WO2019109147A1

WO2019109147A1 - Methods of treating cancer with leukotriene receptor antagonists

Info

Publication number: WO2019109147A1
Application number: PCT/AU2018/051310
Authority: WO
Inventors: Stephen Kenneth O'Mara
Original assignee: Omara Stephen Kenneth
Priority date: 2017-12-06
Filing date: 2018-12-06
Publication date: 2019-06-13

Abstract

Provided herein are methods for treating cancer, comprising administering an effective amount of a leukotriene receptor antagonist, optionally in combination with a CYP inhibitor. Also provided are methods for increasing the sensitivity of a cancer to chemotherapy, comprising administering an effective amount of a leukotriene receptor antagonist, optionally in combination with a CYP inhibitor. In particular embodiments the leukotriene receptor antagonist is montelukast or a pharmaceutically acceptable salt thereof and the CYP inhibitor is gemfibrozil or a pharmaceutically acceptable salt thereof.

Description

METHODS OF TREATING CANCER WITH LEUKOTRIENE RECEPTOR ANTAGONISTS

Technical field

[001] The present invention relates generally to methods for the treatment of cancer, for example multiple myeloma, for use as an adjunct to chemotherapy.

Background of the invention

[002] Chemotherapy remains an effective front line treatment option for many cancers. There are a wide variety of chemotherapeutic agents, and combinations of such agents, available for cancer treatment. However tumor cells equally possess a wide variety of mechanisms for survival in the face of chemotherapeutic agents. Many tumor cells are resistant, or develop resistance to, chemotherapeutic agents resulting in cancers being refractory to standard chemotherapeutic treatment protocols. In many instances, cancers can display multidrug resistance.

[003] ATP-binding cassette proteins (ABCC), also called multidrug resistant proteins (MRP) are a family of at least twelve transport proteins involved in the cellular efflux of anions across cell membranes. They transport a variety of molecules including some chemotherapy agents, chemotherapy-glutathione conjugates, oxidized glutathione (GSSG), leukotrienes and cyclic nucleotides and reduced Glutathione (GSH). MRP, by exporting a variety of intracellular anions out of the cytoplasm and organelles, are important regulators of cell oxidation reduction homeostasis. Upregulated expression of MRP-l in cancer is considered to convey advantages in tumor cell survival.

[004] Multiple myeloma is a haematological cancer characterised by infiltration of bone and bone marrow by myeloma cells forming tumor masses. The disease is typically progressive and fatal. Symptoms include anemia, renal damage and high globulin levels in blood and increased susceptibility to bacterial infections. Standard treatment for multiple myeloma is combination chemotherapy, typically either CTD (cyclophosphamide, thalidomide and dexamethasone) or CyBorD (cyclophosphamide, bortezomib and dexamethasone). Despite the use of chemotherapy, and newer therapeutic approaches such as autologous stem cell transplantation, most patients with multiple myeloma cannot he cured and median survival is only two to three years.

[005] There remains a significant need for safe and effective methods of treating cancer, particularly cancers that are refractory to standard chemotherapy treatments. In the case of multiple myeloma, in view of the poor prognosis of those with the disease and the often refractory nature of the disease to commonl used chemotherapeutic agents there is an urgent need to the development of novel treatment approaches.

Summary of the invention

[006] A first aspect of the present invention provides a method for treating cancer in a subject, comprising administering to the subject an effective amount of a leukotriene receptor antagonist.

[007] In a particular embodiment, the leukotriene receptor antagonist is montelukast or a pharmaceutically acceptable salt thereof.

[008] The cancer may be refractory to chemotherapy. In a particular embodiment, the method is employed as an adjunct to chemotherapy. In a particular embodiment, the treatment increases the sensitivity of the cancer to chemotherapy. The chemotherapy may be combination chemotherapy. In exemplary embodiment, the combination chemotherapy may comprise treatment with a combination of cyclophosphamide, bortezornib and dexamethasone or with a combination of cyclophosphamide, thalidomide and dexamethasone.

[009] The method may be employed as an adjunct to, for example, radiotherapy, monoclonal antibody therapy, hormone therapy, the administration of checkpoint inhibitors, T cell therapy such as chimeric antigen receptor (CAR) T cell therapy or stem cell transplantation, such as autologous stem cell transplantation.

[0010] In a particular embodiment, the cancer is a haematological cancer, such as myeloma, leukemia or lymphoma. In particular embodiments, the cancer is a haematological cancer selected from, for example, multiple myeloma, acute myeloid leukaemia, chronic lymphocytic leukaemia, non-Hodgkins lymphoma and Richter's Syndrome. In a particular embodiment, the cancer is multiple myeloma. The multiple myeloma may be, for example, kappa light chain disease or lambda light chain disease.

[0011] The cancer may be a solid tumour. In an exemplary embodiment the embodiment, the tumour may be a lung cancer tumour or a gastrointestinal stromal tumour.

[0012] The method may further comprise administration to the subject of a cytochrome P450 (CYP) inhibitor. Typically the CYP is CYP2C8. In an exemplary embodiment the CYP inhibitor is gemfibrozil or a pharmaceutically acceptable salt thereof.

[0013] A second aspect of the present invention provides a method for treating a haematological cancer in a subject, comprising administering to the subject an effective amount of montelukast or a pharmaceutically acceptable salt thereof.

[0014] Optionally, the method further comprises administration to the subject of a cytochrome P450 (CYP) inhibitor. In an exemplary embodiment the CYP is CYP2C8. In an exemplary embodiment the CYP inhibitor is gemfibrozil or a pharmaceutically acceptable salt thereof.

[0015] The haematological cancer may be refractory or sensitive to chemotherapy.

[0016] A third aspect of the present invention provides a method for increasing the sensitivity of a cancer to chemotherapy, the method comprising administering to a subject in need thereof an effective amount of a leukotriene receptor antagonist.

[0017] In a particular embodiment, the leukotriene receptor antagonist is montelukast or a pharmaceutically acceptable salt thereof.

[0018] The cancer may be refractory to the chemotherapy in the absence of administration of the leukotriene receptor antagonist. The chemotherapy may be combination chemotherapy. In exemplary embodiment, the combination chemotherapy may comprise treatment with a combination of cyclophosphamide, bortezomib and dexamethasone or with a combination of cyclophosphamide, thalidomide and dexamethasone. [0019] In a particular embodiment, the cancer is a haematological cancer, such as myeloma, leukemia or lymphoma. In particular embodiments, the cancer is a haematological cancer selected from, for example, multiple myeloma, acute myeloid leukaemia, chronic lymphocytic leukaemia, non-Hodgkins lymphoma and Richter's Syndrome. In a particular embodiment, the cancer is multiple myeloma. The multiple myeloma may be, for example, kappa light chain disease or lambda light chain disease.

[0020] The cancer may be a solid tumour. In an exemplary embodiment the embodiment, the tumour may be a lung cancer tumour or a gastro-intestinal stromal tumour.

[0021] The method may further comprise administration to the subject of a fibrate, optionally gemfibrozil or a pharmaceutically acceptable salt thereof.

[0022] A fourth aspect of the present invention provides a method for reducing paraprotein levels in a subject having a haematological cancer, the method comprising administering to the subject a leukotriene receptor antagonist, wherein treatment with the leukotriene receptor antagonist results in lower paraprotein levels in the blood or urine than in the absence of the treatment.

[0023] In a particular embodiment, the leukotriene receptor antagonist is montelukast or a pharmaceutically acceptable salt thereof.

[0024] The method may further comprise administration to the subject of a fibrate, optionally gemfibrozil or a pharmaceutically acceptable salt thereof.

[0025] The method may be performed as an adjunct to, or otherwise in combination with, one or more alternative treatments for haematological cancers such as chemotherapy or autologous stem cell transplantation.

Brief description of the figures

[0026] Embodiments of the present invention are described and exemplified herein, by way of non-limiting example only, with reference to the following figures.

[0027] Figure 1. Graph plotting paraprotein in five multiple myeloma subjects (pl to p5), receiving CyBorD treatment, as a percentage of initial paraprotein. Progression follows maximum response to CyBorD which is the point at which montelukast and gemfibrozil were administered, resulting in an improvement of response with 1-2 cycles. The final data point represents the best response in paraprotein after study completion.

[0028] Figure 2. Graph demonstrating changes in paraprotein levels (%) in five subjects having multiple myeloma.

Detailed description of the invention

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the disclosure belongs. All patents, patent applications, published applications and publications, databases, websites and other published materials referred to throughout the entire disclosure, unless noted otherwise, are incorporated by reference in their entirety. In the event that there is a plurality of definitions for terms, those in this section prevail.

[0030] In the context of the present specification, the terms "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0031] In the context of the present specification, the term "comprising" means "including principally but not necessarily solely". Furthermore, variations of the word "comprising", such as "comprise" and "comprises", have correspondingly varied meanings.

[0032] In the context of the present specification, the term "about" is understood to refer to a range of values that a person of skill in the art would consider equivalent to the recited value in the context of achieving the same function or result.

[0033] As used herein the term "effective amount” includes within its meaning a non toxic but sufficient amount or dose of an agent or compound to provide the desired effect. The exact amount or dose required will vary from subject to subject depending on factors such as the subject being treated, the age and general condition of the subject, the severity of the condition being treated, the particular agent being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact“effective amount”. However, for any given case, an appropriate“effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.

[0034] As used herein the terms "treating" and“treatment” refer to any and all uses which remedy a condition or one or more symptoms, or otherwise hinder, retard, or reverse the progression of a condition or one or more symptoms thereof in any way whatsoever. Thus the terms "treating" and the like are to be considered in their broadest context. For example, treatment does not necessarily imply that a subject is treated until total recovery. Where a condition displays or is characterized by multiple symptoms, the treatment need not necessarily remedy, prevent, hinder, retard, or reverse all of said symptoms, but may prevent, hinder, retard, or reverse one or more of said symptoms.

[0035] The term“subject” as used herein refers to mammals and includes humans, primates, livestock animals (e.g. sheep, pigs, cattle, horses, donkeys), laboratory test animals (e.g. mice, rabbits, rats, guinea pigs), performance and show animals (e.g. horses, livestock, dogs, cats), companion animals (e.g. dogs, cats) and captive wild animals. Typically, the mammal is human or a laboratory test animal. Even more typically, the mammal is a human.

[0036] As used herein the term“paraprotein” refers to a monoclonal immunoglobulin or immunoglobulin light chain present in the blood or urine. In the context of multiple myeloma, paraprotein may also be referred to as myeloma protein.

[0037] As exemplified herein the present inventor has surprisingly found that montelukast, optionally in combination with gemfibrozil, improved the response to CyBorD combination chemotherapy in multiple myeloma patients. The inventor found that treatment with montelukast and gemfibrozil significantly reduced blood paraprotein levels in subjects undergoing CyBorD chemotherapy. Montelukast with gemfibrozil was also found to improve the response to treatment and symptoms of acute myeloid leukaemia, chronic lymphocytic leukaemia, non-Hodgkins lymphoma, Richter's Syndrome, lung cancer and gastro-intestinal stromal tumours and appears to reduce transfusion dependency. [0038] Without wishing to be bound by theory, the inventor suggests that the administration of montelukast may increase mitochondrial stress during chemotherapy and promote the downstream activation of cell death. As this process acts‘downstream’ of the many cancer chemotherapy-resistance mechanisms, the inventor suggests that the inhibition of MRP may result in increased tumor cell death by changing the balance between pro- and anti-apoptotic mechanisms controlling cell death.

[0039] Accordingly, provided herein are methods for treating cancer in a subject, comprising administering to the subject an effective amount of a leukotriene receptor antagonist.

[0040] Also provided herein are methods for increasing the sensitivity of a cancer to chemotherapy, the method comprising administering to a subject in need thereof an effective amount of a leukotriene receptor antagonist.

[0041] Also provided herein are methods for reducing paraprotein levels in a subject having multiple myeloma, the method comprising administering to the subject a leukotriene receptor antagonist, wherein treatment with the leukotriene receptor antagonist results in lower paraprotein levels in the blood or urine than in the absence of the treatment.

[0042] Optionally, the above treatments may be combined with administration of a fibrate such as gemfibrozil or a pharmaceutically acceptable salt thereof, such that the leukotriene receptor antagonist is coadministered with the fibrate. By“coadministered” is meant simultaneous administration in the same formulation or in two different formulations via the same or different routes or sequential administration by the same or different routes. By “sequential” administration is meant a time difference of, for example, from seconds, minutes, hours, days, weeks or months between the administration of the two formulations or therapies. The formulations or therapies may be administered in any order.

[0043] Montelukast ((R, E)-2-(l-((l-(3-(2-(7-chloroquinolin-2-yl) vinyl)- phenyl)-3-(2- (2-hydroxypropan-2-y!) phenyl) propyl thio) -methyl) cyclopropyl) acetic acid) is a leukotriene receptor antagonist that is currently used in the treatment of asthma, typically in the form of a sodium salt (montelukast sodium, also referred to herein as montelukast). While montelukast is exemplified herein, those skilled in the art will appreciate that other leukotriene receptor antagonists may be employed in place of, or in addition to montelukast. Exemplary leukotriene receptor antagonists include montelukast, zafirlukast, pranlukast and pharmaceutically acceptable salts thereof.

[0044] Embodiments of the present invention contemplate the administration of an effective amount of a leukotriene receptor antagonist such as montelukast. Montelukast has shown to be safe when treating asthma with therapeutic doses of between 5 and lOmg, although there is no toxicity at doses up to 60 times the standard dose in children (4mg/kg). No maximum tolerated dose of montelukast has been established. It has a half- life of elimination of 4-5 hours and is rapidly absorbed in two to three hours orally. Thus, in accordance with embodiments of the present invention, an exemplary effective amount of montelukast may be between about 1 mg and about 10000 mg per day, between about 5 mg and about 5000 mg per day, or between about 10 mg and about 1000 mg per day. For example, an effective amount of montelukast may be about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, about 8000 mg, about 9000 mg or about 10000 mg per day. In exemplary embodiments, the effective amount may be about 20 mg per day or about 40 mg per day. The effective amount may be provided in a single dose or more than one divided doses per day. In exemplary embodiments, the effective amount is administered over two or more doses per day.

[0045] Notwithstanding, the effective amount or individual dose level of the administered leukotriene receptor antagonist such as montelukast will depend upon a variety of factors including the type and severity of the condition being treated and the stage of the condition; the activity and nature of the specific agent employed; the composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of sequestration of compounds; the duration of the treatment; drugs used in combination or coincidental with the treatment, together with other related factors well known in medicine. One skilled in the art would be able, by routine experimentation, to determine a non-toxic effective amount or dose which would be suitable to treat subjects. These may be determined on a case-by-case basis. It will also be apparent to one of ordinary skill in the art that the optimal course of treatment, such as, the number of doses administered per day, week (or other frequency) for a defined number of days, weeks (or other length of time) can be ascertained by those skilled in the art without undue experimentation.

[0046] Montelukast metabolism and excretion is inhibited significantly by the lipid lowering agent gemfibrozil. It has been reported that gemfibrozil increases the AUC of a single dose of montelukast by a factor of 4.5. Accordingly, embodiments of the present invention contemplate the administration of a cytochrome P450 (CYP) inhibitor, typically an inhibitor of, for example, CYP2C8, CYP2A8 or CYP2C9. In an exemplary embodiment the CYP inhibitor is a strong CYP2C8 inhibitor such as gemfibrozil or a pharmaceutically acceptable salt thereof, or clopidogrel, the acyl-P-glucuronide metabolite or a pharmaceutically acceptable salt thereof. Other suitable CYP2C8 inhibitors include fluvoxamine, ketoconazole, itraconazole, fenofibrate, fenofibri acid, nicardipine, quercetin, simvastatin, spironolactone, trimethoprim, and vilazodone. The CYP inhibitor may be an inhibitor of CYP2C9 such as, for example, fluconazole, amiodarone, fluvoxamine, miconazole, oxandrolone, voriconazole, capecitabine, sulfamethoxazole, etravirine, fluvastatin, imipramine, metronidazole, tigecycline, zafirlukast, fenofibrate, fenofibric acid, fluoxetine, leflunomide, and nateglinide. Alternatively the inhibitor may be a COX-2 inhibitor such as, for example, sulindac, diclofenac, celecoxib, meloxicam, etodolac, etoricoxib and lumiracoxib.

[0047] The effective amount of the inhibitor such as gemfibrozil or a pharmaceutically acceptable salt thereof, can be determined by the person skilled in the art, by routine experimentation. This may be determined on a case-by-case basis. For example, the effective amount or individual dose level of the administered fibrate such as gemfibrozil will depend upon a variety of factors including the type and severity of the condition being treated and the stage of the condition; the activity and nature of the specific agent employed; the composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of sequestration of compounds; the duration of the treatment; drugs used in combination or coincidental with the treatment, together with other related factors well known in medicine. It will also be apparent to one of ordinary skill in the art that the optimal course of treatment, such as, the number of doses administered per day, week (or other frequency) for a defined number of days, weeks (or other length of time) can be ascertained by those skilled in the art without undue experimentation.

[0048] In an exemplary embodiment, the gemfibrozil may be administered in an amount of between about 100 mg and about 1000 mg per day. For example, the gemfibrozil ay be administered in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg or about 1000 mg per day. In exemplary embodiments, the effective amount may be about 600 mg per day. The effective amount may be provided in a single dose or more than one divided doses per day. In exemplary embodiments, the effective amount is administered over one or two doses per day.

[0049] In embodiments in which a leukotriene receptor antagonist such as montelukast and a fibrate such as gemfibrozil are administered in combination, the agents may be administered in the same or different compositions. Where the agents are administered in different compositions, the compositions may be administered by the same or different routes.

[0050] Methods of the present invention are suitable for the treatment of any cancer, in particular those cancers for which chemotherapy is a viable primary means of treatment, and for those cancers that display, or are known to develop resistance to chemotherapeutic agents. By way of example, suitable cancers include haematological cancers, such as myeloma (multiple myeloma), leukemia including acute myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL), lymphoma including non-Hodgkins lymphoma (NHL), and Richter's Syndrome. However the skilled addressee will appreciate that the scope of the present invention is not so limited and the treatment of any cancer is encompassed. By way of example only the cancer may be prostate cancer, breast cancer, colon cancer, lung cancer, gastrointestinal cancer, pancreatic cancer, kidney cancer, bone cancer, ovarian cancer, testicular cancer, bowel cancer, stomach cancer, a head and neck cancer, a brain tumour, acute myeloid leukaemia, acute lymphoblastic leukaemia, a sarcomas such as osteosarcoma or ewings disease, non hodgkins lymphoma, chronic lymphatic leukaemia, hodgkins disease, or a myeloproliferative disordersuch as essential thrombocythaemia, polycythaemia rubera vera or myelofibrosis. [0051] In particular embodiments, the cancer is a haematological cancer such as multiple myeloma, leukemia or lymphoma. Exemplary forms of multiple myeloma to which the present invention may be directed include active (symptomatic) multiple myeloma, light chain myeloma (such as lambda light chain disease and kappa light chain disease) and smouldering (indolent) multiple myeloma.

[0052] The methods of the invention may be employed as an adjunct to chemotherapy. The chemotherapy may comprise the administration of any one or more chemotherapeutic agents suitable for the treatment of the specific cancer in question. The chemotherapy may be combination chemotherapy, such as for example, CTD (cyclophosphamide, thalidomide and dexamethasone), CyBorD (cyclophosphamide, bortezomib and dexamethasone), or COMP (cyclophosphamide, vincristine, methotrexate and prednisone). Suitable chemotherapeutic agents that may be employed alone, or in any combination, include but are not limited to: alkylating agents such as cyclophosphamide, mechlorethamine, busulphan, chlorambucil, melphalan, bendamustine and nitrosureas; anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin and valrubicin; taxanes such as paclitaxel and docetaxel; proteosome inhibitors such as bortezomib, carfilzamib and ixazomib, kinase inhibitors such as erlotinib, gefitinib and vemurafenib; topoisomerase inhibitors such as topotecan, irinotecan tenoposide and etoposide; purine analogues including 6-mercaptopurine and 6- thioguanine; antitumour antibiotics including actinomycin D; platinum-based agents such as carboplatin, cisplatin and oxaliplatin; vinca alkaloids such as vinblastine and vincristine; and nucletotide analogs such as azacitidine, fluorouracil, gemcitabine and methotrexate; vinorelbine; capecitabine; ixabepilone; albumin-bound paclitaxel (nab-paclitaxel or abraxane; and eribulin.

[0053] The chemotherapy or chemotherapeutic agents may be administered to the subject via any route, at any dosage and for any number of cycles typically used to treat the cancer in question, and the scope of the present invention is not limited by reference to any specific routes, dosages or cycles.

[0054] The methods of the invention may be employed as an adjunct to other suitable cancer treatments such as, for example, radiotherapy, monoclonal antibody therapy, hormone therapy, the administration of checkpoint inhibitors, T cell therapy such as chimeric antigen receptor (CAR) T cell therapy and stem cell transplantation, such as autologous stem cell transplantation.

[0055] Exemplary monoclonal antibodies include alemtuzumab, rituximab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, daratumumab, cetuximab, elotuzamab,obinutuzumab, ofatumumab, and pembrolizumab.

[0056] Exemplary hormones include letrozole, anastrozole, exemestane, tamoxifen, leuprolide, goserelin, triptorelin, histrelin, abiraterone, flutamide, bicalutamidee, nilutamide, enzalutamide and, cyproterone.

[0057] In accordance with the present invention leukotriene receptor antagonists and fibrates may be administered by any convenient or suitable route. For example administration may be parenteral (including, for example, intraarterial, intravenous, intramuscular, subcutaneous), oral, nasal, mucosal (including sublingual), intracavitary or topical. Thus compositions comprising either or both leukotriene receptor antagonists and fibrates may be formulated in a variety of forms including solutions, suspensions, emulsions, and solid forms and are typically formulated so as to be suitable for the chosen route of administration, for example as capsules, tablets, caplets, elixirs for oral ingestion, in an aerosol form suitable for administration by inhalation (such as by intranasal inhalation or oral inhalation), ointment, cream, gel, jelly or lotion suitable for topical administration, or in an injectible formulation suitable for parenteral administration. The chosen route of administration will depend on a number of factors including the condition to be treated and the desired outcome. The most advantageous route for any given circumstance can be determined by those skilled in the art.

[0058] In general, suitable compositions may be prepared according to methods which are known to those of ordinary skill in the art and may include a pharmaceutically acceptable diluent, adjuvant and/or excipient. The diluents, adjuvants and excipients must be "acceptable" in terms of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof.

[0059] Examples of pharmaceutically acceptable diluents are demineralised or distilled water; saline solution; vegetable based oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oil, arachis oil or coconut oil; silicone oils, including polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysolpoxane; volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose; lower alkanols, for example ethanol or iso-propanol; lower aralkanols; lower polyalkylene glycols or lower alkylene glycols, for example polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, 1, 3-butylene glycol or glycerin; fatty acid esters such as isopropyl palmitate, isopropyl myristate or ethyl oleate; polyvinylpyrridone; agar; carrageenan; gum tragacanth or gum acacia, and petroleum jelly. Typically, the carrier or carriers will form from 1% to 99.9% by weight of the compositions.

[0060] For administration as an injectable solution or suspension, non-toxic parenterally acceptable diluents or carriers can include, Ringer's solution, medium chain triglyceride (MCT), isotonic saline, phosphate buffered saline, ethanol and 1 ,2 propylene glycol. Some examples of suitable carriers, diluents, excipients and adjuvants for oral use include peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum acacia, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatine and lecithin. In addition these oral formulations may contain suitable flavouring and colourings agents. When used in capsule form the capsules may be coated with compounds such as glyceryl monostearate or glyceryl distearate which delay disintegration.

[0061] Solid forms for oral administration may contain binders acceptable in human and veterinary pharmaceutical practice, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatine, com starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0062] Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.

[0063] Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, poly-vinyl- pyrrolidone, sodium alginate or acetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.

[0064] Emulsions for oral administration may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as guar gum, gum acacia or gum tragacanth.

[0065] Methods for preparing parenterally administrable compositions are apparent to those skilled in the art, and are described in more detail in, for example, Remington's Pharmaceutical Science, l5th ed., Mack Publishing Company, Easton, Pa., hereby incorporated by reference herein. The composition may incorporate any suitable surfactant such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included. [0066] Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 20^th Edition, Williams & Wilkins, Pennsylvania, USA. The carrier will depend on the route of administration, and again the person skilled in the art will readily be able to determine the most suitable formulation for each particular case.

[0067] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0068] In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non limiting examples.

[0069] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Examples

Example 1 Case study: administration of montelukast in conjunction with CyBorD in multiple myeloma

[0070] A female age 65 with stage 3 newly diagnosed myeloma presented with a combination of fractures, bone pain, anemia (89 g/L) and mild renal failure. Alkaline phosphatase was raised. EGFR was reduced to 33ml/min. Albumin was 44g/L. A trace of kappa light chains was detected on EPG. Serum light kappa chains were elevated at 262mg/L, with a kappadambda ratio of 120. Beta 2 microglobulin was raised at 5.6. The bone marrow showed a nodular pattern of multiple myeloma (CD 138 positive) detected on the trephine. The subject was hydrated and placed on sodium bicarbonate. There was an improvement in renal function prior to chemotherapy with CTD (cyclophosphamide, thalidomide and dexamethasone).

[0071] The subject received 8 weeks’ CTD therapy with thalidomide at lOOmg per day, dexamethasone 20mg weekly and cyclophosphamide lOOmg daily orally. During the period of therapy, the kappa light chain increased sequentially from to 262 to 1100 mg/L and then to l668mg/L at 8 weeks. The kappa: lambda ratio increased from 120 to 930. EGFR was maintained 52ml/min. Neutrophils had dropped to 1.8. The anemia was unresolved. This combination of results was consistent with progressive disease. The assessment of the subject’s likely overall survival was 9 -18 months at this stage due to poor response to initial treatment.

[0072] Subsequently, cyclophosphamide/bortezimib/dexamethasone combination chemotherapy (CyBorD) was administered with montelukast (lOOmg over 24 hours). Following 8 doses (2 cycles) the kappa light chain had decreased to 7.6 mg/F (normal) with a kappa: lambda ratio was still elevated at 4.8. After 3 cycles of CyBorD chemotherapy the kappa: lambda ratio was also normal at 0.9. This is consistent with a complete response in the serum light chain.

[0073] A bone marrow biopsy and urine EPG was performed to determine response. The bone marrow aspirate contained no visible plasma cells. Flow cytometry determined there were no mature B cells or plasma cells detected. Bone marrow trephine displayed no evidence of multiple myeloma (CD138 positivity was present in 0.5% of bone marrow cells using immunohistochemistry of trephine). These cells were not monoclonal on kappa/ lambda staining. There were also groups of CD 10 positive haematogones in the trephine suggesting that B cell reconstitution was taking place.

[0074] There was no increased toxicity. EGFR was stable at 56ml/min. There was a large improvement in the subject’s general wellbeing. Hemoglobin improved to l09g/F on chemotherapy. There was a transient thrombocytopenia down to 85 x l0⁹/F. This rapidly recovered to over 200 x 10 / F in 1 week. Neutrophils had recovered to a normal level of 2.9. There was no neutropenia during the treatment period. There was no hepatic or renal toxicity. The subject developed level 1 sensory paresthesia affecting the tips of toes only (common after thalidomide and bortezomib treatment). There was some mild hair thinning (cyclophosphamide). The subject developed fevers about 6 hours after each bortezomib dose (this occurs in 30% of patients on standard regime). No evidence of infection was detected, and the subject subsequently received 4mg of dexamethasone after each dose of bortezomib to prevent symptoms. The subject suffered an episode of Herpes Zoster on the left L3 dermatome in the post treatment period, which responded to antivirals, which is common in myeloma patients receiving treatment.

[0075] Treatment with this regimen led to a rapid and complete response (sCR) after having rapidly progressive disease on first line therapy. There was no increase in toxicity over standard chemotherapy. The subject is now 20 months from diagnosis after having consolidation with high dose chemotherapy and peripheral blood stem cell transplant (PBSCT). The subject is well without evidence of relapse. There was no difficulty harvesting stem cells after montelukast administration.

Example 2 Treatment of chemotherapy refractory multiple myeloma with montelukast and gemfibroizil

[0076] A small group of 5 patients with demonstrated resistance to CyBorD as evidenced by either 1) progressive disease, 2) plateauing of response or 3) loss of response while on CyBorD were offered montelukast and gemfibrozil in addition to continued CyBorD. The trial was registered with the ANZCTR and ethics approval was sort and granted to use montelukast off label to treat multiple myeloma. The subjects consented after the potential risks and benefits were explained. They were continually given an update of the results and toxicities of other subjects receiving montelukast. They had the opportunity to withdraw consent at any time both before and during the treatment phase.

[0077] Five subjects were recruited to the study. All demonstrated resistance to CyBorD treatment, as evidenced by either progressive disease, plateauing of response or loss of response while on CyBorD. All but one subject had previously been administered immunomodulators for treatment of multiple myeloma. The subjects had 2 or 3 cycles of CyBorD prior to the present study and were in a poor prognosis group due to being refractory to treatment. The subjects had a median of five different regimens before the present study including stem cell transplant. Lambda light chain myeloma was over represented in the patients that received therapy, being present in four out of five subjects. Lambda light chain myeloma carries a significantly worse prognosis than standard multiple myeloma. Two subjects also had AL amyloid. One subject had severe NYHC 4 at her original diagnosis and at relapse stage NYHC 2. This group therefore have a much poorer prognosis than the average multiple myeloma patients.

[0078] Subject demographics and response to treatment prior to this study are shown in Table 1.

Table 1

CTD, Cyclophosphamide Thalidomide Dexamethasone; CyBorD, Cyclophosphamide Bortezomib Dexamethasone; CCF, Congestive Cardiac failure; SD, stable disease; PD, progressive disease; PR, Partial response; CR, complete response. [0079] In the present study, in addition to CyBorD: subjects pl to p4 were orally administered 10 mg - 60 mg montelukast once or twice daily and 600 mg gemfibrozil once or twice daily; and subject p5 was administered 10 mg montelukast twice daily and 600 mg gemfibrozil twice daily. Subjects were reviewed weekly with extensive blood testing. Bortezomib administration and toxicity assessment and management was performed weekly. Subjects p3 and p5 received only received one cycle of CyBorD/montelukast/gemfibrozil treatment. The remaining subjects received two cycles of treatment. There was no toxicity associated with doses of 10 mg - 60 mg montelukast and 600 mg gemfibrozil.

[0080] Data was analyzed using Student’s paired t-test comparing the maximal/stable percentage response in paraprotein to CyBorD and comparing this with the paraprotein level after one or two cycles of CyBorD/montelukast/gemfibrozil. Toxicity was assessed using WHO criteria. Response was assessed using the International Myeloma Working Group criteria.

[0081] No significant toxicity was reported or observed in any of the subjects following treatment. There was a tendency for the patients sense of wellbeing to improve. There was no evidence of either hepatic or renal toxicity. Pre-existing neuropathy did not worsen. There was a non-significant tendency for markers of toxicity to improve. There were no deaths or hospital admissions. One subject developed anemia that did not require transfusion. There were no episodes of grade 2 or higher thrombocytopenia. Stem cells were subsequently harvested from subject p3 without difficulty. This subject then had high dose therapy and stem cell transplantation which failed to have any effect on the paraprotein level, suggesting no further advantage from stem cell transplantation.

[0082] As shown in Figure 1, prior to initiation of treatment with montelukast and gemfibrozil, mean percentage response in paraprotein had deteriorated from maximal 32% reduction to total 25% reduction between CyBorD cycles. All five subjects showed improvement in paraprotein levels following treatment with montelukast and gemfibrozil compared to CyBorD alone (Figures 1 and 2).

[0083] With reference to Figure 2, there was a 7% increase in paraprotein levels from maximum response to CyBorD to the point prior to the initiation of montelukast and gemfibrozil administration. Statistical analysis (p<0.0l) showed that there was a doubling in response of paraprotein levels from 25% to 51% following CyBorD/montelukast/gemfibrozil treatment. A further response increase to 64% was achieved with montelukast treatment continued with other myeloma treatments (p<0.0l).

[0084] Subject pl showed significant clinical improvement with resolution of bone pain and anemia. There was a partial remission in bone marrow involvement down to 9% plasma cells. This was the first time in four years that the subject had reached this level of clinical improvement. Subject pl has been off all treatment for multiple myeloma for 8 months with no signs of progression. Subsequent to CyBorD/montelukast/gemfibrozil treatment four subjects continued taking montelukast with other myeloma treatments.

[0085] In summary, the administration of montelukast and gemfibrozil lead to an improvement in the response to combination chemotherapy in all five patients (p<0.0l, Student’s T test). Four of the five patients achieved a partial response including a VGPR following the addition of montelukast and gemfibrozil. The other had a partial response in bone marrow alone. The five patients are alive at a median of 15 months post treatment despite having highly advanced and refractory disease. Median progression free survival has not been reached and is over 8 months.

Example 3 Treatment of multiple myeloma with montelukast and gemfibroizil

[0086] The CyBorD drug regimen when administered to patients with multiple myeloma results in a complete response rate of 40% in previously untreated multiple myeloma and a complete response rate of 8% in relapsed or refractory myeloma. As described herein, Montelukast and Gemfibrozil when used in poor prognosis multiple myeloma, deepens the response and reverses resistance to Bortezomib based treatment. The response was demonstrable within 1 cycle of CyBorD (28 days) and there was no additional toxicity. The question then arises as to whether these agents when used up front earlier in the disease process leads to deeper and more rapid response.

[0087] Three patients with relapsed/refractory multiple myeloma and two patients with high risk de novo disease were given Montelukast 30mg orally twice daily with Gemfibrozil 600mg orally twice daily in combination with CyBorD regimen. Patient 1 and 2 had progressive disease while on CTD treatment including a patient with multiple soft tissue plasmacytomas and 17r deletion. The third patient had dialysis dependent renal failure for a period of 3 months prior to receiving treatment. The fourth patient had recurrent nephrotic syndrome on the basis of AL Amyloid previously treated 6 years earlier with CTD. The fifth patient had multiple myeloma with suspected cardiac amyloid causing cardiac failure. The expected number of complete responders in this cohort was 1/5 and an expected ORR of 60%.

[0088] Four of the five patients achieved a complete haematological response in paraprotein with a mean time to complete response of less than 35 days (80% CR). One patient achieved a haematological partial response (ORR 100%; expected 2= 40%).

[0089] Treatment is continuing and it is anticipated that all four patients in complete remission will undergo bone marrow biopsy and minimal residual disease assessment at the completion of four cycles of treatment. Patient 1 has been in complete remission for a period of two years.

[0090] The soft tissue plasmacytomas resolved in 10 days, The symptoms signs of nephrotic syndrome improved markedly in 10 days. The renal failure appeared to improve (lower creatinine, more urine output) in 3 weeks.

[0091] One patient was also found to have stage II co-existing breast cancer which partially responded to non-breast cancer chemotherapy. There was a partial response with post mastectomy histology.

[0092] The addition of Montelukast to standard CyBorD chemotherapy in high risk patients leads to an extremely rapid and much deeper response in most patients treated with CyBorD chemotherapy. There is little toxicity. The ORR is 100% with a haematological CR rate of 80%. Example 4 Treatment of various cancers with montelukast and gemfibrozil

[0093] The inventor then investigated the effect of combination therapy of montelukast and gemfibrozil on patients with various different haematological malignancies. All patients gave informed consent. 14 patients (age range - 67-92; median age 84) on palliative oral treatment regimens for a variety of haematological malignancies (acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), non-Hodgkins lymphoma (NHL) and Richter's Syndrome) or solid tumours were given Montelukast 30mg twice daily as well as 600mg Gemfibrozil twice daily. The effect on transfusions, admissions to hospital, clinical response as well as general wellbeing was measured. Treatment regimens included low dose oral chlorambucil in CLL, single agent 6-TG or busulphan in non-responsive AML, and oral prednisolone, cyclophosphamide and etoposide in aggressive NHL. Two patients with solid tumours received no additional chemotherapy.

[0094] Two out of four patients on palliative AML treatment responded to the montelukast and gemfibrozil combination. Patient 1 became transfusion independent after 1 month. Patient 2 has had a response in peripheral blood after failing 6 months treatment with Azacytidine. Five out of five patients with CLL on 2 mg of oral chlorambucil per day had a marked improvement in lymphocyte counts following the montelukast and gemfibrozil combination therapy. One of one patient with Waldenstroms macroglobulinaemia became transfusion independent and showed response following the montelukast and gemfibrozil combination therapy, after previously having no response to single agent chlorambucil. One of one patient with Richter’s transformation of CLL had complete resolution of B symptoms and complete resolution on PET scan measured at 2 months following the montelukast and gemfibrozil combination therapy. One of one patient with myeloma with bone marrow failure became transfusion independent following the montelukast and gemfibrozil combination therapy, with improved white cell counts and improved performance status from 4 to 2. One of one patient with progressive disease following chemotherapy for lung cancer had an improvement in performance status from 3 tol as well as a reduction in tumour size following the montelukast and gemfibrozil combination therapy. Two of two patients with aggressive lymphoma had a complete response in less than 4 weeks with transformed lymphoma and angio- immunoblastic NHL following the montelukast and gemfibrozil combination therapy. One of one patient with end stage airways disease and advanced non responsive gastro intestinal stromal tumour (GIST) went from ECOG 4 to ECOG 2 after 3 weeks of treatment with montelukast and gemfibrozil. Fourteen of sixteen patients have shown demonstrable benefit.

[0095] Montelukast and Gemfibrozil both given alone and when added to palliative chemotherapy appear to improve the response to treatment and symptoms in the majority of patients and appear to reduce transfusion dependency. There has been a marked improvement in performance status. There have also been some highly significant responses in otherwise incurable poor prognosis malignancies.

Claims

1. A method for treating cancer in a subject, comprising administering to the subject an effective amount of a leukotriene receptor antagonist.

2. A method according to claim 1, wherein the leukotriene receptor antagonist is montelukast or a pharmaceutically acceptable salt thereof.

3. A method according to claim 1 or claim 2, wherein the method is employed as an adjunct to chemotherapy, radiotherapy, monclonal antibody therapy, hormone therapy, the administration of checkpoint inhibitors, T cell therapy, or stem cell transplantation.

4. A method according to any one of claims 1 to 3, wherein the treatment increases the sensitivity of the cancer to chemotherapy.

5. A method according to claim 4, wherein the chemotherapy is combination chemotherapy.

6. A method according to any one of claims 1 to 5, wherein the cancer is a haematological cancer.

7. A method according to any one of claims 1 to 6, wherein the cancer is selected from myeloma, leukemia or lymphoma.

8. A method according to claim 7, wherein the myeloma is multiple myeloma.

9. A method according to claim 7, wherein the cancer is acute myeloid leukaemia, chronic lymphocytic leukaemia, non-Hodgkins lymphoma or Richter's Syndrome.

10. A method according to any one of claims 1 to 5, wherein the cancer is a solid tumour.

11. A method according to claim 10, wherein the cancer is lung cancer or a gastrointestinal cancer.

12. A method according to any one of claims 1 to 11, further comprising administration to the subject of a cytochrome P450 (CYP) inhibitor.

13. A method according to claim 10, wherein the CYP is CYP2C8.

14. A method according to claim 10 or claim 11, wherein the CYP inhibitor is gemfibrozil or a pharmaceutically acceptable salt thereof.

15. A method for increasing the sensitivity of a cancer to chemotherapy, the method comprising administering to a subject in need thereof an effective amount of a leukotriene receptor antagonist.

16. A method according to claim 15, wherein the method further comprises administration of a CYP inhibitor.

17. A method according to claim 16, wherein the CYP inhibitor is gemfibrozil or a pharmaceutically acceptable salt thereof.

18. A method for reducing paraprotein levels in a subject having multiple myeloma, the method comprising administering to the subject a leukotriene receptor antagonist, wherein treatment with the leukotriene receptor antagonist results in lower paraprotein levels in the blood or urine than in the absence of the treatment.

19. A method according to claim 18, wherein the method further comprises administration of a CYP inhibitor.

20. A method according to claim 19, wherein the CYP inhibitor is gemfibrozil or a pharmaceutically acceptable salt thereof.