WO2023138576A1 - Combinaison pharmaceutique d'oxyde d'arylphosphore spirocyclique et d'anticorps anti-egfr - Google Patents

Combinaison pharmaceutique d'oxyde d'arylphosphore spirocyclique et d'anticorps anti-egfr Download PDF

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WO2023138576A1
WO2023138576A1 PCT/CN2023/072607 CN2023072607W WO2023138576A1 WO 2023138576 A1 WO2023138576 A1 WO 2023138576A1 CN 2023072607 W CN2023072607 W CN 2023072607W WO 2023138576 A1 WO2023138576 A1 WO 2023138576A1
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formula
compound
egfr
lung cancer
group
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PCT/CN2023/072607
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English (en)
Chinese (zh)
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郑善松
郑庆梅
陈冬妹
王新美
董欣
张欣
段会成
马翠翠
张臣伟
赵树雍
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齐鲁制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry and relates to a combined pharmaceutical composition for treating tumors. Specifically, the present invention relates to the drug combination of spirocyclic aryl phosphorus oxide and antibody and its use in the preparation of antitumor drugs.
  • Anaplastic lymphoma kinase is a receptor tyrosine kinase (RTK) and a member of the insulin receptor (IR) superfamily.
  • ALK was first discovered in 60-80% of anaplastic large cell lymphoma (ALCLS) cell lines in the form of fusion protein NPM (nucleophosmin)-ALK. NPM-ALK was caused by t(2;5) chromosome translocation.
  • ALK fusion proteins have been identified in various human cancers such as breast cancer, colorectal cancer, inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma (DLBCL), and most notably in non-small cell lung cancer (NSCLC). Therefore, the kinase activity associated with ALK fusion proteins is considered to play a very important role in the survival and proliferation of human cancer cells.
  • IMT inflammatory myofibroblastic tumor
  • DLBCL diffuse large B-cell lymphoma
  • NSCLC non-small cell lung cancer
  • the ALK gene provides a signaling instruction for receptor tyrosine kinases to transmit signals from the cell surface into the cell. This process begins when a kinase is stimulated at the cell surface and then attaches to a similar kinase (dimerization). After dimerization, the kinase is tagged with a phosphate group, a process called phosphorylation. Phosphorylation-activated kinase, an activated kinase is another protein capable of transferring a phosphate group into the cell, activating a series of proteins that continue through the signaling pathway. These signaling pathways are important for many cellular processes, such as cell growth and division (proliferation) or maturation (differentiation).
  • ALK is rearranged such that the tyrosine kinase domain of ALK is fused to the 5′-terminal domain of another protein, such as echinoderm microtubule-associated protein-like 4 (EML4) in NSCLC or nucleophosphoprotein (NPM) in anaplastic large cell lymphoma.
  • EML4 echinoderm microtubule-associated protein-like 4
  • NPM nucleophosphoprotein
  • the 5'-end of the fusion protein usually contains a coiled-coil or leucine zipper domain, which oligomerizes the fusion protein and leads to ligand-dependent activation of the ALK tyrosine kinase. This in turn constitutively activates downstream signaling pathways such as Ras/MAPK, PI3K/AKT, and JAK/STAT.
  • ALK-driven lung cancers respond and regress following treatment with ALK small-molecule tyrosine kinase inhibitors. This finding demonstrates "oncogene dependency," whereby cancer cells become dependent on oncogenic driver genes and are thus highly sensitive to suppressing oncogenes.
  • Crizotinib is the first ALK inhibitor approved by the FDA for the treatment of ALK-positive lung cancer. Although patients initially responded very well to crizotinib therapy, most patients relapsed during the first year of treatment due to the development of drug resistance. In April 2014, the FDA approved Ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), including patients who are effective and resistant to crizotinib. However, drug resistance always occurs with the prolongation of treatment time, so that the drug loses its effectiveness.
  • ALK anaplastic lymphoma kinase
  • NSCLC metastatic non-small cell lung cancer
  • Spirocyclic aryl phosphine oxide chemical name: (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, is a novel ALK/ROS1 inhibitor for the treatment of ALK/ROS1 positive non-small cell lung cancer. It has the following structural formula:
  • the compound of formula I inhibits the phosphorylation of ALK by inhibiting the activation of ALK kinase, thereby preventing the phosphorylation of downstream signaling molecules, such as ERK, STAT5 and AKT.
  • the compound of formula I inhibits the activation of ROS1 by inhibiting the phosphorylation of ROS1 fusion kinase, This in turn prevents the phosphorylation of downstream signaling molecules such as ERK or AKT.
  • patent WO2016/000581 discloses spirocyclic aryl phosphorus oxides as ALK inhibitors
  • patent CN106928275 discloses the preparation method and intermediates of spirocyclic aryl phosphorus oxides
  • patent CN110407877 discloses polymorphic forms of spirocyclic aryl phosphorus oxides.
  • epidermal growth factor receptor is related to the occurrence and development of many tumors.
  • EGFR normally helps regulate the growth of cells in the body, but it can also stimulate the growth of cancer cells.
  • EGFR is present on the surface of cancer cells and is activated when proteins present in the body that bind to EGFR, such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-alpha). Binding changes the morphology of EGFR, stimulating the growth of tumor cells.
  • EGFR-positive tumors are characterized by high malignancy and strong invasion, and the level of EGFR expression is related to prognosis. Therefore, it has also become an important target of current tumor molecular targeted therapy.
  • HER1/EGFR is abnormally expressed in solid tumors, and its clinical manifestations are metastasis, shortened survival time, poor prognosis, and resistance to chemotherapy and hormone therapy. Blocking HER1/EGFR can inhibit the formation of tumors and improve the above conditions at the same time.
  • EGFR monoclonal antibodies competes with endogenous ligands for binding to EGFR, and produces anti-tumor effects by inhibiting the activation of tyrosine kinase and promoting the internalization of EGFR.
  • anti-EGFR monoclonal antibodies there are 3 kinds of anti-EGFR monoclonal antibodies on the market at home and abroad. Compared with other chemotherapeutic drugs, these antibodies have strong specificity and small side effects, and have achieved good clinical curative effect.
  • Panitumumab is the first fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Panitumumab can specifically bind to EGFR in normal and tumor cells and is a competitive inhibitor of EGFR ligands. Non-clinical studies have shown that the combination of panitumumab and EGFR can prevent ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, inhibit cell growth and induce apoptosis, reduce the production of pro-inflammatory cytokines and angiogenesis factors and the internalization of EGFR.
  • EGFR epidermal growth factor receptor
  • the purpose of the present invention is to provide a combination pharmaceutical composition, which comprises ALK inhibitor and anti-EGFR antibody.
  • the pharmaceutical composition of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as an ALK inhibitor, and an anti-EGFR antibody.
  • the anti-EGFR antibody in the above combined pharmaceutical composition is panitumumab.
  • the above-mentioned combined pharmaceutical composition is a non-fixed combination.
  • the anti-EGFR antibody and the compound of formula I, or a pharmaceutically acceptable salt thereof, in the non-fixed combination are each in the form of a pharmaceutical composition.
  • a kit of a pharmaceutical combination for treating lung tumors which contains (a) a first pharmaceutical composition comprising an anti-EGFR antibody; and (b) a second pharmaceutical composition comprising a compound of formula I as an active ingredient.
  • the present invention also provides an application of a combined pharmaceutical composition in the preparation of a drug for treating and/or preventing lung cancer, the combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an ALK inhibitor, and an anti-EGFR antibody.
  • the anti-EGFR antibody in the above use is panitumumab.
  • the panitumumab used in the above application can be selected from Vectibix or its biosimilars.
  • the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above application are each in the form of a pharmaceutical composition.
  • the lung cancer in the above application is positive for EGFR sensitive mutation.
  • the lung cancer mentioned in the above application is early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer.
  • the lung cancer described in the above application is early-middle stage, locally advanced, and advanced metastatic non-small cell lung cancer that is positive for EGFR sensitive mutations.
  • the lung cancer in the above application is non-small cell lung cancer that has not been treated with an EGFR inhibitor or failed to be treated with an EGFR inhibitor.
  • the lung cancer in the above application is a non-small cell lung cancer with positive EGFR sensitive mutation, T790M mutation and C797S mutation that has failed treatment with irreversible EGFR inhibitors such as osimertinib.
  • the lung cancer in the above application is non-small cell lung cancer with Del19 mutation, T790M mutation and C797S mutation.
  • the lung cancer in the above application is non-small cell lung cancer with L858R mutation, T790M mutation and C797S mutation.
  • the non-small cell lung cancer in the above application is adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma or large cell carcinoma.
  • the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above application are each in the form of a pharmaceutical composition, and can be administered simultaneously, sequentially or at intervals.
  • the present invention also provides a method for treating a subject suffering from cancer or tumor comprising administering to said subject a therapeutically effective amount of an ALK inhibitor and a therapeutically effective amount of an anti-EGFR antibody.
  • the ALK inhibitor in the above treatment method is a spirocyclic aryl phosphorus oxide represented by formula I.
  • the anti-EGFR antibody in the above treatment method is panitumumab.
  • the panitumumab in the above treatment method can be selected from Vectibix or its biosimilars.
  • the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above treatment method are each in the form of a pharmaceutical composition.
  • the lung cancer in the above treatment method is positive for EGFR sensitive mutation.
  • the lung cancer mentioned in the above treatment method is early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer.
  • the lung cancer described in the above treatment method is early-middle stage, locally advanced, and advanced metastatic non-small cell lung cancer that is positive for EGFR sensitive mutations.
  • the lung cancer in the above treatment method is non-small cell lung cancer that has not been treated with an EGFR inhibitor or failed to be treated with an EGFR inhibitor.
  • the lung cancer mentioned in the above treatment method is non-small cell lung cancer with EGFR sensitive mutation positive, T790M mutation and C797S mutation that failed to be treated with irreversible EGFR inhibitors such as osimertinib.
  • the lung cancer in the above treatment method is non-small cell lung cancer with Del19 mutation, T790M mutation and C797S mutation.
  • the lung cancer in the above treatment method is non-small cell lung cancer with L858R mutation, T790M mutation and C797S mutation.
  • the non-small cell lung cancer in the above treatment method is adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma or large cell carcinoma.
  • the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above treatment method are each in the form of a pharmaceutical composition, and can be administered simultaneously, sequentially or at intervals.
  • the present invention also provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating lung cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with an anti-EGFR antibody.
  • the present invention also provides a use of an anti-EGFR antibody for treating lung cancer.
  • the anti-EGFR antibody is used in combination with the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the anti-EGFR antibody used above is selected from panitumumab.
  • the panitumumab used in the above use can be selected from Vectibix or its biosimilars.
  • the present invention also provides a pharmaceutical pack, which comprises a single-packaged pharmaceutical composition in an independent container, which comprises a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof in one container, and a pharmaceutical composition containing an anti-EGFR antibody in a second container.
  • compositions of compounds of formula I can be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Oral administration is preferred, eg as a tablet.
  • the dosage of the pharmaceutical composition of the compound of formula I is about 60 mg/time to 180 mg/time; or the dosage is about 90 mg/time to 180 mg/time.
  • the pharmaceutical composition of the compound of formula I is administered about 60 mg-180 mg; or about 90 mg-180 mg each time.
  • the compound of formula I is a spirocyclic aryl phosphorus oxide with a chemical name of (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, which is a newly developed highly selective anaplastic lymphoma kinase (ALK) inhibitor, which has the following structural formula:
  • panitumumab trade name Vectibix, developed by Amgen Corporation of the United States, is the first fully humanized monoclonal antibody, which targets the epidermal growth factor receptor (EGFR), and was approved by the FDA at the end of 2005 for the treatment of metastatic colorectal cancer after chemotherapy failure.
  • EGFR epidermal growth factor receptor
  • QL1203 (recombinant anti-EGFR fully human monoclonal antibody injection), is a biosimilar to panitumumab.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • antibody refers to a binding protein having at least one antigen binding domain.
  • Antibodies and fragments thereof of the present invention may be whole antibodies or any fragments thereof. Accordingly, the antibodies and fragments of the invention include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein can be of the IgG1, IgG2, IgG3 or IgG4 isotype.
  • humanized antibody refers to an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may contain substitutions in the framework regions such that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.
  • mAb refers to an antibody molecule of single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope, or, in the case of bispecific monoclonal antibodies, dual binding specificities for two different epitopes. A mAb is an example of an isolated antibody. mAbs can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.
  • anti-EGFR antibody refers to an antibody that binds EGFR with sufficient affinity and specificity.
  • the selected antibody typically has a binding affinity for EGFR, for example, the antibody can bind EGFR with a Kd value from 1 pM to 100 nM.
  • antibody affinity can be determined by surface plasmon resonance-based assays such as the BIAcore assay described in PCT Publication WO2005/012359; by enzyme-linked immunosorbent assays (ELISA); and competition assays such as RIA's.
  • the anti-EGFR antibodies of the invention can be used as therapeutic agents in targeting and interfering with diseases or disorders in which EGFR activity is implicated.
  • the antibodies can be tested for other biological activities, eg, to assess their efficacy as therapeutic agents.
  • Such assays are known in the art and depend on the target antigen and the intended application of the antibody. Examples include HUVEC inhibition assays; tumor cell growth inhibition assays (eg, as described in WO89/06692); antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) assays (eg, patent US 5,500,362); and agonist activity or hematopoietic assays (see WO95/27062).
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) preventing the disease or symptom in a patient susceptible to the disease or symptom but not yet diagnosed with the disease; (b) inhibiting the symptom of the disease, i.e. preventing its development; or (c) relieving the symptom of the disease, i.e. causing regression of the disease or symptom.
  • the term "subject” refers to mammals, such as rodents, felines, canines, and primates.
  • the subject of the invention is a human.
  • administering means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration for anti-EGFR antibodies include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion.
  • parenteral administration refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation.
  • the anti-EGFR antibody is administered non-parenterally, and in certain embodiments, orally.
  • non-parenteral routes include topical, epidermal, or mucosal
  • the route of administration is, for example, intranasal, vaginal, rectal, sublingual or topical. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.
  • subject includes any human or non-human animal.
  • non-human animal includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the subject is a human.
  • subject and patient are used interchangeably in certain contexts herein.
  • a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is any amount of the drug which, when used alone or in combination with another therapeutic agent, protects a subject from disease onset or promotes regression of disease as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or prevention of impairment or disability resulting from disease affliction.
  • the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predicting efficacy in humans, or by measuring the activity of the agent in in vitro assays.
  • a therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of drug that inhibits the onset or recurrence of cancer when administered alone or in combination with an antineoplastic agent to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of cancer recurrence.
  • the prophylactically effective amount completely prevents the occurrence or recurrence of cancer.
  • “Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of the occurrence or recurrence of cancer, or preventing the occurrence or recurrence of cancer altogether.
  • a “recurrent” cancer is one that regenerates at the original site or at a distant site after responding to initial treatment (eg, surgery).
  • a “locally recurrent” cancer is one that, after treatment, arises in the same location as a previously treated cancer.
  • Metalstatic cancer is cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • fixed combination means that the active ingredients (eg, anti-EGFR antibody or compound of formula I) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.
  • active ingredients eg, anti-EGFR antibody or compound of formula I
  • non-fixed combination means that two or more active components are administered to a subject simultaneously, concurrently or sequentially as independent entities (eg, pharmaceutical composition, preparation) without specific time limit, wherein the active components administered to the subject reach a therapeutically effective level.
  • examples of non-fixed combinations are cocktail therapy, eg administration of 3 or more active ingredients.
  • the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of "fixed combinations" or independent entities of any one or more active components.
  • pharmaceutical composition refers to a mixture of one or more active ingredients of the present application (such as anti-EGFR antibody or compound of formula I) or its pharmaceutical combination and pharmaceutically acceptable excipients.
  • active ingredients of the present application such as anti-EGFR antibody or compound of formula I
  • pharmaceutical composition is to facilitate administration of a compound of the present application, or a pharmaceutical combination thereof, to a subject.
  • the term "synergistic effect” refers to the simple addition of two or more ingredients (eg, anti-EGFR antibody or compound of formula I) that produce an effect (eg, inhibition of lung cancer growth) that is greater than the effect of the ingredients administered alone.
  • the components in the combined drug combination of the present invention can be formulated separately.
  • the components in the combination pharmaceutical composition of the present invention can be formulated into a pharmaceutical composition suitable for single or multiple administration.
  • the components in the combined pharmaceutical composition of the present invention can be administered alone, or part or all of them can be administered together.
  • the components in the combined pharmaceutical composition of the present invention may be administered substantially differently, or part or all of them may be administered substantially simultaneously.
  • the components in the combined pharmaceutical composition of the present invention can be administered independently, or part or all of them together, in various suitable routes, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes).
  • the components of the combined pharmaceutical composition of the present invention can be administered independently, or part or all of them can be administered together orally or by injection, such as intravenous injection or intraperitoneal injection.
  • the components in the combined pharmaceutical composition of the present invention can be each independently, or some or all of them can be suitable dosage forms together, including, but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms of sustained release preparations for oral or parenteral administration.
  • suitable dosage forms including, but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms of sustained release preparations for oral or parenteral administration.
  • the components in the combined pharmaceutical composition of the present invention may be each independently, or part or all of them together contain pharmaceutically acceptable carriers and/or excipients.
  • the combination pharmaceutical compositions of the present invention may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a lung cancer therapeutic agent.
  • the curative effect of the compound of formula I and anti-EGFR antibody alone or in combination on lung tumors was investigated.
  • the compound of formula I had an obvious synergistic effect with the anti-EGFR antibody, breaking the established immune tolerance of the body to tumor cells.
  • Fig. 1 is the tumor growth curve of human lung cancer cell line H1975 EGFR (Del19/T790M/C797S) xenograft tumor model tumor-bearing mice after administration of test drug formula I compound, QL1203, Vectibix, formula I compound and QL1203 combination and formula I compound and Vectibix combination;
  • Fig. 2 is the relative tumor growth curve of the human lung cancer cell line H1975 EGFR (Del19/T790M/C797S) xenograft tumor model tumor-bearing mice given the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203 and the combination of the compound of formula I and Vectibix;
  • Fig. 3 is the tumor growth curve of the Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model tumor-bearing mice given the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203 and the combination of the compound of formula I and Vectibix;
  • Figure 4 is the relative tumor growth curve of the Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model tumor-bearing mice administered with the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203, and the combination of the compound of formula I and Vectibix.
  • Example 1 In vivo drug on H1975 EGFR (Del19/T790M/C797S) subcutaneous xenograft tumor BALB/c nude mouse model effect
  • the purpose of this experiment is to evaluate the in vivo efficacy of small molecular formula I compound combined with panitumumab on H1975 EGFR (Del19/T790M/C797S) subcutaneous xenograft tumor BALB/c nude mouse model.
  • mice Animal groups and dosing regimens for in vivo efficacy experiments Note: 1.N: the number of mice in each group. 2. Administration volume: the compound of formula I was administered according to the body weight of the mice at 10 ⁇ L/g; the fixed volume of QL1203 and Vectibix was 200 ⁇ L/mouse. Vehicle is a mixed solution of 5% absolute ethanol and polyoxyethylene 40 hydrogenated castor oil (1:1) + 95% sterile water for injection. 3. Frequency of preparation of all medicines: ready-to-use.
  • panitumumab trade name Vectibix
  • Amgen Corporation of the United States.
  • QL1203 (recombinant anti-EGFR fully human monoclonal antibody injection), is a biosimilar to Vectibix.
  • the cell line H1975 EGFR (Del19/T790M/C797S) was cultured in vitro, and the culture conditions were RPMI1640 medium plus 10% fetal bovine serum, 1% double antibody (penicillin/streptomycin solution), 10 ⁇ g/ml blasticidin, and cultured at 37°C in 5% CO 2 . Subculture by routine centrifugation twice a week. When the confluence of the cells is 80%-90% and the number reaches the requirement, the cells are collected, counted and inoculated.
  • PBS containing 5 ⁇ 106 H1975 EGFR (Del19/T790M/C797S) cells was mixed with Matrigel at a ratio of 1:1 (final volume: 100 ⁇ L) and inoculated subcutaneously in the axilla of the right forelimb of each mouse, and grouped administration began when the average tumor volume of the animals reached 185mm3 . See Table 1-2 for experimental groups and dosing regimens.
  • Test substance preparation method Note: The drug needs to be mixed gently before administration.
  • the health status and death of the animals were monitored every day. Routine inspections included observing the effects of tumor growth and drug treatment on the daily behavior of the animals, such as behavioral activities, food and water intake (visual inspection only), changes in body weight (body weight was measured once a day), appearance signs or other abnormal conditions. Animal deaths and side effects within groups were recorded based on the number of animals in each group.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured with vernier calipers three times a week.
  • TGI % or relative tumor proliferation rate T/C (%).
  • TGI (%) reflects tumor growth inhibition rate. Calculation of TGI(%):
  • TGI (%) ⁇ (1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group))/(Average tumor volume at the end of treatment of the vehicle control group-Average tumor volume at the beginning of treatment of the vehicle control group)] ⁇ 100%.
  • T/C% TRTV/CRTV ⁇ 100% (TRTV: RTV of treatment group; CRTV: RTV of negative control group).
  • the body weight of experimental animals was used as a reference index for indirect determination of drug toxicity.
  • the vehicle group, the compound of formula I 25mg/kg and 75mg/kg group, the QL1203 0.1mg/group, the Vectibix 0.1mg/group, the compound of formula I 25mg/kg+QL1203 0.1mg/combination group and the compound of formula I 25mg/kg+Vectibix 0.1mg/combination group the animal body weight remained stable, and the compound of formula I 75mg/kg+Vectibix 0.1 mg/mouse and the compound of formula I 75mg/kg+QL1203 0.1mg/mouse combined group, the body weight of individual mice decreased in the later stage of administration. All mice had no disease and death.
  • H1975 EGFR (Del19/T790M/C797S) xenograft tumor female BALB/c nude mouse model
  • the changes in tumor volume in each group given the compound of formula I are shown in Table 1-5.
  • Table 1-5 Tumor volume of each group at different time points Note: a. Mean ⁇ SEM, b. Days after administration.
  • the H1975 EGFR (Del19/T790M/C797S) xenograft tumor female BALB/c nude mouse model was administered with the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203, and the combination of compound of formula I and Vectibix.
  • the tumor growth curves and relative tumor growth curves of each group are shown in Figure 1 and Figure 2.
  • the cp value was calculated based on the relative tumor volume, and the Vehicle group was used as the control, and the T-test was used for analysis and comparison between the two groups;
  • the dp value is calculated according to the relative tumor volume, with the compound of formula I 25mg/kg group as the control, and the compound of formula I 25mg/kg+QL1203 0.1mg/only or the compound of formula I 25mg/kg+Vectibix 0.1mg/group for analysis and comparison between the two groups by T-test;
  • the ep value is calculated based on the relative tumor volume, with the compound of formula I 75 mg/kg group as the control, and the compound of formula I 75 mg/kg+QL1203 0.1 mg/only or the compound of formula I 75 mg/kg+Vectibix 0.1 mg/
  • the tumor volume of the tumor-bearing mice in the vehicle control group reached 1,683 mm 3 .
  • the compound of formula I 25 mg/kg, QL1203 0.1 mg/body and Vectibix 0.1 mg/body alone had no obvious tumor inhibitory effect
  • the compound of formula I at a dose of 25 mg/kg combined with QL1203 or Vectibix had a certain delay effect on tumor growth
  • the compound of formula I combined with QL1203 or Vectibix at a dose of 75 mg/kg had a significantly enhanced tumor inhibitory effect.
  • the purpose of this experiment is to evaluate the in vivo efficacy of small molecular formula I compound combined with panitumumab on Baf3 EGFR (L858R/T790M/C797S) subcutaneous xenograft tumor BALB/c nude mouse model.
  • mice Animal groups and dosing regimens for in vivo efficacy experiments Note: aN: number of mice in each group; b. If the body weight drops by more than 15%, the mice will be treated with drug withdrawal and observed until their body weight returns to more than 10% before continuing to administer the drug; c.
  • the vehicle is a mixed solution of 5% absolute ethanol and polyoxyethylene 40 hydrogenated castor oil (1:1) + 95% sterile water for injection.
  • the cell line Baf3 EGFR (L858R/T790M/C797S) was cultured in vitro, and the culture conditions were RPMI1640 medium plus 10% fetal bovine serum, 1% double antibody (penicillin/streptomycin solution), 37 ° C, 5% CO 2 culture. Subculture by routine centrifugation twice a week. When the confluence of the cells is 80%-90% and the number reaches the requirement, the cells are collected, counted and inoculated.
  • PBS containing 5 ⁇ 10 5 Baf3 EGFR (L858R/T790M/C797S) cells was mixed with Matrigel at a ratio of 1:1 (final volume 100 ⁇ L) and inoculated subcutaneously in the right forelimb armpit of each mouse.
  • the average tumor volume of the enrolled animals reached 105 mm 3 and began to be administered into groups. See Table 2-1 for experimental groups and dosing regimens.
  • Test substance preparation method Note: The drug is prepared and used now, and the drug needs to be mixed gently before administration.
  • the health status and death of the animals were monitored every day. Routine inspections included observing the effects of tumor growth and drug treatment on the daily behavior of the animals, such as behavioral activities, food and water intake (visual inspection only), changes in body weight (body weight was measured once a day), appearance signs or other abnormal conditions. Animal deaths and side effects within groups were recorded based on the number of animals in each group.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured with vernier calipers three times a week.
  • TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [1-(average tumor volume at the end of administration of a treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of the vehicle control group-average tumor volume at the beginning of treatment of the vehicle control group)] ⁇ 100%.
  • mice in each group survived on the 10th day and each treatment group showed a better therapeutic effect, the experiment ended on the 14th day, so statistical analysis was performed based on the data on the 10th day and the 14th day to evaluate the differences between the groups.
  • the comparison between the two groups was analyzed by T-test, and SPSS 17.0 was used for all data analysis. p ⁇ 0.05 considered significant difference.
  • the body weight of the animals in the vehicle group, QL1203 0.1mg/group and Vectibix 0.1mg/group remained stable, and some animals in the formula I compound 75mg/kg single drug group, the formula I compound 75mg/kg+QL1203 0.1mg/group and the formula I compound 75mg/kg+Vectibix 0.1mg/group group showed weight loss, but no animal became ill or died.
  • Baf3 EGFR (L858R/T790M/C797S) xenograft tumor female BALB/c nude mouse model was administered with the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203, and the combination of compound of formula I and Vectibix.
  • the changes in tumor volume in each group are shown in Table 2-3.
  • Table 2-3 Tumor volume of each group at different time points Note: a. Mean ⁇ SEM; b. Days after administration.
  • Baf3 EGFR (L858R/T790M/C797S) xenograft tumor female BALB/c nude mouse model was given the compound of formula I, QL1203, Vectibix, the combination of compound of formula I and QL1203 and the combination of compound of formula I and Vectibix.
  • the tumor growth curves and relative tumor growth curves of each group are shown in Figure 3 and Figure 4.
  • Table 2-4 Evaluation of antitumor efficacy of Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model (calculated based on the tumor volume on day 10 after administration) Note: a. Mean ⁇ SEM; b.
  • the cp value was analyzed by T-test according to the relative tumor volume of each mouse in different groups and the vehicle group as the control;
  • the dp value is analyzed using T-test according to the relative tumor volume of each mouse in different groups with formula I compound 75mg/kg group as a control;
  • the ep value was analyzed by T-test according to the relative tumor volume of each mouse in different groups, and the QL1203 0.1mg/mouse group was used as the control;
  • the fp value was analyzed by T-test according to the relative tumor volume of each mouse in different groups, and the compound of formula I 75mg/kg+Vectibix 0.1mg/group was used as the control group.
  • the bp value is analyzed by T-test according to the relative tumor volume of each mouse in different groups with the formula I compound 75mg/kg group as a control;
  • the cp value was analyzed by T-test according to the relative tumor volume of each mouse in different groups, and the QL1203 0.1 mg/mouse group was used as the control;
  • the dp value is analyzed by T-test according to the relative tumor volume of each mouse in different groups with formula I compound 75mg/kg+Vectibix 0.1mg/ group as a control; e.
  • the tumor volume is greater than 0 and less than the initial tumor volume, it is regarded as partial regression;
  • f At the end of the experiment, a tumor volume of 0 is considered as complete regression.
  • the combination group of the compound of formula I and QL1203 or the combination group of the compound of formula I and Vectibix has significantly better antitumor effect than that of the compound of formula I, QL1203 or Vectibix alone (p ⁇ 0.05).
  • the antitumor effect is significantly enhanced, and has an obvious synergistic effect.

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Abstract

Est divulguée une combinaison pharmaceutique d'un inhibiteur d'ALK et d'un anticorps, qui comprend un oxyde d'arylphosphore spirocyclique et un anticorps anti-EGFR, l'inhibiteur d'ALK étant un composé de formule (I) ou un sel de qualité pharmaceutique de celui-ci. La combinaison pharmaceutique de la présente invention est utilisée pour traiter le cancer du poumon et présente une bonne activité antitumorale.
PCT/CN2023/072607 2022-01-18 2023-01-17 Combinaison pharmaceutique d'oxyde d'arylphosphore spirocyclique et d'anticorps anti-egfr WO2023138576A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105330698A (zh) * 2014-07-04 2016-02-17 南京明德新药研发股份有限公司 螺环芳基磷氧化物和硫化物
US20170129909A1 (en) * 2014-07-04 2017-05-11 Quilu Pharmaceutical Co., Ltd. Spirocyclic aryl phosphorus oxide and aryl phosphorus sulfide
WO2018108064A1 (fr) * 2016-12-13 2018-06-21 南京明德新药研发股份有限公司 Composé spiro-aryl-phosphore-oxygène comme quatrième génération d'inhibiteur de kinase egfr
CN110772638A (zh) * 2018-07-31 2020-02-11 苏州亚盛药业有限公司 Fak/alk/ros1抑制剂与egfr抑制剂的组合治疗癌症的方法
CN112996534A (zh) * 2018-08-07 2021-06-18 因斯瑞拜奥有限公司 结合间变性淋巴瘤激酶抑制剂进行egf/egfr通路抑制的方法和组合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105330698A (zh) * 2014-07-04 2016-02-17 南京明德新药研发股份有限公司 螺环芳基磷氧化物和硫化物
US20170129909A1 (en) * 2014-07-04 2017-05-11 Quilu Pharmaceutical Co., Ltd. Spirocyclic aryl phosphorus oxide and aryl phosphorus sulfide
WO2018108064A1 (fr) * 2016-12-13 2018-06-21 南京明德新药研发股份有限公司 Composé spiro-aryl-phosphore-oxygène comme quatrième génération d'inhibiteur de kinase egfr
CN110772638A (zh) * 2018-07-31 2020-02-11 苏州亚盛药业有限公司 Fak/alk/ros1抑制剂与egfr抑制剂的组合治疗癌症的方法
CN112996534A (zh) * 2018-08-07 2021-06-18 因斯瑞拜奥有限公司 结合间变性淋巴瘤激酶抑制剂进行egf/egfr通路抑制的方法和组合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
INOUE YUKIHISA; MATSUBARA OSAMU; OHIRA YUMI; ENDO SATOSHI; JINN YASUTO: "A case of synchronous multiple primary lung adenocarcinomas harboring epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement successfully treated with combination of osimertinib and alectinib", RESPIRATORY MEDICINE CME, vol. 33, 1 January 2021 (2021-01-01), AMSTERDAM, NL , XP086713229, ISSN: 2213-0071, DOI: 10.1016/j.rmcr.2021.101418 *
S. GARCIA-ROMAN ET AL.: "Anti-EGF Antibodies Increase the Effect of ALK and MEK Inhibitors in ALK and KRAS NSCLC and CRC Cell Lines", JOURNAL OF THORACIC ONCOLOGY, vol. 13, no. 105, 1 October 2018 (2018-10-01), pages S582, XP002796968 *

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