect on relative body weight in mice with Sofositinib and gemcitabine combination
Example 3 inhibition of non-small cell lung cancer NCI-H460 tumor growth by Sofositinib in combination with paclitaxel
NCI-H460(HTB-177 TM) cells were cultured in the culture medium and culture conditions recommended by ATCC. Subcutaneous tumor model construction: NCI-H460 tumor cells were suspended in serum-free RPMI1640 medium, and male BALB/c nude mice (Shanghai Lai laboratory animal Co., ltd.) were implanted subcutaneously in the right flank at an inoculum level of 3X10 6 cells/mouse.
Pharmacodynamics study: when the average tumor volume grew to approximately 210mm 3, the mice were randomly divided into 4 groups by tumor volume and dosed the next Day after the grouping (grouping diary was Day 0) for 19 days. Paclitaxel is diluted by 0.9% physiological saline for injection and is administrated by intraperitoneal injection at a dose of 10mg/kg twice a week; sofositinib is added into 0.5% sodium carboxymethyl cellulose, and is prepared into suspension by an ultrasonic method, and the suspension is orally and gastro-orally administrated at a dosage of 40mg/kg twice a day.
The transplanted tumor diameter was measured with a vernier caliper at regular intervals, the tumor volume was calculated (tumor volume=0.5×long diameter×short diameter 2), and the weight of the mice was weighed. Tumor growth inhibition (tumor growth inhibition, TGI) was calculated for each treatment group after the last measurement using the tumor growth inhibition calculation formula.
The tumor growth inhibition rate calculation formula is: TGI (%) = [1- (TV Dt( treatment group )-TVD0( treatment group ))/(TVDt( Control group )-TVD0( Control group )) ]x100%. Where TV D0 represents the tumor volume obtained by grouping the first measurements and TV Dt represents the tumor volume at a later measurement. Statistical analysis of tumor volume changes was performed using the Student t test method.
The calculation formula of the relative weight of mice (RBW%) is that rbw=bw Dt/BW D0×100％.BWD0 represents the weight of the animals obtained when the group is first weighed, and BW Dt represents the weight of the animals at each subsequent weighing.
Experimental results:
The NCI-H460 model test results are shown in Table 3 and FIGS. 5-6. In the experiment, the inhibition rates of the small molecular compound sovantinib and the chemotherapeutic agent taxol on the tumor growth are 26.9% and 4.3% respectively, the inhibition rate of the combined administration group is 55.2%, and the tumor volume of the combined administration group has obvious statistical difference (P < 0.01) compared with that of the two single administration groups. The experimental data suggest that the combined administration of the soratinib and the chemotherapeutic agent paclitaxel can enhance the inhibition effect on the tumor growth of the NCI-H460 model of the non-small cell lung cancer.
In addition, mice in each single group grew rapidly and behaved normally during the observation period, suggesting that animals had good tolerance to the single drug of the combination of soratinib and paclitaxel, but the combination of soratinib and paclitaxel had some effect on the relative body weight of the animals (about 7% reduction in body weight from the initial body weight) and no death of the animals.
TABLE 3 inhibition of non-small cell lung cancer NCI-H460 tumor growth and Effect on relative body weight in mice by Sofositinib and paclitaxel combination
Example 4 inhibition of colorectal cancer HT-29 tumor growth by combination of Sofositinib and irinotecan
HT-29(HTB-38 TM) cells were cultured in the culture medium and culture conditions recommended by ATCC. Subcutaneous tumor model construction: HT-29 tumor cells were suspended in serum-free McCoy's 5a medium and implanted subcutaneously in the right flank of male BALB/c nude mice (Shanghai Lai laboratory animal Co., ltd.) at an inoculum size of 3X 10 6 cells/mouse.
Pharmacodynamics study: when the average tumor volume grew to about 170mm 3, the mice were randomly divided into 4 groups by tumor volume and dosed the next Day after the grouping (grouping diary was Day 0) for 21 days. Irinotecan (CPT-11) was diluted with 0.9% physiological saline for injection and administered by intraperitoneal injection at a dose of 10mg/kg twice weekly; sofositinib is added into 0.5% sodium carboxymethyl cellulose, and is prepared into suspension by an ultrasonic method, and the suspension is orally and gastro-orally administrated at a dosage of 40mg/kg twice a day.
The transplanted tumor diameter was measured with a vernier caliper at regular intervals, the tumor volume was calculated (tumor volume=0.5×long diameter×short diameter 2), and the weight of the mice was weighed. Tumor growth inhibition (tumor growth inhibition, TGI) was calculated for each treatment group after the last measurement using the tumor growth inhibition calculation formula.
The tumor growth inhibition rate calculation formula is: TGI (%) = [1- (TV Dt( treatment group )-TVD0( treatment group ))/(TVDt( Control group )-TVD0( Control group )) ]x100%. Where TV D0 represents the tumor volume obtained by grouping the first measurements and TV Dt represents the tumor volume at a later measurement. Statistical analysis of tumor volume changes was performed using the Student t test method.
The calculation formula of the relative weight of mice (RBW%) is that rbw=bw Dt/BW D0×100％.BWD0 represents the weight of the animals obtained when the group is first weighed, and BW Dt represents the weight of the animals at each subsequent weighing.
Experimental results:
HT-29 model experiments A result is shown in Table 4 and FIGS. 7-8. In the experiment, the inhibition rates of the small molecular compound sovantinib and the chemotherapeutic irinotecan on the tumor growth are respectively 37.0% and 42.4%, the inhibition rate of the combined administration group is 62.7%, and the tumor volume of the combined administration group has obvious statistical difference (P < 0.01) compared with that of the two single administration groups. The experimental data suggest that the combined use of the soratinib and the chemotherapeutic irinotecan can enhance the inhibition effect on the tumor growth of the colorectal cancer HT-29 model.
In addition, the relative body weight of the combination of the soratinib and the irinotecan in the observation period is slightly increased compared with that of the mice in the irinotecan single drug group, and the animal acts normally, which suggests that the combination of the soratinib and the chemotherapeutic drug, namely the irinotecan, has good tolerance.
TABLE 4 inhibition of colorectal cancer HT-29 tumor growth and Effect on relative body weight in mice with Sofositinib in combination with irinotecan
EXAMPLE 5 inhibition of colorectal cancer HT-29 tumor growth by combination of Sofositinib and 5-fluorouracil
HT-29(HTB-38 TM) cells were cultured in the culture medium and culture conditions recommended by ATCC. Subcutaneous tumor model construction: HT-29 tumor cells were suspended in serum-free McCoy's 5a medium and implanted subcutaneously in the right flank of male BALB/c nude mice (Shanghai Lai laboratory animal Co., ltd.) at an inoculum size of 3X 10 6 cells/mouse.
Pharmacodynamics study: when the average tumor volume grew to about 170mm 3, the mice were randomly divided into 4 groups by tumor volume and dosed the next Day after the grouping (grouping diary was Day 0) for 21 days. 5-fluorouracil is diluted with 0.9% physiological saline for injection and administered intravenously at a dose of 50mg/kg once a week; sofositinib is added into 0.5% sodium carboxymethyl cellulose, and is prepared into suspension by an ultrasonic method, and is orally and gastrographically administrated at a dosage of 30mg/kg twice a day.
The transplanted tumor diameter was measured with a vernier caliper at regular intervals, the tumor volume was calculated (tumor volume=0.5×long diameter×short diameter 2), and the weight of the mice was weighed. Tumor growth inhibition (tumor growth inhibition, TGI) was calculated for each treatment group after the last measurement using the tumor growth inhibition calculation formula.
The tumor growth inhibition rate calculation formula is: TGI (%) = [1- (TV Dt( treatment group )-TVD0( treatment group ))/(TVDt( Control group )-TVD0( Control group )) ]x100%. Where TV D0 represents the tumor volume obtained by grouping the first measurements and TV Dt represents the tumor volume at a later measurement. Statistical analysis of tumor volume changes was performed using the Student t test method.
The calculation formula of the relative weight of mice (RBW%) is that rbw=bw Dt/BW D0×100％.BWD0 represents the weight of the animals obtained when the group is first weighed, and BW Dt represents the weight of the animals at each subsequent weighing.
Experimental results:
The results of the HT-29 model experiments are shown in Table 5 and FIGS. 9-10. In the experiment, the inhibition rates of the small molecular compound sovantinib and the chemotherapeutic drug 5-fluorouracil on tumor growth are 35.0% and 22.7% respectively, the inhibition rate of the combined drug group is 54.7%, and compared with the two single drug groups, the tumor volume of the combined drug group has obvious statistical difference (P <0.05 or P < 0.01). The experimental data suggest that the combination of the soratinib and the chemotherapeutic drug 5-fluorouracil can enhance the inhibition effect on the tumor growth of the colorectal cancer HT-29 model.
In addition, the relative body weight of the combination administration group of the soratinib and the 5-fluorouracil is slightly increased in the later period of the experiment compared with that of a single 5-fluorouracil group mouse during the observation period, and the animal acts normally, so that the 5-fluorouracil combination administration of the soratinib and the chemotherapeutic agent is well tolerated.
TABLE 5 inhibition of colorectal cancer HT-29 tumor growth and Effect on relative body weight in mice by Sofositinib in combination with 5-fluorouracil

Claims (1)

1. Use of a pharmaceutical combination consisting of (i) a multi-receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) a chemotherapeutic agent in the manufacture of a medicament for the prevention or treatment of cancer in an individual suffering from or at risk of suffering from cancer;
Wherein the multi-receptor tyrosine kinase inhibitor is soratinib of formula (I) or a pharmaceutically acceptable salt thereof;
the chemotherapeutic agent is 5-fluorouracil, wherein the cancer is colon cancer.
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