Regorafenib in combination with PD-1 / PD-L1(2) inhibitors for cancer treatment

Abstract

To provide combination pharmaceuticals for treating, preventing or managing diseases and conditions including hyperproliferative disorders such as cancer in humans and other mammals.SOLUTION: Disclosed is a combination pharmaceutical comprising regorafenib or its hydrate, solvate, metabolite or pharmaceutically acceptable salt or a polymorph thereof and a PD-1 / PD-L1(2) inhibitor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides a method for treating and preventing diseases and conditions, including hyperproliferative disorders such as cancer in humans and other mammals. Regorafenib or its hydrates, solvates, metabolites or drugs for the prevention or management of and a pharmaceutical composition containing a physiologically acceptable salt or polymorph thereof and a PD-1 / PD-L1(2) inhibitor. It relates to pharmaceutical compositions and pharmaceutical combinations. [Background technology]

[0002] Regorafenib is a 4{4-[3-(4-chloro-3-trifluoromethylphenyl) -ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide It is a compound represented by formula (I).

[0003] TIFF0007806119000001.tif36141Regorafenib inhibits VEGFR, PDGFR, raf, p38, and / or flt Potent anticancer agent with various activities, including inhibitory activity against N-3 kinase signaling molecules , anti-angiogenic and anti-metastatic agents, and are described in WO 2005 / 009961. As previously reported, hyperproliferative disorders such as cancers, tumors, lymphomas, sarcomas, and leukemias are It can be used to treat a variety of diseases and conditions. Currently, it is used in the treatment of colon cancer and gastrointestinal stromal tumors under certain conditions. In addition, salts of the compounds of formula (I), such as the salts thereof, are also approved for the treatment of ovarian cancer and liver cancer. The acid salt, mesylate and phenylsulfonate salts are described in WO 2005 / 009961. The monohydrate of the compound of formula (I) is described in WO 2008 / 043446 An improved process for the production of high purity regorafenib is described in This is described in International Publication No. 2011 / 128261.

[0004] Recently, the PD-1 / PD-L1(2) signaling pathway has been recognized as an important regulator of immune system activity. In cancer, tumor cells express PD-L1, a ligand for PD-1. This allows them to avoid being killed by the host immune system. Recently, inhibitors against PD-L1 and PD-L2 have been developed to disrupt this immunosuppressive mechanism. It has shown remarkable clinical efficacy by extending overall survival in patients with various types of cancer. Some of these inhibitors are effective in treating melanoma, NSCLC, HNSCC, RCC, bladder cancer, and NH It has been approved for various cancer indications, including L. in other indications, and / or Numerous additional clinical trials are underway in combination with various other antitumor agents to improve therapeutic activity. This is currently underway (Iwai et al., J. Biomedical Sci. (2017) 24:26, 1-11;Sweis and Luke, Pharm.Res.(2017)120, 1-9; Bersanelle and Buti, World Journal o f Clinical Oncology,(2017)8(1), 37-53;Par k et al., Arch.Pharm.Res.(2016)39,1577-15 87).

[0005] PD-1 inhibitors are biological agents, primarily immunoglobulins of the G subclass, Binds to and blocks the activity of programmed cell death protein 1, also known as PD-1 Known PD-1 inhibitors include nivolumab (Opdivo, BMS-936558, M DX1106), pembrolizumab (Keytruda, MK-3475, Lambrolizumab Mab), pidilizumab (CT-011), PDR-001, JS001, STI-A1 110, AMP-224, and AMP-514 (MEDI0680). The latter two is a PD-L2 fusion protein (Iwai et al., J. Biomedical Sci. (2 017)24:26,1-11;Menon et al., Cancers(2016 )8,106,1-21).

[0006] PD-1 (CD279) is expressed primarily on activated CD4+ and CD8+ T cells and macrophages. A receptor protein expressed as a monomer on the surface of various immune cells, including activated B cells. It is a protein found on natural killer (NK) cells and antigen-presenting cells (APCs). The extracellular domain of this type I membrane protein contains a single IgV-like domain and This is followed by a transmembrane domain and an immunoreceptor tyrosine-based inhibitory and switch motif ( It consists of a cytoplasmic domain containing ITIM and ITSM. Upon binding to PD-L2 or PD-L2, the phosphatase SHP-2 is recruited and binds to the T cell receptor (T It dephosphorylates the kinase ZAP70, a key component of the CR signaling complex. This blocks TCR signaling, inhibiting T cell cytotoxicity and interferon gamma production. Furthermore, PD-1 ligation down-modulates the T cell receptor. Upregulation of E3-ubiquitin ligases CBL-b and c-CBL, which trigger the ubiquitination of PD-1 pre-regulates Pdcdl Encoded by the gene TC Activation of R and T cells, such as transforming growth factor β and eomesodermin The transcription factors NFATcl, IRF9, and FoxO1 are activated by starvation signals. Activation-induced expression of PD-1 indicates that this receptor is rather involved in the immune response of peripheral tissues. These findings suggest that it regulates the later stages of the response (effector phase, memory response, and chronic infection). This is in contrast to CTLA-4, which is an early and primal component of the immune response. Another immune checkpoint protein that is more active during the aging phase is CTLA- Inhibitors of 4 (e.g., ipilimumab) appear to be poorly tolerated by patients (Iwai et al., J. Biomedical Sci.(2017)24:26,1-11;Sweis an d Luke, Pharm.Res.(2017)120,1-9;Park et a l., Arch.Pharm.Res.(2016)39,1577-1587).

[0007] PD-L1 inhibitors are biologics, primarily immunoglobulins of the G subclass. , which bind to the ligand of PD-1 and block its activity. Known PD-L1 inhibitors include: Atezolizumab (Tecentriq, MPDL3280A), durvalumab (MED I4736), avelumab (MSB0010718C), BMS-936559 (MDX 1105) and LY3300054.

[0008] PD-L1 (B7-H1, CD274) is one of the ligands for PD-1. 1 is a method for the identification of many different immune cell populations (e.g., T-, B-, NK cells, DCs, monocytes, macrophages, etc.). The phage is expressed on the cell surface of activated vascular endothelial cells, as well as in melanoma, lung, ovarian, and PD-L1 is widely expressed on epithelial cells, including tumor cells of various entities, such as colon and pancreatic cancers. The expression of interferon-γ, interferon type I and gamma chain cytokines (IL- These cytokines are enhanced by proinflammatory cytokines such as inflammatory cytokines 2, 4, 7, 9, 15, and 21. As mentioned above, T cell activation is inhibited by interaction with PD-1, which This suppresses the immune response (Park et al., Arch. Pharm. Res. ( 2016)39,1577-1587;Menon et al., Cancers(2 016)8, 106, 1-21).

[0009] PD-L2 (CD273, B7-DC) has been shown to bind to PD-1. The second ligand is also a membrane-bound protein, and its expression is localized to small cells of the immune system. It is restricted to a subset (DCs and macrophages) and is found in cancers such as liver, cervix, and esophagus. Currently, PD-L2 is used as a fusion protein. It is currently being developed as a therapeutic agent that blocks the activity of PD-1, and ultimately L2 inhibitors may also emerge as therapeutic agents. In the first instance, PD-1 / PD-L1 inhibitors include antibody preparations. Research is ongoing into other types of PD-1 / PD-L1(2) inhibitors, including small molecules and peptides. Examples of small molecule inhibitors of PD-1 / PD-L1 that have been described include BMS -202, BMS-8, BMS-37 (Zak et al., Structure.2 017 Aug 1;25(8):1163-1174;Guzik et al., J Med Chem.2017 Jul 13;60(13):5857-5867), CA-170, CA-137 (Tuck D ICI Symposium March 2017) and and caffeoylquinic acid compounds (Han et al., Anal Biochem. 2014). 18 Apr 15;547:52-56). An example of a peptide inhibitor is Maute et al.(Proc Natl Acad Sci USA.2015 Nov 24;112(47):E6506-14). Furthermore, GSKa / β inhibitors Small molecule inhibitors that affect PD-1 transcription, such as the anti-PD-1 drug SB415286, have also been identified. (Taylor et al., Cancer Res. 2018 Feb 1 ;78(3):706-717). WO 2015 / 11993 describes a combination of VEGF inhibitors and PD-1 inhibitors for the treatment of cancer. Combinations of antagonists have been described. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2005 / 009961 [Patent Document 2] International Publication No. 2008 / 043446 [Patent Document 3] International Publication No. 2011 / 128261 [Patent Document 4] International Publication No. 2015 / 11993 [Non-patent literature]

[0011] [Non-Patent Document 1] J.Biomedical Sci.(2017)24:26,1-11 [Non-patent document 2] Pharm.Res.(2017)120,1-9 [Non-patent document 3] World Journal of Clinical Oncology,(2017)8(1), 37-53 [Non-patent document 4] Arch.Pharm.Res.(2016)39,1577-1587) [Non-Patent Document 5] Cancers(2016)8,106,1-21 [Non-patent document 6] Cancer Res.2018 Feb 1;78(3):706-717 Summary of the Invention [Problem to be solved by the invention]

[0012] The objective of the present invention is to develop a combination of regorafenib and a PD-1 / PD-L1(2) inhibitor. The goal is to improve cancer treatment by administering [Means for solving the problem]

[0013] Surprisingly, the combination of regorafenib and a PD-1 / PD-L1(2) inhibitor , significant efficacy improvement over the sum of monotherapies, particularly significant antitumor and / or antimetastatic efficacy Furthermore, the side effect profile (e.g., hand-foot syndrome, elevated blood pressure, fatigue) It can improve symptoms such as diarrhea and mucosal inflammation. The present invention relates to regorafenib, a compound of formula (I): TIFF0007806119000002.tif36132 or a hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, or a polymorph thereof and combinations including PD-1 / PD-L1(2) inhibitors. [Brief explanation of the drawings]

[0014] [Figure 1] Figure 1: Antitumor activity of regorafenib and anti-PD-1 alone and in combination in the syngeneic murine MC38 CRC model. v + i = vehicle + isotype, a) = regimen a), b) = regimen b), c) = regimen c), d) = regimen d), e) = regimen e). DETAILED DESCRIPTION OF THE INVENTION

[0015] The term "compound of formula (I)" or "regorafenib" refers to 4-{4-[({[4 -chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3- fluorophenoxy}-N-methylpyridine-2-carboxamide It is being done. For the purposes of this invention solvate is a chemical compound with which solvent molecules form stoichiometric complexes in the solid state. The solvent molecules include, for example, water, ethanol, and methyl These include, but are not limited to, phenols. hydrate is a particular form of solvate, in which the solvent molecule is water. Hydrates of salts of the compounds of the present invention are, for example, hemihydrates, monohydrates or dihydrates of the compounds or salts. The monohydrate of regorafenib is preferred. For the purposes of this invention salt is preferably a pharmaceutically acceptable salt of a compound according to the invention. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include hydrochloric acid, hydrobromic acid, sulfuric acid, and the like. , phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p -Toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalene Sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, Citric acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, etc. In addition, pharmaceutically acceptable salts include those derived from inorganic and organic acids. Ba, Li + , Na + or K + ), alkaline earth cations (e.g., Mg+2 , Ca +2 or Ba +2 ), salts of inorganic bases such as salts containing ammonium cations, and fats Aliphatic and aromatic substituted ammonium, triethylamine, N,N-diethylamine, N , N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine ( DMAP), 1,4-diazabichloro[2.2.2]octane (DABCO), 1,5-di Azabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[ 5.4.0] resulting from the protonation or overalkylation of undec-7-ene (DBU) These include acid salts of organic bases containing quaternary ammonium cations such as regorafenib. The hydrochloride, mesylate or phenylsulfonate salts of benzophenone are preferred. For the purposes of the present invention, Metabolites 4-[4-({[4-chloro- 3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy 4-[4-({[4- Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoro phenoxy]-N-(hydroxymethyl)pyridine-2-carboxamide, 4-[4-( {[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3- fluorophenoxy]pyridine-2-carboxamide and 4-[4-({[4-chloro -3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy oxy]pyridine-2-carboxamide 1-oxide.

[0016] Preferred compounds of the present invention are regorafenib and the monohydrate form of regorafenib It is a thing. The compounds of the present invention can be prepared by use of known chemical reactions and procedures. The term "PD-1 / PD-L1(2) inhibitor" refers to nivolumab (Opdivo, B MS-936558, MDX1106), pembrolizumab (Keytruda, MK- 3475, lambrolizumab), pidilizumab (CT-011), PDR-001, J S001, STI-A1110, AMP-224 and AMP-514 (MEDI068 0), or atezolizumab (T ecentriq, MPDL3280A), durvalumab (MEDI4736), Abe Lumab (MSB0010718C), BMS-936559 (MDX1105) and L anti-PD-L1 antibodies, including but not limited to Y3300054, or anti-PD-L2 Refers to antibodies. Nivolumab, pembrolizumab, or pidilizumab are preferred anti-PD-1 antibodies. Desirable.

[0017] Furthermore, atezolizumab, durvalumab, or avelumab are anti-PD-L1 antibodies It is preferable as. The term "PD-1 / PD-L1(2) inhibitor" includes BMS-202, BMS-8, Contains BMS-37, a caffeoylquinic acid compound, and the GSKa / β inhibitor SB415286 It also refers to small molecules and peptides, including but not limited to: Treatment method The present invention also provides a method for treating a hyperproliferative disorder in a mammal, comprising administering to said mammal a compound of formula (I) or (II) comprising administering to said mammal a compound of formula (I) or (II) a method for treating a hyperproliferative disorder in a mammal, ... The present invention relates to a method for using the composition and a method for treating a disorder. The method includes administering an amount of the combination to a mammal, including a human, in need thereof. Proliferative disorders include those affecting the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, Solid tumors such as thyroid and parathyroid carcinomas and their distant metastases, including, but not limited to, These disorders also include, but are not limited to, lymphoma, sarcoma, and leukemia. Examples of breast cancer include invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. These include, but are not limited to: Examples of cancers of the respiratory tract include small cell and non-small cell lung cancer, as well as bronchial adenoma and pleuropulmonary blastoma. These include, but are not limited to: Examples of brain cancer include brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, mesodermoma, These include, but are not limited to, ependymomas, as well as neuroectodermal and pineal tumors.

[0018] Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive tract include endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, and vulvar cancer. These include, but are not limited to, uterine sarcoma and uterine sarcoma. Gastrointestinal tumors include anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, and rectal cancer. Cancers of the small intestine, small intestine, and salivary gland are examples of cancers that can be diagnosed as ulcerative colitis. It is preferably applied to colon cancer. Application to gastrointestinal stromal tumors (GIST) is also preferred. Tumors of the urinary tract include cancers of the bladder, penis, kidney, renal pelvis, ureter, and urethra. Not limited to.

[0019] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma. Examples of liver cancer include hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar transformation), cholangiocarcinoma (hepatic cholangiocarcinoma), and mixed hepatocellular-cholangiocarcinoma. Application to hepatocellular carcinoma is preferred.

[0020] Skin cancers include squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma. This includes, but is not limited to, chromoma skin cancer. Head and neck cancers include laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, and lip and oral cavity cancer. However, it is not limited to these. Lymphomas include AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and Hodgkin's lymphoma. These include, but are not limited to, rheumatoid arthritis, rheumatoid arthritis, and lymphoma of the central nervous system. Sarcomas include soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and striated muscle sarcoma. Including, but not limited to, sarcoma. Leukemia includes acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and chronic lymphocytic leukemia. These include, but are not limited to, myeloid leukemia, and hairy cell leukemia.

[0021] These disorders are well characterized in humans but also exist in other mammals with similar etiologies. These conditions can be treated by administering the pharmaceutical composition of the present invention.

[0022] Known standard laboratory techniques for evaluating compounds useful in treating hyperproliferative disorders, standard Standard pharmacological assays for toxicity testing and determining treatment for the above conditions in mammals. B) and comparing those results with those of known drugs used to treat the condition. Based on this, the effective dosage of the compounds of the present invention for the treatment of each desired indication can be readily determined. The amount of active ingredient administered in the treatment of these conditions will vary depending on the particular compound and dosage used. dosage, method of administration, duration of treatment, age and sex of the patient, and the nature and extent of the condition to be treated This can vary greatly depending on considerations such as the range of The present invention further provides a compound of the invention for the preparation of a pharmaceutical composition for the treatment of the aforementioned disorders. Provides for the use of Administration The combination of the present invention can be administered, for example, orally, parenterally, enterally, intravenously, intraperitoneally, topically, transdermal (e.g., using any standard patch), ophthalmic, nasal, topical, parenteral, aerosol any route, including inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, intrathecal, etc. They can be administered in any form by any effective route. It can be administered in combination with an active ingredient or an inactive ingredient. Regorafenib is preferably administered orally, for example as a tablet.

[0023] Preferably, the PD-1 / PD-L1(2) inhibitor can be administered intravenously.

[0024] The combinations of the present invention can be converted into conventional formulations in known manner, including liquid formulations. The formulation may be a tablet or solid formulation, such as regular and enteric-coated tablets, capsules, pills, Powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid air Examples of suitable emulsions include, but are not limited to, sols and emulsions. In general, the use of the above-described inventive combinations helps to:

[0025] (1) Reduce tumor growth or inhibit tumor growth compared with administration of either drug alone provides better efficacy in eradicating (2) providing a method of administration that uses lower doses of chemotherapy; (3) adverse pharmacology beyond that observed with single-agent chemotherapy and certain other combination therapies; provide chemotherapy treatments that are well tolerated by patients with few adverse events, (4) Providing treatment for a wide variety of cancer types in mammals, particularly humans. provide, (5) provide a higher response rate among treated patients; (6) Prolonging survival of treated patients compared with standard chemotherapy treatment; (7) increase the time it takes for tumors to progress, and / or (8) At least as effective as known cases where other combination anticancer drugs have an inhibitory effect It produces results with efficacy and tolerability comparable to those of single agents. A "combination" for the purposes of this invention refers to a dosage form containing all of the components (a so-called fixed combination). combinations), and combination packs containing ingredients separated from each other, as well as When used for prophylaxis or treatment, it also refers to components administered simultaneously or sequentially. .

[0026] The amount of active ingredient administered will depend on the particular compound and dosage unit used, the mode of administration and the age, sex, and general condition of the patient being treated, the symptoms being treated, the nature and extent, rate of drug metabolism and excretion, potential drug combinations and drug-drug interactions The number of samples can vary widely depending on considerations such as use. A particularly interesting embodiment of the invention is a dose of 4 to 400 mg, preferably 10 to 200 mg, more preferably 10 to 200 mg. More preferably, regorafenib is administered in an amount of 10 to 100 mg, and 0 mg of regorafenib is administered in an amount of 0.5 mg based on the patient's body weight. PD-1 / PD- The combination includes administration of an L1(2) inhibitor. According to the present invention, regorafenib and a PD-1 / PD-L1(2) inhibitor are administered simultaneously. It can be given. In a further embodiment of the invention, regorafenib is administered first, followed by PD-1 / PD -L1(2) inhibitors are administered. Alternatively, a PD-1 / PD-L1(2) inhibitor may be administered first, followed by regorafenib. The drug is administered intravenously, which is the preferred method of administration. The pharmaceutical composition of the present invention is administered one or more times a day, preferably up to three times a day, more preferably up to two times a day. Regorafenib is administered via the oral route, and PD via the intravenous route. Administration of PD-1 / PD-L1(2) inhibitors is preferred. However, body weight, individual response to the active ingredient, type of formulation, and administration may have an effect. Depending on the time or interval of exposure, it may be advantageous to deviate from the specified amounts. In some cases, less than the minimum amount above may be sufficient, while in other cases the above may be sufficient. If relatively large doses are administered, these should be taken several times a day. Divided administration is recommended. The combination comprises an effective amount of a compound of Formula I and a PD-1 / PD-L1(2) inhibitor. and achieve a greater therapeutic effect than when either compound is used alone. . The relative ratios of each compound in the combination are based on their respective mechanisms of action and disease biology. The relative ratios of each compound can vary widely. Where appropriate, one or more of the drugs in the combination may be controlled-release to provide a single dosage form, a combination In a combined pack, kit, or in separate, independent dosage forms, the compounds provide the desired therapeutic activity. It is also possible to do so. The present invention comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention. Pharmaceutically acceptable carriers are relatively non-toxic and suitable for the administration of active ingredients. It is harmless to patients at concentrations consistent with effective activity, so that side effects caused by the carrier are not Any carrier that does not impair the beneficial effect of the compound. A pharmaceutically effective amount of a compound is a specific amount of a compound administered during treatment. It is a quantity that has a consequence or influence on a certain state. For oral administration, the compounds may be administered in the form of solid dispersions, capsules, pills, tablets, troches, lozenges, etc. The compound may be formulated into a solid or liquid preparation such as a melt, powder, solution, suspension or emulsion. and may be prepared by techniques for the manufacture of pharmaceutical compositions known to those skilled in the art. Solid unit dosage forms may contain, for example, surfactants, lubricants, and additives such as lactose, sucrose, phosphate Regular hard or soft shells containing inert fillers such as calcium, cornstarch, etc. It may be in a gelatin type capsule.

[0027] In another embodiment, the compounds of the present invention are useful in the preparation of sugars containing lactose, sucrose, and corn starch. with conventional tablet bases such as cornstarch; or with binders such as acacia, cornstarch, or gelatin. Potato starch, alginic acid, corn starch, guar gum, tragacanth gum, alginic acid Disintegrants, such as cassia, to aid in disintegration and dissolution of the tablet after administration; e.g., talc, tablets, such as stearic acid or stearates of magnesium, calcium, or zinc To improve the flow of the granulation and prevent the tablet material from adhering to the surfaces of the tablet die and punches dyes, colorants, and paper additives to enhance tablet aesthetics and patient acceptance - Combine with flavorings such as mint, wintergreen oil, or cherry flavoring Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate. and water and alcohol (e.g., ethanol, benzyl alcohol, and polyethylene and a diluent such as an alcohol, a pharmaceutically acceptable surfactant, a suspending agent, or an emulsion. The physical form of the unit dosage form may or may not contain a coating. Various other materials may be present to modify the state of the formulation. For example, tablets, pills or Capsules may be coated with shellac, sugar, or both.

[0028] Dispersible powders and granules are suitable for the preparation of aqueous suspensions. They are suitable for dispersing or wetting The active ingredient is mixed with a dispersing agent, a suspending agent, and one or more preservatives. The surfactants or wetting agents and suspending agents are exemplified by those already mentioned above. Excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.

[0029] The pharmaceutical compositions of the present invention may be in the form of an oil-in-water emulsion. The oil phase may be liquid paraffin. Suitable emulsifiers include: (1) acacia oil, (2) sorbitol, (3) sorbitol, (4) sorbitol, (5) sorbitol, (6) sorbitol, (7) sorbitol, (8) sorbitol, (9) sorbitol, (10) sorbitol, (11) sorbitol, (12) sorbitol, (13) sorbitol, (14) sorbitol, (15) sorbitol, (16) sorbitol (2) natural gums such as gum tragacanth and gum sorbitan; (3) natural phosphatides such as soy lecithin; 3) Derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate (4) Condensation products of the above partial esters with ethylene oxide The emulsion may be prepared by dissolving the emulsion in a solvent, such as polyoxyethylene sorbitan monooleate. Sweetening and flavoring agents may also be included. Oily suspensions may be prepared using vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil. Formulating by suspending the active ingredient in oil or mineral oil such as liquid paraffin The oily suspensions can be prepared in a range of solutions, for example, beeswax, hard paraffin or cetyl alcohol. Thickening agents may be included. The suspension may also contain thickening agents, for example ethyl p-hydroxybenzoate or p - one or more preservatives, such as n-propyl hydroxybenzoate; one or more coloring agents; one or more flavorings; and one or more sweeteners, such as sucrose or saccharin. That's fine. Syrups and elixirs can be formulated with, for example, glycerol, propylene glycol, sodium hydroxide, sorbitol ... They may also be formulated with sweeteners such as sorbitol or sucrose. Contains no demulcents, preservatives such as methyl and propyl parabens, as well as flavorings and Coloring agents may also be included. The compounds of the present invention may be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or intravenously. Inject the pharmaceutical carrier, which may be a sterile liquid or mixture of liquids (water; saline; dextromethorphan; benzoyl peroxidase ... Aqueous solutions of sucrose and related sugars; ethanol, isopropanol, or hexane Alcohols such as diethyl alcohol; propylene glycol or polyethylene glycol glycols such as 2,2-dimethyl-1,1-dioxolane-4-methanol; glycerol ketals; ethers such as poly(ethylene glycol) 400; oils; fats Fatty acids; fatty acid esters or fatty acid glycerides; or acetylated fatty acid glycerides, etc. ) in a physiologically acceptable diluent with a pharmaceutically acceptable additive (soap or detergent) Surfactants such as pectin, carbomer, methylcellulose, hydroxypropyl methylcellulose suspending agents such as cellulose or carboxymethylcellulose; or emulsifying agents and and administering the compound as an injectable formulation, with or without other pharmaceutical adjuvants. It can also be done as follows.

[0030] Examples of oils that can be used in the parenteral formulations of the invention include those of petroleum, animal, vegetable, or synthetic origin. For example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, wase Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters include, for example, ethyl oleate and myristic acid. and isopropyl myristate. Suitable soaps include alkali metal soaps of fatty acids, Suitable detergents include cationic detergents, ammonium and triethanolamine salts. For example, dimethyldialkylammonium halides, alkylpyridinium halides and and alkylamine acetates, and anionic surfactants such as alkyl, Aryl and olefin sulfonates, alkyl, olefin, ether and monoglucan and nonionic surfactants, e.g., glycerides sulfates and sulfosuccinates. , fatty amine oxides, fatty acid alkanolamides and poly(oxyethylene oxypropane) propylene) or ethylene oxide or propylene oxide copolymers, or amphoteric surfactants, such as alkyl-β-aminopropionates and 2-alkyl- Included are midazoline quaternary ammonium salts, as well as mixtures of the above. The parenteral compositions of the present invention typically contain from about 0.5% to about 25% by weight of active ingredient in solution. Preservatives and buffers may also be used to advantage. To eliminate or eliminate such compositions, such compositions have a hydrophilic-lipophilic balance (HBL) of about 12 to about 17. The surfactant in such a formulation may include a non-ionic surfactant having a HLB. The amount of surfactant is in the range of about 5% to about 15% by weight. The HLB may be a single component or a mixture of two or more components having the desired HLB. Examples of surfactants used in parenteral formulations are polyethylene sorbitan fatty acid esters. classes, such as sorbitan monooleate, and propylene oxide and propylene glycol It is a high molecular weight adduct of ethylene oxide with a hydrophobic base formed by the condensation of glycol. do. The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. Examples of suitable cellulose acetates include sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, and the like. propyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth Suitable dispersing or wetting agents, such as gum acacia and gum lauric acid; natural phosphatase, such as lecithin; esters; condensation products of fatty acids with alkylene oxides, e.g., polyoxyethylene stearyl esters; condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g., heptadecaethylene ethylene glycol monooleate; polyoxyethylene sorbitol monooleate, etc. Condensation products of oxides with partial esters derived from fatty acids and hexitols; is a compound obtained by combining ethylene oxide, such as polyoxyethylene sorbitan monooleate. Condensation products of fatty acids and partial esters derived from hexitol anhydrides are used. It can be formulated according to known methods. The sterile injectable preparation may be prepared by administering sterile injectable solution in a non-toxic parenterally acceptable diluent or solvent. The diluents and solvents that can be used include, for example, , water, Ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0031] The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. The composition contains a drug that is solid at room temperature but liquid at rectal temperature, and therefore It can be prepared by mixing with a suitable non-irritating excipient that will melt in the rectum and release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.

[0032] Controlled release formulations for parenteral administration include those known in the art such as liposomes, polymeric microspheres, and the like. These include rospheric and polymeric gel formulations. The pharmaceutical composition of the present invention may be in the form of a solid dispersion. Glass solutions, glass suspensions, amorphous precipitates in crystalline carriers, eutectic or monocrystalline compounds or composites It can be body formation and combinations thereof.

[0033] One aspect of the invention that is of particular interest is a pharmaceutical composition comprising a solid dispersion, the matrix of which The materials are polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyalkylene glycol (i.e., polyethylene glycol), hydroxyalkyl cellulose ( hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e. (hydroxypropyl methylcellulose), carboxymethyl cellulose, sodium carbonate Carboxymethyl cellulose, ethyl cellulose, polymethacrylate, polyvinyl alcohol alcohol, polyvinyl acetate, vinyl alcohol / vinyl acetate copolymer, polyglycolized glycol Celite, xanthan gum, carrageenan, chitosan, chitin, polydextrin, dextrin Pharmaceutically acceptable polymers include phosphates, starches, proteins, and the like. Another aspect of the present invention is a pharmaceutical composition comprising a solid dispersion, the matrix of which is e.g. For example, sucrose, lactose, fructose, maltose, raffinose, sorbitol, Lactitol, mannitol, maltitol, erythritol, inositol, trehalose sugar, isomalt, inulin, maltodextrin, β-cyclodextrin, hydroxy Dipropyl-β-cyclodextrin or sulfobutylether cyclodextrin which includes sugars and / or sugar alcohols and / or cyclodextrins. Additional suitable carriers useful in forming the matrix of the solid dispersion include alcohols, organic acids, , organic bases, amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxyethylene These include, but are not limited to, sorbitan fatty acid esters and urea. The solid dispersion of regorafenib in the matrix is ​​prepared by adding surfactants, fillers, disintegrants, and recrystallization agents. Crystallization inhibitor, plasticizer, antifoaming agent, antioxidant, anti-adhesive agent, pH adjuster, flow promoter, lubricant The composition may contain certain additional pharmaceutically acceptable ingredients such as: The solid dispersions of the present invention can be prepared by melt / melt techniques, hot melt extrusion, solvent evaporation (i.e., freezing), and other methods. methods such as sinter drying, spray drying or layering of granular powders, co-precipitation, supercritical fluid technology and electrospinning. The solid dispersions are prepared according to methods known in the art for the manufacture of such solid dispersions. The compositions of the present invention may contain other ingredients, commonly referred to as carriers or diluents, as necessary or desired. Conventional pharmaceutically acceptable ingredients may also be included. Conventional procedures for preparing the compounds are available. A commonly used compound that can be used appropriately to formulate the composition for the intended route of administration. Pharmaceutical ingredients include: Acidifying agents (examples include acetic acid, citric acid, fumaric acid, hydrochloric acid, and nitric acid) including but not limited to); Alkalizing agents (examples include ammonia solution, ammonium carbonate, diethanolamine, molybdenum, Nonethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide including, but not limited to, sodium, triethanolamine, and trolamine); Adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon) ; Aerosol propellants (examples include carbon dioxide, CCl2F2, F2ClC-CClF2 and including, but not limited to, CClF3; air displacing agents (examples include, but are not limited to, nitrogen and argon); Antifungal preservatives (e.g., benzoic acid, butylparaben, ethylparaben, methylparaben) (including but not limited to benzoyl peroxide, propylparaben, sodium benzoate) ; Antibacterial preservatives (e.g., benzalkonium chloride, benzethonium chloride, benzyl Alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl including but not limited to alcohol, phenylmercuric nitrate, and thimerosal); Antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylated hydrochloride) Dihydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, Propyl ascorbate, sodium ascorbate, sodium bisulfite, formaldehyde Including, but not limited to, sodium sulfoxylate, sodium metabisulfite stomach); Binders (e.g., block polymers, natural and synthetic rubbers, polyacrylates, poly These include polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers. including but not limited to); Buffers (e.g., potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium phosphate anhydrous, sodium citrate dihydrate. stomach); Carriers (e.g., acacia syrup, flavored syrup, flavored elixir, cherry syrup) syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, These include, but are not limited to, Mayonnaise Oil, Bacteriostatic Sodium Chloride Injection, and Bacteriostatic Water for Injection. do not have); Chelating agents (examples include, but are not limited to, edetate disodium and edetic acid) not specified); Coloring agents (examples include FD&C Red No. 3, FD&C Red No. 20, FD &C Yellow No.6, FD&C Blue No.2, D&C Green No.5, D&C Orange No.5, D&C Red No.8, Caramel and including, but not limited to, iron oxide and red iron oxide); clarifiers (examples include, but are not limited to, bentonite); Emulsifiers (e.g., acacia, cetomacrogol, cetyl alcohol, monostearic acid) Glyceryl, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate including but not limited to phosphates); Encapsulating agents (examples include gelatin and cellulose acetate phthalate) (including but not limited to); Flavorings (examples include anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint) including, but not limited to, coconut oil and vanillin); Humectants (examples include glycerol, propylene glycol, and sorbitol) (but not limited to); abrasives (examples include, but are not limited to, mineral oil and glycerin); Oils (e.g., peanut oil, mineral oil, olive oil, sesame oil, vegetable oil) including, but not limited to; Ointment bases (e.g., lanolin, hydrophilic ointments, polyethylene glycol ointments, petrolatum) These include, but are not limited to, acetone, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment. do not have); Penetration enhancers (transdermal delivery) (e.g., monohydroxy or polyhydroxy alcohols, Monohydric or polyhydric alcohols, saturated or unsaturated fatty acids, saturated or unsaturated fatty acid esters , saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes , including but not limited to, amides, ethers, ketones and ureas); Plasticizers (examples include, but are not limited to, diethyl phthalate and glycerol) (cannot be); Solvents (e.g., ethanol, corn oil, cottonseed oil, glycerol, isopropanol) , mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, sterile water for irrigation including, but not limited to; Hardeners (e.g., cetyl alcohol, cetyl ester wax, microcrystalline Wax, paraffin, stearyl alcohol, white wax, yellow wax including but not limited to); Suppository bases (examples include cocoa butter and polyethylene glycol (mixtures) including but not limited to); Surfactants (e.g., benzalkonium chloride, nonoxynol 10, octoxynol 9, Polysorbate 80, Sodium Lauryl Sulfate, Sorbitan Monopalmitate including but not limited to); Suspending agents (e.g., agar, bentonite, carbomer, carboxymethylcellulose) Sodium, Hydroxyethylcellulose, Hydroxypropylcellulose, Hydroxy Propylmethylcellulose, kaolin, methylcellulose, tragacanth and veegum including, but not limited to); Sweeteners (e.g., aspartame, dextrose, glycerol, mannitol) , propylene glycol, sodium saccharin, sorbitol and sucrose including, but not limited to; Tablet anti-adherents (examples include magnesium stearate and talc) including but not limited to); Tablet binders (e.g., acacia, alginic acid, carboxymethylcellulose Thorium, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methyl cellulose , non-crosslinked polyvinylpyrrolidone, and pregelatinized starch. not be); Tablet and capsule diluents (e.g., dibasic calcium phosphate, kaolin, milk) Sugar, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate Examples of suitable oleic acid salts include, but are not limited to, sodium, sodium phosphate, sorbitol, and starch. not be); Tablet coatings (e.g., liquid glucose, hydroxyethyl cellulose, Hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose , ethyl cellulose, cellulose acetate phthalate, and shellac not be); Direct compression excipients for tablets (examples include dibasic calcium phosphate, (including but not limited to); Tablet disintegrants (e.g., alginic acid, calcium carboxymethylcellulose, finely divided tablets) Crystalline cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, sodium alginate These include, but are not limited to, starch, sodium starch glycolate, and starch. do not have); Tablet glidants (examples include colloidal silica, cornstarch, and talc) , including but not limited to); Tablet lubricants (e.g., calcium stearate, magnesium stearate, mineral oil) , stearic acid, zinc stearate); Tablet / capsule opacifiers (examples include, but are not limited to, titanium dioxide) ); Tablet finishing agents (examples include carnauba wax and white wax) (but not limited to); Thickeners (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin) not specified); Tonicity agents (examples include, but are not limited to, dextrose and sodium chloride) not be); Thickeners (examples include alginate, bentonite, carbomer, carboxymethyl cellulose) Sodium phosphate, methylcellulose, polyvinylpyrrolidone, sodium alginate, tetrahydrofuran including, but not limited to, gacanth; and Wetting agents (e.g., heptadecaethyleneoxycetanol, lecithin, monooleic acid sodium) sorbitol, polyoxyethylene sorbitol monooleate, and poly stearate including, but not limited to, oxyethylene). It is believed that one skilled in the art using the preceding information can utilize the present invention to its fullest extent. [Example]

[0034] Example 1 : Regorafenib and anti-mouse PD-1 antibody (RMPl-14, Peng et al., Cancer Res., (2012) 72(20), 5209-5218) The activity was examined in a syngeneic murine MC38 CRC model.

[0035] method : MC38 syngeneic tumors were grown subcutaneously in mice and treated with regorafenib according to the following regimen: and / or treated with anti-mouse PD-1 antibody (RMP1-14).

[0036] a) Regorafenib alone, once daily at a dose of 3 mg / kg per day, with Pluron icF68 / PEG400 / Propylene Glycol (15 / 42.5 / 42.5+20%) water) as a po (oral) formulation for 15 days, and 10 mg / kg of non-binding rIgG2a The isotype control (clone 2A3) was incubated in PBS (phosphate buffered saline) It was administered as an ip (intraperitoneal) formulation every three days for five doses.

[0037] b) Anti-mouse PD-1 antibody (RMP1-14) alone at a dose of 10 mg / kg, PBS ip formulation every 3 days for 5 doses, and Pluronic F68 / PEG400 / Pro Pyrene glycol (15 / 42.5 / 42.5 + 20% water) vehicle as po formulation The drug was administered once daily for 15 days.

[0038] c) Concomitant administration of regorafenib once daily at a dose of 3 mg / kg per day; Pluronic F68 / PEG400 / Propylene Glycol (15 / 42.5 / 42 0.5 + 20% water) for 4 days as a po formulation, and anti-mouse PD-1 antibody (RMP1-1 4) was administered at a dose of 10 mg / kg as an ip formulation in PBS every 3 days for 5 doses.

[0039] d) Sequential administration: regorafenib initially at a dose of 3 mg / kg once daily. In terms of volume, Pluronic F68 / PEG400 / propylene glycol (15 / 42.5 / 42.5 + 20% water) for 4 days followed by randomization on the 5th day. Murine PD-1 antibody (RMP1-14) was administered ip in PBS at a dose of 10 mg / kg. The dose was administered every three days for four doses.

[0040] e) Sequential administration: First, anti-mouse PD-1 antibody (RMP1-14) at 10 mg / kg g dose as an i.p. formulation in PBS twice every 3 days followed by treatment on day 5 after randomization , regorafenib once daily at a dose of 3 mg / kg per day, PluronicF6 8 / PEG400 / propylene glycol (15 / 42.5 / 42.5) po formulation The drug was administered for 10 days. Control animals received regorafenib and vehicle (Pluronic F68 / PEG400 / Pluronic propylene glycol (15 / 42.5 / 42.5 + 20% water) and unbound isopropyl alcohol The control antibody (rat IgG2a, clone 2A3) was also administered simultaneously. Monitor by caliper measurement and calculate the tumor size using the formula: axb (where a and b are the long and short diameters of the tumor, respectively). Tumor area was calculated using the RT-PCR method. Tumor weight was measured after the completion of the study. Troll (T / C) was calculated using vehicle-treated animals as the reference.

[0041] result : Both regorafenib and anti-mouse PD-1 antibody controlled the growth of MC38 tumors. This effect was suppressed when regorafenib was administered either simultaneously or after anti-PD1 therapy. The effect was significantly enhanced when TIFF0007806119000003.tif121151 Example 2 : Regorafenib and anti-mouse PD-1 antibody (RMPl-14, Peng et al., Cancer Res., (2012) 72(20), 5209-5218) The activity was examined in a syngeneic murine CT26 CRC model.

[0042] CT26 syngeneic tumors were grown orthotopically in mice (Abou-Elkacem et al. l., Mol Cancer Ther., 2013 Jul;12(7):1322- 31), and regorafenib and / or anti-mouse PD-1 antibody according to the following regimen ( Treatment was with RMP1-14).

[0043] a) Regorafenib, with formulation vehicle alone as a control, for 10 days. Nib alone was administered once daily at a dose of 30 mg / kg per day, and Pluronic F68 / P EG400 / propylene glycol / water (12 / 34 / 34 / 20) oral formulation or 3 days of a nonspecific control antibody at a dose of 20 mg / kg in PBS. The drug was administered in combination with intraperitoneal (ip) administration every day.

[0044] b) Anti-mouse PD-1 antibody (RMP1) was used, while a non-specific antibody was used as a control. -14) Administered alone at a dose of 20 mg / kg as an ip formulation in PBS every 3 days for 4 doses. Ta.

[0045] c) Combination: Regorafenib once daily at 20 mg / kg per day By volume, Pluronic F68 / PEG400 / propylene glycol / water (12 / 34 / 34 / 20) as a po formulation for 10 days, and anti-mouse PD-1 antibody (RMP1-1 4) was administered at a dose of 20 mg / kg as an ip formulation in PBS every 3 days for 4 doses. .

[0046] After treatment was stopped, tumor regrowth (data not shown) and the appearance of liver metastases (Table 2) were observed. To investigate this, some mice were observed for an additional 11 days. At the end of the period, the mice were sacrificed and the liver surface was visually screened for metastases. Next, the number of mice with liver metastases was related to the total number of mice in each test group. TIFF0007806119000004.tif80168In Table 2, the test systems used are indicated by a "+". After treatment, 0 of 6 animals in the PD-1 group and 4 of 6 animals in the PD-1 group showed metastases. On the other hand, after 25 days of treatment, the combination of regorafenib and the control antibody Eight animals showed metastases, but none were treated with the combination of regorafenib and PD-1. Surprisingly, no animals in the study showed metastasis.

Claims

1. A combination drug comprising regorafenib and avelumab (MSB0010718C).

2. 2. The pharmaceutical combination according to claim 1, which is a combination pack containing components separate from each other.

3. 3. The pharmaceutical combination according to claim 1 or 2, wherein the components are administered simultaneously or sequentially in separate dosage forms for use in treating the same disease.

4. The pharmaceutical combination according to any one of claims 1 to 3 for use as a medicament for the treatment of hyperproliferative disorders.

5. 5. The pharmaceutical combination of claim 4, wherein the hyperproliferative disorder is selected from the group consisting of breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, gastrointestinal tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer and parathyroid cancer and distant metastases thereof.

6. 5. The pharmaceutical combination of claim 4, wherein the hyperproliferative disorder is selected from the group consisting of anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

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