WO2020102304A1 - Combinaison d'un inhibiteur de kinase et d'un électrolyte, compositions et procédés la comprenant - Google Patents

Combinaison d'un inhibiteur de kinase et d'un électrolyte, compositions et procédés la comprenant Download PDF

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Publication number
WO2020102304A1
WO2020102304A1 PCT/US2019/061121 US2019061121W WO2020102304A1 WO 2020102304 A1 WO2020102304 A1 WO 2020102304A1 US 2019061121 W US2019061121 W US 2019061121W WO 2020102304 A1 WO2020102304 A1 WO 2020102304A1
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Prior art keywords
cancer
tarloxotinib
electrolyte
subject
compound
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PCT/US2019/061121
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English (en)
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Vijaya TIRUNAGARU
Jay Mason
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Rain Therapeutics Inc.
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Publication of WO2020102304A1 publication Critical patent/WO2020102304A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • TKIs kinase inhibitors
  • TKIs such as tarloxotinib
  • QT prolongation or prolongation of the QT interval
  • Drug-induced QT prolongation is a serious condition that acts as a marker for risk of progression to Torsades de Pointes (TdP), although QT prolongation does not always progress to TdP.
  • TdP Torsades de Pointes
  • electrolyte disturbances for example, potassium, magnesium, and calcium
  • genetics for example, polymorphisms increase TdP risk
  • drug therapy for example, QT prolonging medications.
  • the QT interval represents the time required for ventricular tissue repolarization after ventricular depolarization.
  • Medications may alter the QT interval, increasing the duration of repolarization and reducing the amplitude of the T-wave, a state known as T-wave flattening.
  • Medication- induced QT prolongation commonly occurs through alterations of intracellular ion channels. Prolonged depolarization is associated with increased function of inward sodium channels (INa).
  • Medications may reduce repolarization by inhibiting the outward potassium channels (IKr). Potassium and magnesium electrolyte abnormalities alter the function of IKr, increasing the risk of arrhythmias or QT prolongation and TdP. Supplementation with magnesium or potassium is known to reduce or resolve cardiac abnormal rhythms. (See, for example, Choy AM et al. Circulation.
  • the administration of potassium creates an increased efflux of potassium, which shortens the QTc interval (See, for example, Kapoor JR, J. Am Coll. Cardiol. 2008; 52(19): 1605. Because electrolyte imbalances are common in hospitalized patients, it is important to monitor these values and determine whether supplementation is needed.
  • TKIs such as tarloxotinib
  • Anti-cancer efficacy of TKIs can be dose-dependent and correlated with higher doses and systemic exposure.
  • tarloxotinib tarloxotinib
  • combinations, compositions, formulations, and methods of use thereof comprising administering TKIs with a concomitant electrolyte supplementation, e.g., magnesium and potassium supplementation, to reduce the severity or prevent the emergence of certain cardiac toxicities, such as QTc prolongation.
  • a concomitant electrolyte supplementation e.g., magnesium and potassium supplementation
  • compositions, formulations, and methods of use thereof comprising administering TKIs with a concomitant electrolyte supplementation, e.g., magnesium and potassium supplementation, to improve cancer patient toleration of treatment with TKIs and toleration of sustained maximal dose treatment, which can be associated with greater anti-cancer benefit for patients.
  • a concomitant electrolyte supplementation e.g., magnesium and potassium supplementation
  • a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of (2E)-4- ⁇ [4-(3-bromo-4- chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino ⁇ -N,N-dimethyl-N-[(l-methyl-4-nitro-lH- imidazol-5-yl)methyl]-4-oxo-2-buten-l -ammonium bromide (Compound A), or a pharmaceutically acceptable salt or solvate thereof, and administering to the subject an electrolyte supplementation.
  • the electrolyte supplementation is selected from the group consisting of potassium, magnesium, and calcium. In some embodiments, the electrolyte supplementation is potassium ion. In some embodiments, administering the electrolyte decreases the risk of the patient developing a toxicity associated with administering Compound A. In some embodiments, the toxicity is a cardiac toxicity. In some embodiments, the toxicity is QT prolongation. In some embodiments, Compound A is administered prior to the electrolyte supplementation. In some embodiments, the electrolyte supplementation is administered prior to Compound A. In some embodiments, Compound A and the electrolyte supplementation are administered simultaneously. In some embodiments, the cancer is non small cell lung cancer.
  • a pharmaceutical combination comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, an electrolyte supplementation, and a pharmaceutically acceptable excipient.
  • a method of reducing or preventing QT prolongation in a subject having cancer comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • a method of reducing or preventing cardiotoxicity in a subject having cancer comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • a method of increasing tolerance to a dose of Compound A in a subject comprising administering to the subject a dose of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation, wherein the dose of Compound A is higher than the dose of Compound A administered without the electrolyte supplementation.
  • a method for treating cancer in a subject comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt of solvate thereof, determining a serum concentration of an electrolyte in the subject, and administering to the subject an electrolyte supplementation comprising the electrolyte if the determined serum concentration of the electrolyte is below a normal serum concentration.
  • a method for treating cancer in a subject comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt of solvate thereof, and co-administering to the subject an electrolyte supplementation comprising the electrolyte, wherein the co-administration can be simultaneous.
  • the electrolyte supplementation is a potassium supplementation, wherein the electrolyte is potassium ion.
  • administration of the potassium supplementation increases the potassium concentration to from about 0.5 to about 6.0 mEq/L above the normal potassium serum concentration in the subject.
  • a compound which is Compound A, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer wherein the treatment comprises administering the compound in combination with an electrolyte supplementation.
  • a pharmaceutical combination comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for use in the treatment of cancer.
  • composition comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for use in the treatment of cancer.
  • a pharmaceutical combination comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for the treatment of cancer in a patient.
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for the treatment of cancer in a patient.
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation in the manufacture of a medicament for the treatment of cancer in a patient.
  • a combination comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation in the manufacture of a medicament for the treatment of cancer in a patient.
  • FIGs. 1A-1B depicts the effect of tarloxotinib (FIG. 1A) and tarloxotinib + KC1 (FIG. IB) on atrial conduction (PR intervals).
  • FIGs. 2A-2B depicts the effect of tarloxotinib (FIG. 2A) and tarloxotinib + KC1 (FIG. 2B) on the ventricular depolarization process (QRS complex).
  • FIGs. 3A-3B depicts the effect of tarloxotinib (FIG. 3A) and tarloxotinib + KC1 (FIG. 3B) on the ventricular repolarization (QT and QTc intervals).
  • FIGs. 4A-4B depicts the effect of tarloxotinib (FIG. 4A) and tarloxotinib + KC1 (FIG. 4B) on the corrected QT interval (QTc).
  • FIG. 5 depicts the preparate post-dose effect of tarloxotinib and combinations on heart- rate corrected QT intervals.
  • FIGs. 6A-6B depicts the effect of tarloxotinib (FIG. 6A) and tarloxotinib + KC1 (FIG. 6B) on heart rate.
  • FIGs. 7A-7B depicts the effect of potassium supplementation on ventricular repolarization
  • FIG. 7A depicts the correlation between serum K + levels and QTcF change from the baseline post 180 min after Tarloxotinib infusion to NSCLC patients on cycle 1 day 1
  • FIG. 7B depicts the effect of Tarlox (line“A”) and Tarlox + KC1 (line“B”) on dQTc, based on the QTc values depicted in FIG. 4.
  • FIG. 8 depicts the effects of infusion administration of Saline, 5 mg/kg tarloxotinib and 1.5 mEq/kg KC1 on cardiovascular parameters in guinea pigs.
  • FIG. 9 depicts effects of infusion administration of 0.5 mEq/kg KC1, 5 mg/kg tarloxotinib, and 1 mEq/kg KC1 on cardiovascular parameters in guinea pigs.
  • FIG. 10 depicts effects of infusion administration of 5 mg/kg tarloxotinib and two oral dosing regimens of KC1 on dQTc(F) in guinea pigs.
  • the present disclosure relates in part to the discovery that combinations of small molecule tyrosine kinase inhibitors (TKIs) and an electrolyte supplementation can be used as a combination therapy to treat or prevent cancers and reduce TKI-induced toxicity effects to the patient.
  • the present disclosure relates in part to the discovery that combinations of small molecule tyrosine kinase inhibitors (TKIs) and an electrolyte supplementation may be used as a combination therapy to treat cancers and reduce TKI-induced toxicity effects to the patient.
  • the TKIs are nitromethylaryl quaternary ammonium salts (also referred to as NMQ prodrugs).
  • the TKI is (E)-4-((4-((3-bromo-4- chlorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)-N,N-dimethyl-N-((l-methyl-4- nitro-lH-imidazol-5-yl)methyl)-4-oxobut-2-en-l-aminium salt (bromide) (also referred to herein as “(2E)-4- ⁇ [4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino ⁇ -N,N- dimethyl-N-[(l -methyl-4-nitro- lH-imidazol-5-yl)methyl] -4-oxo-2-buten- 1 -ammonium bromide”; also referred to herein as Compound A, RN-4000, TRLX, tarloxotin
  • the combination comprises Compound A and an electrolyte supplementation. In some embodiments, the combination comprises Compound B and an electrolyte supplementation. In some embodiments, the combination comprises Compound A, Compound B and an electrolyte supplementation. In some embodiments, the electrolyte supplementation is selected from potassium ion and/or magnesium ion. In some embodiments, the electrolyte supplementation is potassium ion. In some embodiments, the electrolyte supplementation is magnesium ion. In some embodiments, the combinations of the TKI and the electrolyte supplementation are used to treat or prevent cancers while reducing TKI-induced toxicity in the patient.
  • the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • Compound A may exist as a cation or salt.
  • the salt is, for example, a bromide salt.
  • the term“electrolyte”, refers to physiologically relevant free ions.
  • Representative such free ions include, but are not limited to sodium (Na + ), potassium (K + ), calcium (Ca 2+ ), magnesium (Mg 2+ ), chloride (CU), phosphate (P04 ). and bicarbonate (HCCh ).
  • the articles“a” and“an” are used to refer to one or to more than one (i.e.. to at least one) of the grammatical object of the article.
  • “an element” means one element or more than one element.
  • a disease or disorder is“alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.
  • the terms“alkyl”,“alkenyl”,“alkynyl” and“alkoxy” include both straight chain and branched chain groups, as well as unsubstituted and substituted groups.
  • the optional substituents may include, without limitation, halogen, C1-C6 alkoxy, CN, OH, NH2, NO2, NH(Ci-Ce alkyl), N(Ci-Ce alkyl) 2 , COMB, CO(Ci-Ce alkyl), SO2NH2, and S0 2 (Ci-C 6 alkyl).
  • aromatic nitroheterocycle means an aromatic heterocyclic moiety substituted at any ring position by one or more nitro (NO2) groups.
  • the aromatic heterocyclic moiety may be a monocyclic or bi cyclic ring comprising 4 to 12 atoms of which at least one atom is chosen from nitrogen, sulphur, or oxygen.
  • the aromatic heterocyclic moiety may be carbon or nitrogen linked.
  • the aromatic heterocyclic moiety may additionally be substituted by one or more additional substituents at any available ring carbon or heteroatom.
  • the substituents may include, but are not limited to the groups as defined for R26 in Formula V.
  • aromatic nitrocarbocycle means a benzene moiety substituted at any position by one or more nitro (NO2) groups.
  • two adjacent ring carbon atoms may optionally be linked to form a fused carbocyclic or heterocyclic ring.
  • the benzene moiety, and optional fused ring may additionally be substituted by one or more additional substituents at any available carbon or heteroatom.
  • the substituents may include, but are not limited to, the groups as defined for R26 in Formula V.
  • the terms “co-administered” and “co-administration” refer to administering to the subject a compound contemplated herein or pharmaceutically acceptable salt thereof along with a compound that may also treat the disorders or diseases contemplated herein.
  • the co-administered compounds are administered separately as part of a single therapeutic approach.
  • the co-administered compounds are administered in any kind of combination as part of a single therapeutic approach.
  • the co-administered compound may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and/or as a solution.
  • composition or“pharmaceutical composition” refers to a mixture of at least one compound contemplated herein with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, nasal, pulmonary, and topical administration.
  • the term “container” includes any receptacle for holding the pharmaceutical composition or to add protection to manage stability and or water-uptake.
  • the container is the packaging that contains the pharmaceutical composition such as liquid (solution or suspension); semisolid; lyophilized solid; or solution, powder, or lyophilized formulation present in dual chambers.
  • the container is not the packaging that contains the pharmaceutical composition, /. e.. the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition.
  • packaging techniques are well known in the art.
  • the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product.
  • the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating, preventing, or reducing a breathing disorder in a patient.
  • A“disease” as used herein is a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject’s health continues to deteriorate.
  • A“disorder” as used herein in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favourable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject’s state of health.
  • the terms“effective amount,”“pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of a compound or agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. That result may be reduction and/or alleviation of the signs or symptoms of a disease, or any other desired alteration of a biological system.
  • An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. A therapeutic benefit or improvement need not be complete ablation of any one, most, or all symptoms, complications, consequences, or underlying causes associated with the disorder or disease.
  • a satisfactory endpoint is achieved when there is a transient, medium, or long term, incremental improvement in a subject’s condition, or a partial reduction in the occurrence, frequency, severity, progression, or duration, or inhibition or reversal, of one or more associated adverse symptoms, complications, consequences, or underlying causes, worsening, or progression (e.g., stabilizing one or more symptoms or complications of the condition, disorder, or disease), of the disorder or disease, over a duration of time (e.g., hours, days, weeks, months, or years).
  • “instructional material” includes a publication, a recording, a diagram, or any other medium of expression that can be used to communicate the usefulness of a composition and/or compound contemplated herein in a kit.
  • the instructional material of the kit may, for example, be affixed to a container that contains the compound and/or composition contemplated herein.
  • the instructional material of the kit may, for example, be shipped together with a container that contains the compound and/or composition.
  • the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the compound cooperatively. Delivery of the instructional material may be, for example, by physical delivery of the publication or other medium of expression communicating the usefulness of the kit, or may alternatively be achieved by electronic transmission, for example by means of a computer, such as by electronic mail or download from a website.
  • “likelihood”,“likely to”, and similar generally refers to an increase in the probability of an event.
  • “likelihood”,“likely to”, and similar when used in reference to responsiveness to cancer therapy, contemplates an increased probability that the individual will exhibit a reduction in the severity of cancer or the symptoms of cancer or the retardation or slowing of the cancer progression.
  • the term“likelihood”,“likely to”, and similar, when used in reference to responsiveness to cancer therapy can also mean the increase of indicators that may be evidence of the cancer being responsive to treatment.
  • the terms“patient,”“subject” or“individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • the subject is a patient.
  • the patient is an animal.
  • the patient is a mammal.
  • the patient is a human.
  • the subject is a subject in need of treatment thereof.
  • the term“pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e. , the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting a compound disclosed herein.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting a compound disclosed herein to the subject such that it may perform its intended function.
  • such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation, including compounds disclosed herein, and not injurious to the patient.
  • examples of materials that may serve as pharmaceutically acceptable carriers include: sugars (e.g., lactose, glucose, and sucrose); starches (e.g., com starch and potato starch); cellulose, and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate); powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, and soybean oil); glycols (e.g., propylene glycol); polyols (e.g., glycerin, sorbitol, mannitol, and polyethylene glycol); esters (e.g., ethyl oleate and ethyl laurate); agar; buffering agents (e.g., magnesium, magnesium, magnesium
  • “pharmaceutically acceptable carrier” also includes, for example, coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compounds disclosed herein and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions.
  • The“pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compounds disclosed herein.
  • Other additional ingredients that may be included in the pharmaceutical compositions disclosed herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • the language“pharmaceutically acceptable salt” refers to a salt of the compounds of the present disclosure prepared from, for example, pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.
  • the term“prevent,”“preventing” or“prevention,” as used herein, means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences.
  • prodrug refers to a compound that, after administration, is metabolised or otherwise converted to a biologically active or more active compound (e.g., drug) with respect to at least one property.
  • a prodrug, relative to the drug is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered.
  • a prodrug may have, relative to the active drug, altered metabolic stability, altered transport characteristics, fewer side effects, lower toxicity, or improved flavour (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
  • a prodrug may be synthesized using reactants other than the corresponding compound (e.g., drug).
  • A“therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
  • responsiveness refers to the degree of effectiveness of the treatment in lessening or decreasing the symptoms of a disease, disorder, or condition being treated.
  • increased responsiveness when used in reference to a treatment of a cell or a subject, refers to an increase in the effectiveness in lessening or decreasing the symptoms of the disease when measured using any methods known in the art.
  • the increase in the effectiveness is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%.
  • the term“treatment” or“treating” is defined as the application or administration of a therapeutic agent, i.e., a compound disclosed herein (alone or in combination with another pharmaceutical agent), to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein, a symptom of a condition contemplated herein, or the potential to develop a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a condition contemplated herein, the symptoms of a condition contemplated herein or the potential to develop a condition contemplated herein.
  • the term“treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound disclosed herein (alone or in combination with another pharmaceutical agent), to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a condition contemplated herein, the symptoms of a condition contemplated herein or the potential to develop a condition contemplated herein.
  • the term“treatment” or“treating” is defined as the application or administration of a therapeutic agent, i.e., a compound disclosed herein (alone or in combination with another pharmaceutical agent), to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to alleviate, relieve, alter, remedy, ameliorate, improve, or affect a condition contemplated herein, the symptoms of a condition contemplated herein or the potential to develop a condition contemplated herein.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • the term“treatment” or“treating” refers to an action that occurs while an individual is suffering from the specified cancer, which reduces the severity of the cancer or the symptoms of the cancer, and/or retards or slows the progression of the cancer.
  • “treatment” or“treat” refers to an about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% decrease in the rate of progress of a tumour.
  • treatment refers to an about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% decrease in determined tumour burden (i.e., number of cancerous cells present in the individual, and/or the size of the tumour).
  • determined tumour burden i.e., number of cancerous cells present in the individual, and/or the size of the tumour.
  • “treatment” refers to an about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% decrease in any physical symptom(s) of a cancer.
  • “treatment” refers to an about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% increase in the general health of the individual, as determined by any suitable means, such as cell counts, assay results, or other suitable means.
  • a range such as from about 1 to about 6 should be considered to have specifically disclosed sub-ranges such as from about 1 to about 3, from about 1 to about 4, from about 1 to about 5, from about 2 to about 4, from about 2 to about 6, from about 3 to about 6, etc., as well as individual numbers within that range, for example, about 1, about 2, about 2.7, about 3, about 4, about 5, about 5.1, about 5.3, about 5.5, and about 6.
  • reference to a range of 90-100% includes about 91-99%, about 92-98%, about 93-95%, about 91-98%, about 91-97%, about 91-96%, about 91-95%, about 91-94%, about 91-93%, and so forth.
  • Reference to a range of 90-100% also includes about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, etc., as well as about 91.1%, about 91.2%, about 91.3%, about 91.4%, about 91.5%, etc., and about 92.1%, about 92.2%, about 92.3%, about 92.4%, about 92.5%, and so forth.
  • a series of ranges are disclosed throughout the present disclosure. The use of a series of ranges includes combinations of the upper and lower ranges to provide another range. This construction applies regardless of the breadth of the range and in all contexts throughout this present disclosure.
  • TKIs tyrosine kinase inhibitors
  • a“TKG refers to a compound capable of acting as a tyrosine kinase inhibitor, for example, the compounds set forth herein.
  • NMQ prodrugs and/or small molecule EGFR inhibitors include small molecule analogues of Compound A and/or Compound B, to treat or prevent HER-driven cancers.
  • the cancer is a HER-driven drug-resistant cancer.
  • NMQ prodrugs and/or small molecule EGFR inhibitors include, but are not limited to those disclosed in W02010104406, WO2011028135, US20120077811, and US20120202832, each of which is incorporated herein by reference in its entirety.
  • the NMQ prodrugs of quaternary nitrogen salt are compounds of Formula I:
  • X is any negatively charged counterion
  • Ri is -(CH2)nTr, wherein Tr is an aromatic nitroheterocycle or an aromatic nitrocarbocycle and -(CH2)nTr acts as a reductively-activated fragmenting trigger (“reductive trigger”);
  • n is an integer from 0 to 6;
  • R2, R3 and R4 are each independently an aliphatic or an aromatic group of a tertiary amine kinase inhibitor (R2)(R3)(R4)N, or
  • R2, R3, and R4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or
  • R2, R3 and R4 may be absent and two of R2, R3 and R4 form an aromatic heterocyclic amine ring of a kinase inhibitor.
  • the compounds are of Formula II:
  • X is any negatively charged counterion
  • Y is N or C-R7, wherein R7 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, and a group of one of the Formulae Ilia, Illb, or IIIc:
  • T is selected from O, NH, N(CI-C6 alkyl), and a direct bond;
  • n is an integer from 0 to 6;
  • U is selected from OR10, CF3, OCF3, CN, NR11R12, pyrrolidinyl, piperidinyl, piperazinyl, Nl-methylpiperazinyl, morpholinyl, CON(Ri3)(Ri4), S02N(Ri5)(Ri6), N(Ri7)CORi8, N(RI9)S0 2 R 2O , COR21, SOR22, SO2R23, and COOR24;
  • R8, R9, Rio, R11, R12, R13, R14 R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 are independently selected from H and C1-C6 alkyl; Z is N or C-CN;
  • n is an integer from 0 to 6;
  • Ri is a group of the formula (CH2)nTr where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and -(CH2)nTr acts as a reductive trigger;
  • n is an integer from 0 to 6;
  • R2 and R3 are independently selected from C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2CH2OH, and CFhCFkCKCi-Ce alkyl), or
  • R2 and R3 may together form a non-aromatic carbocyclic ring or non-aromatic heterocyclic ring containing at least one heteroatom;
  • R5 is selected from an aniline, an indole, an indoline, an amine, an aminoindole, and an aminoindazole, each of which may be optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CPs, OH, NH 2 , NO2, NH(Ci-Ce alkyl), N(Ci-Ce alkyl) 2 , COMB, CO(Ci-Ce alkyl), SO2MB, and S0 2 (Ci-C 6 alkyl);
  • R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NH(CI-C6 alkyl), N(CI-C6 alkyl)2, and a group of the following Formula
  • V is selected from (CH2)k, O, NH, and N(CI-C6 alkyl);
  • k is an integer from 0 to 6
  • R.25 is selected from H and C1-C6 alkyl.
  • X is selected from halide (e.g., fluoride, chloride, bromide, iodide), methanesulfonate, trifluoromethanesulfonate, acetate, trifluoroacetate, tosylate, lactate, citrate, and formate.
  • halide e.g., fluoride, chloride, bromide, iodide
  • methanesulfonate trifluoromethanesulfonate
  • acetate trifluoroacetate
  • tosylate lactate, citrate, and formate.
  • X is a halide.
  • X is selected from fluoride, chloride, bromide, and iodide.
  • X is fluoride.
  • X is chloride.
  • X is bromide.
  • X is iodide.
  • Ri is a group of one of the following Formulae Va-Vq:
  • R.26 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, CF3, OCF3, F, Cl, Br, I, NO2, CN, COOH, COO(Ci-Ce alkyl), CONH2, CONH(Ci-Ce alkyl), CON(Ci-Ce alkyl) 2 , CO(Ci-Ce alkyl), SO2NH2, S0 2 NH(Ci-C 6 alkyl), S0 2 N(Ci-C 6 alkyl) 2 , S0 2 (Ci-C 6 alkyl), and a group of Formula Ilia, as defined above, wherein * indicates the point of attachment to a group of Formula V;
  • R27 is selected from H, C1-C6 alkyl, and a group of Formula Ilia, as defined above, wherein * indicates the point of attachment to a group of Formula V;
  • R.28 is selected from H and C1-C6 alkyl.
  • Ri is a group of one of the following Formulae Vr-Vae:
  • Ri is a group of Formula Vc, wherein R26 is H and R27 is CFb.
  • Ri is a group of Formula Vd, wherein R26 is selected from H, C1-C6 alkyl (e.g., methyl), C1-C6 alkoxy (e.g., OCH3), C2-C6 alkynyl (e.g., ethynyl), CONH2, CONHMe, CF3, OCF3, Br, NO2, and CN; and R27 is selected from CH 3 , CH2CH2CONH2, and CH2CH2CN.
  • R26 is selected from H, C1-C6 alkyl (e.g., methyl), C1-C6 alkoxy (e.g., OCH3), C2-C6 alkynyl (e.g., ethynyl), CONH2, CONHMe, CF3, OCF3, Br, NO2, and CN; and R27 is selected from CH 3 , CH2CH2CONH2, and CH2CH2CN.
  • Ri is a group of Formula Vd
  • R26 is selected from H and C1-C3 alkyl
  • R27 is selected from H and C 1-C6 alkyl.
  • R26 is selected from H, methyl, ethyl, trifluoromethyl, -CN, - CONH2, and propyn-l-yl; and R27 is C1-C6 alkyl.
  • R26 is H and R27 is C 1-C3 alkyl (e.g., methyl).
  • Ri is a group of Formula Vd, wherein R26 is 1-propynyl and R27 is CH3.
  • Ri is a group of Formula Vq, wherein R26 is selected from H, C1-C6 alkyl (e.g., methyl or ethyl), and C1-C6 alkoxy (e.g., OCH3); and R27 is CH3.
  • Ri is a group of any one of Formulae Vd (1) -Vd (7) :
  • Vd ⁇ 1 Vd ⁇ 2 > Vd ⁇ 3 > Vd ⁇ 4 > Vd ⁇ 5 > Vd ⁇ 6 > Vd ⁇ 7 >
  • R27 is selected from methyl, ethyl, and propyl. In some embodiments R27 is methyl.
  • R2 and R3 form a ring selected from pyrrolidinium, piperidinium, piperazinium, Nl-methylpiperazinium, and morpholinium.
  • R5 is a group of one of the following Formulae Vla-VIg:
  • R.29, rise, R.37, R39, R44, R49, and R54 are independently selected fromH and C1-C6 alkyl;
  • R40, R41, R42, R43, R45, R46, R47, R48, R50, R51, R52, R53, R55, R56, R57, and R58 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(Ci-Ce alkyl), N(Ci-Ce alky 1) 2 , CONH2, CO(Ci-Ce alkyl), SO2NH2, and S0 2 (Ci-C 6 alkyl); and
  • W is N or C-H.
  • Ri is selected from the following:
  • R26 is selected fromH, C1-C6 alkyl (e.g., methyl), C1-C6 alkoxy (e.g., OCH3), C2-C6 alkynyl (e.g., ethynyl), CF3, OCF3, Br, NO2, and CN; and R27 is selected from CH3, CH2CH2CONH2, and CH2CH2CN; or
  • R26 is 1-propynyl and R27 is CH3;
  • R26 is selected from H, C1-C6 alkyl (e.g., methyl and ethyl), and C1-C6 alkoxy (e.g., OCH3); and R27 is CH3;
  • R2 and R3 are independently selected from C1-C6 alkyl, or together form a ring selected from pyrrolidinium, piperidinium, piperazinium, N1 -methylpiperazinium, and morpholinium; and
  • R5 is selected from the following:
  • R29 is H
  • R30, R31, and R32 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(Ci-Ce alkyl), and N(Ci- Ce alkyl)2;
  • R39 is H
  • R40 and R41 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(Ci-Ce alkyl), and N(Ci-Ce alkyl)2
  • R42 and R43 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(Ci-Ce alkyl), and N(CI-C6 alkyl)2
  • W is N or C-H
  • Y is C-H or C-(Ci-C6 alkoxy); Z is N or C-CN;
  • Ri is selected from the following:
  • R26 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkynyl, CF3, OCF3, Br, NO2, and CN, and R27 is selected from CH3, CH2CH2CONH2, and CH2CH2CN; or R26 IS 1-propynyl and R27 is CH3;
  • R26 is selected from H, C1-C6 alkyl (e.g., methyl and ethyl), and C1-C6 alkoxy (e.g., OCH3), and R27 is CH3;
  • R2 and R3 are independently selected from C1-C6 alkyl, or together form a ring selected from pyrrolidinium, piperidinium, piperazinium, Nl-methylpiperazinium, and morpholinium;
  • R5 is selected from the following:
  • R29 is H
  • R30, R31, and R32 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(Ci-Ce alkyl), and N(Ci- Ce alkyl)2;
  • R39 is H
  • R40 and R41 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(Ci-Ce alkyl), and N(Ci-Ce alkyl)2
  • R42 and R43 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(Ci-Ce alkyl), and N(CI-C6 alkyl)2
  • W is N or C-H
  • R6 is H
  • X is any negatively charged counterion
  • n 1 or 2.
  • Y is C-R7, wherein R7 is a group of Formula Illb; Z is N or C- CN;
  • Ri is selected from the following:
  • R26 is selected from H, C1-C6 alkyl (e.g., methyl and ethyl), and C1-C6 alkoxy (e.g., OCH3); and R27 is CFb;
  • R2 and R3 are independently selected from C1-C6 alkyl, or together form a ring selected from pyrrolidinium, piperidinium, piperazinium, N1 -methylpiperazinium, and morpholinium;
  • R5 is selected from the following:
  • R29 is H; and R30, R31, and R32 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -Ce alkynyl, Ci-Ce alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(CI-C6 alkyl), and N(CI-C6 alkyl)2;
  • R39 is H
  • R40 and R41 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -Ce alkynyl, Ci-Ce alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH 2 , NO2, NH(CI-C6 alkyl), and N(CI-C6 alkyl)2
  • R42 and R43 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH2, NO2, NH(CI-C6 alkyl), and N(CI-C6 alky 1)2
  • W is N or C-H
  • R40 and R41 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C 2 -
  • R6 is H
  • X is any negatively charged counterion
  • n 1 or 2.
  • the compounds are of Formula VII:
  • R59 is H, and (a) R60 is (3-chlorobenzyl)oxy- and R6i is chloro;
  • R60 is 2-pyridinylmethoxy and R6i is chloro
  • R60 and R6i are both chloro
  • R60 is chloro and R6i is bromo
  • R60 and R6i are both bromo
  • R60 is fluoro and R6i is ethynyl
  • R60 is chloro and R6i is ethynyl
  • R60 is bromo and R6i is ethynyl
  • R60 is bromo and R6i is fluoro
  • R60 is 2-pyridinylmethoxy and R6i is fluoro
  • R60 is 2-pyridinylmethoxy and R6i is bromo
  • R59, R.60 and R.61 are selected from benzyloxy, 3-chlorobenzyloxy, and 2-pyridinylmethoxy, and when at least one of R59, R.60, and R6i is not benzyloxy, 3- chlorobenzyloxy or 2-pyridinylmethoxy, each of the other R59, R60, or R6i is independently selected from H, halogen, and C2-C4 alkynyl, with the proviso that when one of R59, R60 and R61 is benzyloxy or 2-pyridinylmethoxy, the other two of R59, R60 and R6i are not H;
  • R59, R60 and R6i together with the carbon atoms to which they are attached, form 1 -O-fluorobenzyl)- 1 //-pyrazole. and the other R59, R60 or R6i is selected fromH, halogen, and C2-C4 alkynyl.
  • the compound of Formula VII is a compound according to Formula VIII:
  • R62 is H, and either
  • R63 is (3-chlorobenzyl)oxy- and R64 is chloro;
  • R63 is 2-pyridinylmethoxy and R.64 is chloro
  • R63 is chloro and R64 is bromo
  • R63 is fluoro and R64 is ethynyl
  • R63 is chloro and R64 is ethynyl
  • R63 is bromo and R64 is ethynyl
  • R63 is 2-pyridinylmethoxy and R64 is fluoro;
  • R63 is 2-pyridinylmethoxy and R64 is bromo.
  • the compound of Formula VII is selected from the group consisting of:
  • the compounds are of Formula IX:
  • R59, R60 and R6i are as defined for Formula VII;
  • R65 is selected fromH, methyl, ethyl, trifluoromethyl, -CN, -CONH2, and propyn- l-yl; and
  • R66 is C1-C6 alkyl.
  • the compounds are of Formula X:
  • R59, R.60 and R.61 are as defined for Formula VII; and R.67 is selected from H, methyl, ethyl, trifluoromethyl, -CN, -CONH2, and propyn-l-yl.
  • the compounds are of Formula XI:
  • R62, R63 and R64 are as defined for Formula VIII; and R68 is selected from H, methyl, ethyl, trifluoromethyl, -CN, -CONH2, and propyn-l-yl.
  • X is selected from halide (e.g., fluoride, chloride, bromide, iodide), methanesulfonate, trifluoromethanesulfonate, acetate, trifluoroacetate, tosylate, lactate, citrate and formate.
  • halide e.g., fluoride, chloride, bromide, iodide
  • methanesulfonate e.g., methanesulfonate, trifluoromethanesulfonate, acetate, trifluoroacetate, tosylate, lactate, citrate and formate.
  • the compounds are selected from the group consisting of:
  • the compounds are selected from the group consisting of:
  • the combinations disclosed herein are administered to treat cancer.
  • the cancer to be treated is lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • the cancer is gastric cancer.
  • the cancer is breast cancer.
  • the cancer is head and neck squamous cell carcinoma (HNSCC).
  • the cancer is gastric/gastroesophageal (GE) junction cancer.
  • the cancer is oesophageal cancer.
  • the cancer is salivary cancer.
  • the cancer is ovarian cancer.
  • the cancer is endometrial cancer.
  • the cancer is uterine cancer.
  • the cancer is pancreatic cancer. In some embodiments, the cancer is biliary tract cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is brain and/or spinal cord cancer (glioblastoma). In some embodiments, the cancer is lymphoma, e.g., primary central nervous system lymphoma. In some embodiments, the cancer is leukaemia, e.g., acute lymphoblastic leukaemia.
  • the cancer is selected from the group of lung cancer, gastric cancer, breast cancer, HNSCC, GE junction cancer, oesophageal cancer, salivary cancer, ovarian cancer, endometrial cancer, uterine cancer, prostate cancer, pancreatic cancer, colon cancer, biliary tract cancer, bladder cancer, colorectal, renal, glioblastoma, mesothelioma, adenocarcinoma, lymphoma, and leukaemia.
  • the cancer is selected from bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, and testicular cancer.
  • the cancer is selected from chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, and retinoblastoma, and non-small cell lung cancer.
  • the cancer is brain cancer.
  • the cancer is spinal cord cancer.
  • the cancer is a solid tumour.
  • solid tumours are abnormal masses of tissue that do not contain cysts or liquid areas.
  • solid tumours can be benign or malignant.
  • different types of solid tumours are named for the type of cells that form them (e.g., sarcomas, carcinomas, and lymphomas).
  • the solid tumour can be sarcomas and carcinomas.
  • the solid tumour can be fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumour, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, squamous cell carcinoma of the head and neck (HNSCC), oral carcinoma, gastric carcinoma, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, papillary carcinoma, papillary adeno
  • the solid tumour is malignant melanoma, adrenal carcinoma, breast carcinoma, renal cell cancer, carcinoma of the pancreas, non-small-cell lung carcinoma (NSCLC), or carcinoma of unknown primary.
  • NSCLC non-small-cell lung carcinoma
  • the solid tumour is breast cancer, ovarian cancer, brain cancer, gastric cancer, oesophageal cancer prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, pancreatic cancer, or thyroid cancer.
  • the solid tumour is selected from the groups consisting of carcinoma, melanoma, sarcoma, and chronic granulomatous disease.
  • the combinations disclosed herein can pass the blood-brain barrier.
  • the cancer is brain cancer or spinal cord cancer.
  • the cancer is selected from glioblastoma, glioma, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumours, pineal tumours, primary central nervous system lymphoma, and acute lymphoblastic leukaemia that has crossed the blood-brain barrier.
  • the cancer is secondary brain metastases.
  • the cancer is NSCLC with brain metastases.
  • the concentration of the compounds disclosed herein in the brain is sufficient to treat a CNS cancer or a spinal cord cancer.
  • Compound A passes the blood-brain barrier. In some embodiments, Compound A passes the blood-brain barrier and convert to its active metabolite, Compound B. In some embodiments, Compound A converts to its active metabolite, Compound B, and Compound B then passes the blood-brain barrier. In some embodiments, Compound B passes the blood-brain barrier. In some embodiments, Compound A and/or Compound B pass the blood-brain barrier.
  • a TKI e.g., tarloxotinib (Compound A)
  • the toxicity is a cardiac toxicity.
  • the toxicity is the development of cardiac repolarization effects.
  • the toxicity is QT prolongation.
  • the toxicity results in an increase in QT and/or QTc (“corrected” QT interval).
  • the toxicity results in abnormalities of the ST segment (e.g., ST segment depression).
  • the toxicity results in abnormalities of the T-wave (e.g., T- wave flattening).
  • the toxicity results in Torsades de Pointes (TdP), which is a form of polymorphic ventricular tachycardia that results from a long QT interval (in other words, from QT prolongation).
  • TdP Torsades de Pointes
  • the toxicity results in rapid, irregular QRS complexes (arrhythmia).
  • the toxicity results in ventricular fibrillation.
  • the TKI-induced toxicities as disclosed herein are correlated to an increased dose of the TKI and/or systemic exposure to the TKI.
  • the anti-cancer efficacy of TKIs e.g., Compound A
  • administration of an electrolyte supplementation reduces the toxicity effects of TKI administration in a subject such that a high dose of TKI (e.g., Compound A) can be administered to the subject.
  • an electrolyte supplementation increases the safety profile of the TKI administration.
  • administering reduces the toxicity, e.g., one or more toxicities disclosed herein, effects of TKI administration in a subject, e.g., a cancer subject.
  • electrolyte supplementation reduces the severity of a cardiac toxicity in a subject being treated with a TKI.
  • electrolyte supplementation reduces the severity of QT prolongation in a subject being treated with a TKI.
  • electrolyte supplementation prevents the emergence of a cardiac toxicity in a subject being treated with a TKI.
  • electrolyte supplementation prevents the emergence of QT prolongation in a subject being treated with a TKI.
  • electrolyte supplementation reduces or resolves cardiac abnormal rhythms in subjects being treated with a TKI.
  • electrolyte supplementation includes supplementation of one or more electrolytes selected from the group consisting of sodium (Na + ), potassium (K + ), calcium (Ca 2+ ), magnesium (Mg 2+ ), chloride (Cl ). phosphate (POT ). sulfate (SO4 2 ) and bicarbonate (HCO3 ). and combinations thereof.
  • the electrolyte supplementation is a potassium supplementation.
  • the administration of potassium creates an increased efflux of potassium, which shortens the QTc interval.
  • potassium supplements in the form of potassium chloride, potassium citrate, potassium gluconate, potassium bicarbonate, potassium aspartate, and/or potassium orotate can readily be obtained.
  • high-potassium up to 800 milligrams per serving
  • low- sodium vegetable juices are available.
  • some soft drinks are rich in potassium.
  • some soft drinks contain potassium gluconate, which has a less bitter taste than some other potassium supplements.
  • salt substitutes are high in potassium.
  • foods high in potassium such as raisins, figs, apricots, bananas, sardines, veal, bananas, avocado, sweet potatoes, spinach, watermelon, coconut water, white beans, black beans, edamame, tomato paste, butternut squash, potatoes, Swiss chard, beets, pomegranate, and broccoli may be used as potassium supplements.
  • foods high in potassium may provide potassium that is easily bioavailable and/or may reduce gastrointestinal side effects associated with the administration of potassium salts.
  • the potassium supplement may also be provided as part of a multivitamin.
  • potassium acetate e.g., 2 mEq/mL or 4 mEq/mL for injection
  • potassium acetate e.g., 75 mg, 95 mg, 99 mg, and 180 mg tablets and/or 2 mEq/mL, 10 mEq/50 mL, 20 mEq/50 mL, 10 mEq/100 mL, 20 mEq/100 mL, 30 mEq/100 mL, 40 mEq/100 mL for injection and/or 20 mEq/15 mL, 40 mEq/15 mL liquid and/or 20 mEq or 25 mEq powder for reconstitution, and/or 9 mEq, 10 mEq, Potassium chloride (KC1) tablets 600mg or 750mg or 20 mEq extended release tablets); and potassium gluconate (e.g., 486 mg, 500 mg
  • KC1 potassium acetate
  • KC1 potassium acetate
  • the electrolyte supplementation is a magnesium supplementation.
  • a variety of different magnesium supplemental forms are available.
  • supplements in the form of magnesium chloride, magnesium gluconate, magnesium lactate, magnesium oxide, and/or magnesium sulfate can readily be obtained.
  • foods high in magnesium such as artichoke, banana, figs, almonds, cashews, pine nuts, Brazil nuts, beans, spinach, and tomatoes may be used as magnesium supplements.
  • the magnesium supplement may also be provided as part of a multivitamin.
  • magnesium supplements include magnesium chloride (e.g., 200 mg/ml for injection, 535 mg extended release tablets); magnesium gluconate (3.25 mg/mL, 1000 mg/5 mL liquid; 500 mg tablet); magnesium lactate (84 mg extended release tablet); magnesium oxide (e.g., 140 mg, 600 mg capsules, powder, and/or 200 mg, 250 mg, 400 mg, 420 mg, and 500 mg tablets); and magnesium sulfate (e.g., 40 mg/mL, 80 mg/mL, 125 mg/mL, 500 mg/mL for injection).
  • magnesium chloride e.g., 200 mg/ml for injection, 535 mg extended release tablets
  • magnesium gluconate 3.25 mg/mL, 1000 mg/5 mL liquid; 500 mg tablet
  • magnesium lactate 84 mg extended release tablet
  • magnesium oxide e.g., 140 mg, 600 mg capsules, powder, and/or 200 mg, 250 mg, 400 mg, 420 mg, and 500 mg tablets
  • magnesium sulfate e.
  • the electrolyte supplementation can be administered simultaneously, sequentially, and/or separately from administration of the TKI. In some embodiments, the electrolyte supplementation can be administered simultaneously from administration of the TKI. In some embodiments, the electrolyte supplementation can be administered sequentially from administration of the TKI, wherein the TKI is administered first. In some embodiments, the electrolyte supplementation can be administered sequentially from administration of the TKI, wherein the electrolyte supplementation is administered first. In some embodiments, the electrolyte supplementation can be administered separately from administration of the TKI. In some embodiments, the electrolyte supplementation can be administered as a tablet or a power that is dissolved in a juice. In some embodiments, the electrolyte supplementation can be administered intravenously.
  • the combination comprises Compound A and an electrolyte supplementation.
  • the combination comprises Compound B and an electrolyte supplementation.
  • the combination comprises Compound A, Compound B, and an electrolyte supplementation.
  • the combinations disclosed herein result in decreased toxicity effects in a subject (e.g., decreased toxicity effects due to administration of the TKI when administered with an electrolyte supplementation). In some embodiments, the combinations disclosed herein result in increased subject tolerance to higher doses of TKI. In some embodiments, the combinations disclosed herein exhibit low toxicity effects.
  • the combination of the TKI e.g., a compound of Formula I, II, VII, VIII, IX, X and/or XI, as disclosed herein, and an electrolyte supplementation, as disclosed herein, may refer to a combination wherein the individual agents are physically mixed or wherein the individual agents are physically separated.
  • the TKI and the electrolyte supplementation are physically mixed in the combination.
  • the TKI and the electrolyte supplementation are physically separated in the combination.
  • the electrolyte supplementation is combined in the same formulation with the TKI, either as an addition to the drug product formulation or as a diluent which is mixed with the TKI for IV administration.
  • the TKI and the electrolyte supplementation are physically mixed in a pharmaceutical composition.
  • the TKI and the electrolyte supplementation are physically separated in a pharmaceutical composition.
  • the combination is for simultaneous, separate, or sequential administration.
  • the combination of the TKI and the electrolyte supplementation may be administered: a) as a combination that is part of the same medicament formulation (e.g., part of the same dosage form for simultaneous administration); or b) as a combination of two units, each with one of them for simultaneous, sequential, or separate administration.
  • the compound is (E)-4-((4-((3-bromo-4- chlorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)amino)-N,N-dimethyl-N-((l-methyl-4- nitro-lH-imidazol-5-yl)methyl)-4-oxobut-2-en-l-aminium salt (bromide) (also referred to herein as “(2E)-4- ⁇ [4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino ⁇ -N,N- dimethyl-N-[(l -methyl-4-nitro- lH-imidazol-5-yl)methyl] -4-oxo-2-buten- 1 -ammonium bromide”, Compound A, tarloxotinib, or tarlox), and/or (2////
  • the compounds of Formula I, II, VII, VIII, IX, X and/or XI, as disclosed herein, and the electrolyte supplementation, as disclosed herein, are part of a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
  • the present disclosure contemplates methods of treating a subject with cancer (e.g., the cancers disclosed herein), with the combinations contemplated herein, wherein the treatment is part of a maintenance therapy for subjects with recurring or refractory cancer.
  • the present disclosure contemplates a method of treating a resistant or refractory cancer in a subject with the combinations disclosed herein.
  • the treatment leads to a full response, remission, and/or complete cure in the subject with recurring or refractory cancer.
  • the treatment maintains a stable disease, leads to a partial response (e.g., some tumour regression), or prevents the return of tumours which have fully regressed.
  • a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a TKI, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • the TKI and the electrolyte supplementation are administered separately, simultaneously, or sequentially.
  • the TKI and the electrolyte supplementation are administered simultaneously.
  • the TKI and the electrolyte supplementation are administered in the same dosage form.
  • the TKI and the electrolyte supplementation are administered in separate dosage forms.
  • the TKI and the electrolyte supplementation are administered sequentially.
  • the TKI is administered prior to the electrolyte supplementation. In some embodiments, the electrolyte supplementation is administered prior to the TKI. In some embodiments, the TKI is administered in an amount sufficient to induce a toxicity, e.g., a toxicity disclosed herein, in a subject and the electrolyte supplementation is administered in an amount of prevent such a toxicity from being induced in the subject.
  • a toxicity e.g., a toxicity disclosed herein
  • the TKI is a compound of Formula I, II, VII, VIII, IX, X and/or XI.
  • the compound is of Formula I, II, IX, X and/or XI.
  • the compound is of Formula VII and/or VIII.
  • the compound is one of compounds 12-88 and 91-104.
  • the compound is one of compounds 1-11, 89 and 90.
  • the compound is compound 17.
  • the compound is compound 5.
  • the compound is Compound A.
  • the compound is Compound B.
  • the electrolyte supplementation comprises one or more of potassium, magnesium, sodium, calcium, bicarbonate, chloride, and phosphate.
  • the electrolyte supplementation is potassium ion.
  • the electrolyte supplementation is magnesium ion.
  • the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound selected from the group consisting of “(2E)-4- ⁇ [4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino ⁇ - N,N-dimethyl-N-[(l-methyl-4-nitro-lH-imidazol-5-yl)methyl]-4-oxo-2-buten-l -ammonium bromide” (Compound A), and (2£ , )-/V-[4-(3-bromo-4-chloroanilino)pyrido[3,4-ri]pyrimidin-6- yl]-4-(dimethylamino)-2-butenamide (Compound B), or a salt or solvate thereof, and an electrolyte supplementation.
  • a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • Compound A and the electrolyte supplementation are administered separately, simultaneously, or sequentially.
  • Compound A and the electrolyte supplementation are administered simultaneously.
  • Compound A and the electrolyte supplementation are administered in the same dosage form.
  • Compound A and the electrolyte supplementation are administered in separate dosage forms.
  • Compound A and the electrolyte supplementation are administered sequentially.
  • Compound A is administered prior to the electrolyte supplementation.
  • the electrolyte supplementation is administered prior to Compound A.
  • a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • Compound B and the electrolyte supplementation are administered separately, simultaneously, or sequentially.
  • Compound B and the electrolyte supplementation are administered simultaneously.
  • Compound B and the electrolyte supplementation are administered in the same dosage form.
  • Compound B and the electrolyte supplementation are administered in separate dosage forms.
  • Compound B and the electrolyte supplementation are administered sequentially.
  • Compound B is administered prior to the electrolyte supplementation.
  • the electrolyte supplementation is administered prior to Compound B.
  • a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of Compound A and Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • Compound A, Compound B, and the electrolyte supplementation are administered separately, simultaneously, or sequentially.
  • Compound A, Compound B, and the electrolyte supplementation are administered simultaneously.
  • Compound A, Compound B, and the electrolyte supplementation are administered in the same dosage form.
  • Compound A, Compound B, and the electrolyte supplementation are administered in separate dosage forms.
  • Compound A, Compound B, and the electrolyte supplementation are administered sequentially. In some embodiments, Compound A and Compound B are administered prior to the electrolyte supplementation. In some embodiments, the electrolyte supplementation is administered prior to Compound A and Compound B.
  • the methods provided herein for treating cancer in a subject include administering an amount of Compound A that induces a toxicity in a subject in combination with an electrolyte supplementation.
  • an amount of Compound A that induces a toxicity in a subject in combination with an electrolyte supplementation can be rendered safe and tolerable due to the electrolyte supplementation.
  • a normal amount of Compound A is an amount which is enough to cause cardiac toxicity.
  • the methods provided herein for treating cancer in a subject include administering an amount of Compound B that induces a toxicity in a subject in combination with an electrolyte supplementation.
  • an amount of Compound B that induces a toxicity in a subject in combination with an electrolyte supplementation can be rendered safe and tolerable due to the electrolyte supplementation.
  • a normal amount of Compound B is an amount which is enough to cause cardiac toxicity.
  • the methods provided herein for treating cancer in a subject include administering an amount of Compound A and Compound B that induces a toxicity in a subject in combination with an electrolyte supplementation.
  • an amount of Compound A and Compound B to induce cardiac toxicity can be rendered safe and tolerable due to the electrolyte supplementation.
  • a normal amount of Compound A and Compound B is an amount which is enough to cause cardiac toxicity.
  • a normal amount of a compound of the present disclosure is an amount which is enough to cause cardiac toxicity. In some embodiments, a normal amount of a compound is an amount which is enough to cause cardiac toxicity.
  • a method of inhibiting tumour cell growth comprising administering to the tumour a therapeutically effective amount of a TKI of the present disclosure, and an electrolyte supplementation, as described herein.
  • a method of inhibiting tumour cell growth comprising administering to the tumour a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • a method of inhibiting tumour cell growth comprising administering to the tumour a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • a method of inhibiting tumour cell growth comprising administering to the tumour a therapeutically effective amount of Compound A and Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • the tumour is a solid tumour.
  • the solid tumour is selected from bladder carcinoma, squamous cell carcinoma, transitional cell carcinoma, basal cell carcinoma, renal cell carcinoma, ductal cell carcinoma, and adenocarcinoma.
  • a compound which is a TKI of the present disclosure, for use in the treatment of cancer, wherein the treatment comprises administering the compound in combination with an electrolyte supplementation.
  • Compound A or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer, wherein the treatment comprises administering the compound in combination with an electrolyte supplementation.
  • Compound B or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer, wherein the treatment comprises administering the compound in combination with an electrolyte supplementation.
  • provided herein is Compound A and Compound B, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer, wherein the treatment comprises administering the compound in combination with an electrolyte supplementation.
  • a combination comprising a TKI of the present disclosure, and an electrolyte supplementation for use in the treatment of cancer.
  • a combination comprising Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for use in the treatment of cancer.
  • a combination comprising Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for use in the treatment of cancer.
  • a combination comprising Compound A and Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for use in the treatment of cancer.
  • a use of a combination comprising a therapeutically effective amount of a TKI of the present disclosure, and an electrolyte supplementation for the treatment of cancer in a patient In some embodiments, provided herein is a use of a combination comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for the treatment of cancer in a patient. In some embodiments, provided herein is a use of a combination comprising a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for the treatment of cancer in a patient.
  • provided herein is a use of a combination comprising a therapeutically effective amount of Compound A and Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for the treatment of cancer in a patient.
  • a use of a combination comprising a therapeutically effective amount of a TKI of the present disclosure, and an electrolyte supplementation in the manufacture of a medicament for the treatment of cancer in a subject.
  • a use of a combination comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation in the manufacture of a medicament for the treatment of cancer in a subject.
  • provided herein is a use of a combination comprising a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation in the manufacture of a medicament for the treatment of cancer in a subject.
  • a use of a combination comprising a therapeutically effective amount of Compound A and Compound B, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation in the manufacture of a medicament for the treatment of cancer in a subject.
  • the method of treating cancer in a subject comprises administering to the subject a 0.6 mg/kg dose of tarloxotinib and administering to the subject a 5 mg/kg dose of KC1.
  • a pharmaceutical combination comprises a 0.6 mg/kg dose of tarloxotinib and a 5 mg/kg dose of KC1.
  • a method of reducing or preventing QT prolongation in a subject suffering from cancer comprises administering to the subject a 0.6 mg/kg dose of tarloxotinib and a 5 mg/kg dose of KC1.
  • a method of reducing or preventing cardiotoxicity in a subject suffering from cancer comprises administering to the subject a 0.6 mg/kg dose of tarloxotinib, and a 5 mg/kg dose of KC1.
  • a method of increasing tolerance to a dose of tarloxotinib in a subject comprises administering to the subject a 0.6 mg/kg dose of tarloxotinib and a 5 mg/kg dose of KC1.
  • a method for treating cancer in a subject comprises administering to the subject a 0.6 mg/kg dose of tarloxotinib;
  • a method for treating cancer in a subject comprises administering to the subject a 0.6 mg/kg dose of tarloxotinib and simultaneously co administering to the subject a 5 mg/kg dose of KC1.
  • a pharmaceutical combination comprises a 0.6 mg/kg dose of tarloxotinib, and a 5 mg/kg dose of KC1 for use in the treatment of cancer.
  • use of a combination comprises a 0.6 mg/kg dose of tarloxotinib, and a 5 mg/kg dose of KC1 for the treatment of cancer in a patient.
  • use of a combination comprises a 0.6 mg/kg dose of tarloxotinib, and a 5 mg/kg dose of KC1 in the manufacture of a medicament for the treatment of cancer in a patient.
  • a pharmaceutical composition comprises a 0.6 mg/kg dose of tarloxotinib and a 5 mg/kg dose of KC1.
  • a pharmaceutical composition comprises a 0.6 mg/kg dose of tarloxotinib and a 5 mg/kg dose of KC1 for use in the treatment of cancer.
  • use of a composition comprises a 0.6 mg/kg dose of tarloxotinib and a 5 mg/kg dose of KC1 in the manufacture of a medicament for the treatment of cancer in a patient.
  • the subject is further administered at least one additional agent, or a salt or solvate thereof, that treats or prevents the cancer, as described herein. In some embodiments, the subject is further administered at least one additional agent, or a salt or solvate thereof, that treats or prevents the cancer.
  • the subject is further administered at least one additional agent, or a salt or solvate thereof, that treats the cancer, as described herein. In some embodiments, the subject is further administered at least one additional agent, or a salt or solvate thereof, that treats the cancer.
  • At least one of a compound of any one of Formulae I, II, VII, VIII, IX, X and/or XI, as disclosed herein, and the electrolyte supplementation are administered by at least one route selected from the group comprising inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, intratracheal, optic, intraocular, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.
  • At least one of Compound A and the electrolyte supplementation are administered by at least one route selected from the group comprising inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, intratracheal, optic, intraocular, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.
  • At least one of Compound A and the electrolyte supplementation is administered orally, parenterally, rectally, topically, intravenously, intramuscularly, subcutaneously, or intraperitoneally. In some embodiments, at least one of Compound A and the electrolyte supplementation is administered intraperitoneally. In some embodiments, at least one of Compound A and the electrolyte supplementation is administered intravenously.
  • At least one of Compound B and the electrolyte supplementation are administered by at least one route selected from the group comprising inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, intratracheal, optic, intraocular, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.
  • At least one of Compound B and the electrolyte supplementation is administered orally, parenterally, rectally, topically, intravenously, intramuscularly, subcutaneously, or intraperitoneally. In some embodiments, at least one of Compound B and the electrolyte supplementation is administered intraperitoneally. In some embodiments, at least one of Compound B and the electrolyte supplementation is administered intravenously.
  • At least one of Compound A, Compound B, and the electrolyte supplementation are administered by at least one route selected from the group comprising inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, intratracheal, optic, intraocular, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.
  • At least one of Compound A, Compound B, and the electrolyte supplementation is administered orally, parenterally, rectally, topically, intravenously, intramuscularly, subcutaneously, or intraperitoneally. In some embodiments, at least one of Compound A, Compound B, and the electrolyte supplementation is administered intraperitoneally. In some embodiments, at least one of Compound A, Compound B, and the electrolyte supplementation is administered intravenously.
  • the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject is a human in need of treatment thereof.
  • Compound A is administered by at least one route selected from the group comprising inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, intratracheal, optic, intraocular, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.
  • Compound A is administered orally, parenterally, rectally, topically, intravenously, intramuscularly, subcutaneously, or intraperitoneally.
  • Compound A is administered intraperitoneally. In some embodiments, Compound A is administered intravenously. In some embodiments, Compound B is administered by at least one route selected from the group comprising inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, intratracheal, optic, intraocular, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.
  • Compound B is administered orally, parenterally, rectally, topically, intravenously, intramuscularly, subcutaneously, or intraperitoneally. In some embodiments, Compound B is administered intraperitoneally. In some embodiments, Compound A is administered intravenously.
  • Compound A and Compound B are administered by at least one route selected from the group comprising inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, intratracheal, optic, intraocular, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.
  • Compound A and Compound B are administered orally, parenterally, rectally, topically, intravenously, intramuscularly, subcutaneously, or intraperitoneally.
  • Compound A and Compound B are administered intraperitoneally. In some embodiments, Compound A and Compound B are administered intravenously. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject is a human in need of treatment thereof.
  • the electrolyte supplementation is administered by at least one route selected from the group comprising inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, intratracheal, optic, intraocular, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.
  • the electrolyte supplementation is administered orally, parenterally, rectally, topically, intravenously, intramuscularly, subcutaneously, or intraperitoneally.
  • the electrolyte supplementation is administered intravenously.
  • the subject is a mammal.
  • the mammal is a human.
  • the subj ect is a human in need of treatment thereof.
  • kits comprising a compound of any one of Formulae I, II, VII, VIII, IX, X and/or XI, as disclosed herein, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for preventing or treating a cancer.
  • kits comprising a compound of any one of Formulae I, II, VII, VIII, IX, X and/or XI, as disclosed herein, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for treating a cancer.
  • kits comprising Compound A or Compound B, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for preventing or treating a cancer.
  • the instructional material comprises instructions for treating a cancer.
  • kits comprising Compound A, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for preventing or treating a cancer.
  • kits comprising Compound A, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for treating a cancer.
  • kits comprising Compound B, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for preventing or treating a cancer.
  • kits comprising Compound B, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for treating a cancer.
  • kits comprising Compound A, Compound B, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for preventing or treating a cancer.
  • kits comprising Compound A, Compound B, an electrolyte supplementation, an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for treating a cancer.
  • the compounds (e.g., the TKI and/or the electrolyte supplementation) of the present disclosure may form salts with acids, and such salts are included in the present disclosure.
  • the salts are pharmaceutically acceptable salts.
  • the term“salts” embraces addition salts of free acids that are useful within the methods disclosed herein.
  • pharmaceutically acceptable salt refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present disclosure, such as for example utility in process of synthesis, purification, or formulation of compounds useful within the methods disclosed herein.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include sulphate, hydrogen sulphate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulphuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p- toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric
  • Suitable pharmaceutically acceptable base addition salts of compounds of the present disclosure include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • the salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • the combinations contemplated herein are useful in the methods of the present disclosure when used concurrently with at least one additional compound useful for preventing and/or treating diseases and/or disorders contemplated herein.
  • the combinations contemplated herein are useful in the methods of the present disclosure when used concurrently with at least one additional compound useful for treating diseases and/or disorders contemplated herein.
  • the combinations contemplated herein are useful in the methods of present disclosure in combination with at least one additional agent useful for preventing and/or treating diseases and/or disorders contemplated herein.
  • the combinations contemplated herein are useful in the methods of present disclosure in combination with at least one additional agent useful for treating diseases and/or disorders contemplated herein.
  • additional agents may comprise compounds of the present disclosure or other compounds, such as commercially available compounds, known to treat, prevent, or reduce the symptoms of diseases and/or disorders contemplated herein.
  • These additional agents may comprise compounds of the present disclosure or other compounds, such as commercially available compounds, known to treat or reduce the symptoms of diseases and/or disorders contemplated herein.
  • the combinations contemplated herein, or a salt or solvate thereof can be used concurrently or in combination with one or more agents known to be useful in treating or preventing cancer, such as the cancers described herein.
  • the combinations contemplated herein, or a salt or solvate thereof can be used concurrently or in combination with one or more agents known to be useful in treating cancer, such as the cancers described herein.
  • Non-limiting examples of additional anti-proliferative agents contemplated include, but are not limited to, compounds listed on the cancer chemotherapy drug regimens in the 14 th Edition of the Merck Index (2006), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, proc
  • Additional anti-proliferative agents include other molecular targeted agents that modulate parallel pathways such as MEK 1/2 inhibitors, AKT inhibitors, mTOR inhibitors, and monoclonal antibodies (e.g., Cetuximab). Additional anti-proliferative agents include oxaliplatin, gemcitabine, gefmitib, taxotere, ara A, ara C, herceptin, BCNU, CCNU, DTIC, and actinomycin D. In some embodiments, additional anti proliferative agents include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Eleventh Edition), editor Molinoff et al., publ.
  • a combination of a compound of any one of Formulae I, II, VII, VIII, IX, X and/or XI, as disclosed herein, and an electrolyte supplementation is co administered with at least one additional agent.
  • a combination of a compound of any one of Formulae I, II, VII, VIII, IX, X and/or XI, as disclosed herein, and an electrolyte supplementation is co-formulated with at least one additional agent.
  • the regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the subject either prior to or after the onset of a disease or disorder contemplated herein.
  • several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection.
  • the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • compositions of the present disclosure may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated herein.
  • an effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder contemplated herein.
  • dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non limiting example of an effective dose range for a therapeutic combination contemplated herein is from about 1 to about 5,000 mg/kg of body weight/per day.
  • actual dosage levels of the active ingredients in the pharmaceutical compositions disclosed herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the therapeutically effective amount or dose of a combination of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the subject and the progression of a disease or disorder contemplated herein.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian can start doses of the combinations contemplated herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable dose of a combination of the present disclosure may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg (e.g., about 5 mg to about 250 mg per day).
  • the dose may be administered in a single dosage or in multiple dosages (e.g., from 1 to 4 or more times per day).
  • the amount of each dosage may be the same or different.
  • the amount of each dosage may be the same.
  • the amount of each dosage may be different.
  • the amount of each dosage when multiple dosages are used, the amount of each dosage may be the same or different a dose of about 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.
  • combinations contemplated herein for administration may be in the range of from about 1 pg to about 10,000 mg, about 20 pg to about 9,500 mg, about 40 pg to about 9,000 mg, about 75 pg to about 8,500 mg, about 150 pg to about 7,500 mg, about 200 pg to about 7,000 mg, about 3050 pg to about 6,000 mg, about 500 pg to about 5,000 mg, about 750 pg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments there between.
  • the dose of a combination of the present disclosure is from about 1 mg and about 2,500 mg.
  • a dose of a compound of the present disclosure used in compositions described herein is less than about 10,000 mg, less than about 8,000 mg, less than about 6,000 mg, less than about 5,000 mg, less than about 3,000 mg, less than about 2,000 mg, less than about 1,000 mg, less than about 500 mg, less than about 200 mg, or less than about 50 mg.
  • a dose of an additional agent in the combination as described herein is less than about 1,000 mg, less than about 800 mg, less than about 600 mg, less than about 500 mg, less than about 400 mg, less than about 300 mg, less than about 200 mg, less than about 100 mg, less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, less than about 5 mg, less than about 2 mg, less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the combination comprises a dosage of TKI of from about 0.1 mg/kg of body weight of a subject to about 200 mg/kg of body weight of a subject. In some embodiments, the combination comprises a dosage of TKI of from about 0.1 mg/kg of body weight of a subject to about 100 mg/kg of body weight of a subject, from about 0.1 mg/kg of body weight of a subject to about 50 mg/kg of body weight of a subject, from about 0.1 mg/kg of body weight of a subject to about 25 mg/kg of body weight of a subject, from about 0.1 mg/kg of body weight of a subject to about 20 mg/kg of body weight of a subject, from about 0.1 mg/kg of body weight of a subject to about 15 mg/kg of body weight of a subject, from about 0.1 mg/kg of body weight of a subject to about 10 mg/kg of body weight of a subject, from about 0.1 mg/kg of body weight of a subject to about 5 mg/kg of body weight of a subject.
  • the combination comprises a dosage of TKI of from about 1 mg/kg of body weight of a subject to about 100 mg/kg of body weight of a subject, from about 1 mg/kg of body weight of a subject to about 50 mg/kg of body weight of a subject, from about 1 mg/kg of body weight of a subject to about 25 mg/kg of body weight of a subject, from about 1 mg/kg of body weight of a subject to about 20 mg/kg of body weight of a subject, from about 1 mg/kg of body weight of a subject to about 15 mg/kg of body weight of a subject, from about 1 mg/kg of body weight of a subject to about 10 mg/kg of body weight of a subject, or from about 1 mg/kg of body weight of a subject to about 5 mg/kg of body weight of a subject.
  • the combination comprises a dosage of TKI of from about 10 mg/kg of body weight of a subject to about 100 mg/kg of body weight of a subject, from about 10 mg/kg of body weight of a subject to about 50 mg/kg of body weight of a subject, from about 10 mg/kg of body weight of a subject to about 25 mg/kg of body weight of a subject, from about 10 mg/kg of body weight of a subject to about 20 mg/kg of body weight of a subject, or from about 10 mg/kg of body weight of a subject to about 15 mg/kg of body weight of a subject.
  • the combination comprises a dosage of TKI of from about 20 mg/kg of body weight of a subject to about 100 mg/kg of body weight of a subject, from about 20 mg/kg of body weight of a subject to about 50 mg/kg of body weight of a subject, or from about 20 mg/kg of body weight of a subject to about 25 mg/kg of body weight of a subject.
  • the TKI is Compound A.
  • the TKI is Compound B.
  • the TKI is Compound A and Compound B.
  • the combination comprises a dosage of Compound A of about 50 mg/kg of body weight of a subject.
  • the combination comprises a dosage of Compound B of about 50 mg/kg of body weight of a subject.
  • the combination comprises a dosage of Compound A and Compound B of about 50 mg/kg of body weight of a subject.
  • the combination comprises a dosage of TKI of from about 0.1 mg/kg of body weight of a subject to about 300 mg/m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of TKI of from about 0.1 mg/m 2 of body weight of a subject to about 200 mg/m 2 of body weight of a subject, from about 0.1 mg/m 2 of body weight of a subject to about 150 mg/m 2 of body weight of a subject, from about 0.1 mg/m 2 of body weight of a subject to about 100 mg/m 2 of body weight of a subject, from about 0.1 mg/m 2 of body weight of a subject to about 50 mg/m 2 of body weight of a subject, from about 0.1 mg/m 2 of body weight of a subject to about 25 mg/m 2 of body weight of a subject, from about 0.1 mg/m 2 of body weight of a subject to about 20 mg/m 2 of body weight of a subject, from about 0.1 mg/m 2 of body weight of body weight of a subject to about
  • the combination comprises a dosage of TKI of from about 1 mg/m 2 of body weight of a subject to about 150 mg/m 2 of body weight of a subject, about 1 mg/m 2 of body weight of a subject to about 100 mg/m 2 of body weight of a subject, from about 1 mg/m 2 of body weight of a subject to about 50 mg/m 2 of body weight of a subject, from about 1 mg/m 2 of body weight of a subject to about 25 mg/m 2 of body weight of a subject, from about 1 mg/m 2 of body weight of a subject to about 20 mg/m 2 of body weight of a subject, from about 1 mg/m 2 of body weight of a subject to about 15 mg/m 2 of body weight of a subject, from about 1 mg/m 2 of body weight of a subject to about 10 mg/m 2 of body weight of a subject, or from about mg/m 2 of body weight of a subject to about 5 mg/m 2 of body weight of a subject.
  • the combination comprises a dosage of TKI of from about 10 mg/m 2 of body weight of a subject to about 150 mg/m 2 of body weight of a subject, from about 10 mg/m 2 of body weight of a subject to about 100 mg/m 2 of body weight of a subject, from about 10 mg/m 2 of body weight of a subject to about 50 mg/m 2 of body weight of a subject, from about 10 mg/m 2 of body weight of a subject to about 25 mg/m 2 of body weight of a subject, from about 10 mg/m 2 of body weight of a subject to about 20 mg/m 2 of body weight of a subject, or from about 10 mg/kg of body weight of a subj ect to about 15 mg/m 2 of body weight of a subject.
  • the combination comprises a dosage of TKI of from about 20 mg/m 2 of body weight of a subject to about 150 mg/m 2 of body weight of a subject, from about 20 mg/m 2 of body weight of a subject to about 100 mg/m 2 of body weight of a subject, from about 20 mg/m 2 of body weight of a subject to about 50 mg/m 2 of body weight of a subject, or from about 20 mg/m 2 of body weight of a subject to about 25 mg/m 2 of body weight of a subject.
  • the combination comprises a dosage of TKI of from about 50 mg/m 2 of body weight of a subject to about 150 mg/m 2 of body weight of a subject, from about 50 mg/m 2 of body weight of a subject to about 100 mg/m 2 of body weight of a subject, from about 50 mg/m 2 of body weight of a subject to about 80 mg/m 2 of body weight of a subject, or from about 50 mg/m 2 of body weight of a subject to about 75 mg/m 2 of body weight of a subject.
  • the combination comprises a dosage of TKI of from about 75 mg/m 2 of body weight of a subject to about 150 mg/m 2 of body weight of a subject, or from about 75 mg/m 2 of body weight of a subject to about 100 mg/m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of TKI of from about 80 mg/m 2 of body weight of a subject to about 150 mg/m 2 of body weight of a subject, or from about 80 mg/m 2 of body weight of a subject to about 100 mg/m 2 of body weight of a subject.
  • the combination comprises a dosage of TKI of about 0.1 mg/m 2 , about 1 mg/m 2 , about 5 mg/m 2 , about 10 mg/m 2 , about 15 mg/m 2 , about 20 mg/m 2 , about 25 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 75 mg/m 2 , about 80 mg/m 2 , about 100 mg/m 2 , about 150 mg/m 2 , about 200 mg/m 2 , or about 300 mg/m 2 .
  • the TKI is Compound A. In some embodiments, the TKI is Compound B. In some embodiments, the TKI is Compound A and Compound B. In some embodiments, the combination comprises a dosage of Compound A of about 50 mg/m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound B of about 50 mg/m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A and Compound B of about 50 mg/m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A of from about 0.1 mg/m 2 to about 150 mg/m 2 of body weight of a subject.
  • the combination comprises a dosage of Compound B of from about 0.1 mg/m 2 to about 150 mg/m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A and Compound B of from about 0.1 mg/m 2 to about 150 mg/m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A of about 150 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound B of about 150 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A and Compound B of about 150 mg/ m 2 of body weight of a subject.
  • the combination comprises a dosage of Compound A of about 75 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound B of about 75 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A and Compound B of about 75 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A of about 80 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound B of about 80 mg/ m 2 of body weight of a subject.
  • the combination comprises a dosage of Compound A and Compound B of about 80 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A of about 120 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound B of about 120 mg/ m 2 of body weight of a subject. In some embodiments, the combination comprises a dosage of Compound A and Compound B of about 120 mg/ m 2 of body weight of a subject.
  • the combination comprises a dosage of electrolyte supplementation sufficient to maintain a normal serum concentration of the electrolyte in the subject. In some embodiments, the combination comprises a dosage of electrolyte supplementation sufficient to maintain a serum concentration of the electrolyte in the subject that is greater than a normal serum concentration of the electrolyte.
  • a normal serum concentration for potassium is from about 3.5 mEq/L to about 5.0 mEq/L.
  • a normal serum concentration for magnesium is from about 1.5 mEq/L to about 2.5 mEq/L.
  • a normal serum concentration for calcium is from about 8.5 mEq/L to about 10.2 mEq/L.
  • a normal serum concentration for sodium is from about 135 mEq/L to about 145 mEq/L.
  • a normal serum concentration for chloride is from about 96 mEq/L to about 106 mEq/L.
  • a normal serum concentration for bicarbonate is from about 23 mEq/L to about 30 mEq/L.
  • a normal serum concentration for phosphate is from about 2.5 mg/dL to about 4.5 mg/dL.
  • the combination comprises a dosage of electrolyte supplementation sufficient to maintain a serum concentration of the electrolyte in the subject in the absence of administration of a TKI.
  • the combination comprises a dosage of electrolyte supplementation sufficient to maintain a serum concentration of the electrolyte in the subject that is greater than a serum concentration of the electrolyte in the absence of administration of a TKI.
  • the combination comprises a dosage of electrolyte supplementation sufficient to maintain a normal serum concentration of the electrolyte in the subject in the absence of administration of Compound A. In some embodiments, the combination comprises a dosage of electrolyte supplementation sufficient to maintain a normal serum concentration of the electrolyte in the subject that is greater than a serum concentration of the electrolyte in the absence of administration of Compound A.
  • the combination comprises a dosage of electrolyte supplementation sufficient to maintain a normal serum concentration of the electrolyte in the subject in the absence of administration of Compound B. In some embodiments, the combination comprises a dosage of electrolyte supplementation sufficient to maintain a normal serum concentration of the electrolyte in the subject that is greater than a serum concentration of the electrolyte in the absence of administration of Compound B.
  • the combination comprises a dosage of electrolyte supplementation sufficient to maintain a normal serum concentration of the electrolyte in the subject in the absence of administration of Compound A and Compound B. In some embodiments, the combination comprises a dosage of electrolyte supplementation sufficient to maintain a normal serum concentration of the electrolyte in the subject that is greater than a serum concentration of the electrolyte in the absence of administration of Compound A and Compound B.
  • a dosage of the potassium supplementation is from about 3 mEq/L to about 7 mEq/L. In some embodiments, a dosage of the potassium supplementation is about 6 mEq/L.
  • administration of the potassium supplementation increases the potassium concentration to from about 0.5 mEq/L to about 6.0 mEq/L, from about 0.5 mEq/L to about 5.5 mEq/L, from about 0.5 mEq/L to about 5.0 mEq/L, from about 0.5 mEq/L to about 4.5 mEq/L, from about 0.5 mEq/L to about 4.0 mEq/L, from about 0.5 mEq/L to about 3.5 mEq/L, from about 0.5 mEq/L to about 3.0 mEq/L, from about 0.5 mEq/L to about 2.5 mEq/L, from about 0.5 mEq/L to about 2.0 mEq/L, from about 0.5 mEq/L to about 1.5 mEq/L, or from about 0.5 mEq/L to about 1.0 mEq/Labove the normal serum concentration.
  • the normal serum concentration of potassium is about 3.5 mEq/L
  • administration of the potassium supplementation will increase the potassium concentration from about 0.5 to about 1.0 mEq/L, such that the increased serum concentration of potassium is to from about 4.0 mEq/L to about 4.5 mEq/L.
  • administration of the potassium supplementation increases the potassium concentration from about 0.5 meQ/L to about 6.0 mEq/L, from about 0.5 mEq/L to about 5.5 mEq/L, from about 0.5 mEq/L to about 5.0 mEq/L, from about 0.5 mEq/L to about 4.5 mEq/L, from about 0.5 mEq/L to about 4.0 mEq/L, from about 0.5 mEq/L to about 3.5 mEq/L, from about 0.5 mEq/L to about 3.0 mEq/L, from about 0.5 mEq/L to about 2.5 mEq/L, from about 0.5 mEq/L to about 2.0 mEq/L, from about 0.5 mEq/L to about 1.5 mEq/L, or from about 0.5 mEq/L to about L0 mEq/L above the serum concentration in the absence of administration of
  • the serum concentration of potassium in the absence of administration of a TKI is about 3.5 mEq/L
  • administration of the potassium supplementation will increase the potassium concentration from about 0.5 to about L0 mEq/L, such that the increased serum concentration of potassium is to from about 4.0 mEq/L to about 4.5 mEq/L.
  • the dose of tarloxotinib is 0.25 mg/kg. In some embodiments, the dose of tarloxotinib is 0.3 mg/kg. In some embodiments, the dose of tarloxotinib is 0.35 mg/kg. In some embodiments, the dose of tarloxotinib is 0.4 mg/kg. In some embodiments, the dose of tarloxotinib is 0.45 mg/kg. In some embodiments, the dose of tarloxotinib is 0.5 mg/kg. In some embodiments, the dose of tarloxotinib is 0.55 mg/kg. In some embodiments, the dose of tarloxotinib is 0.6 mg/kg.
  • the dose of tarloxotinib is 0.65 mg/kg. In some embodiments, the dose of tarloxotinib is 0.7 mg/kg. In some embodiments, the dose of tarloxotinib is 0.75 mg/kg. In some embodiments, the dose of tarloxotinib is 0.8 mg/kg. In some embodiments, the dose of tarloxotinib is 0.85 mg/kg. In some embodiments, the dose of tarloxotinib is 0.9 mg/kg. In some embodiments, the dose of tarloxotinib is 0.95 mg/kg. In some embodiments, the dose of tarloxotinib is 1.0 mg/kg. In some embodiments, the dose of tarloxotinib is 1.5 mg/kg. In some embodiments, the dose of tarloxotinib is 2.0 mg/kg.
  • the dose of tarloxotinib is 0.25 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.3 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.35 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.4 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.45 mg/kg and the dose of KC1 is 5mg/kg.
  • the dose of tarloxotinib is 0.5 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.55 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.6 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.65 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.7 mg/kg and the dose of KC1 is 5mg/kg.
  • the dose of tarloxotinib is 0.75 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.8 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.85 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.9 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 0.95 mg/kg and the dose of KC1 is 5mg/kg.
  • the dose of tarloxotinib is 1.0 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 1.5 mg/kg and the dose of KC1 is 5mg/kg. In some embodiments, the dose of tarloxotinib is 2.0 mg/kg and the dose of KC1 is 5 mg/kg.
  • the TKI is independently administered from the electrolyte supplementation, e.g., in two units, but at the same time.
  • the TKI is administered first and then the electrolyte supplementation is separately or sequentially administered.
  • the electrolyte supplementation is administered first and then the TKI is administered, separately or sequentially, as defined.
  • the combinations contemplated herein are administered to the subject in dosages that range from one to five times per day or more.
  • the combinations contemplated herein are administered to the subject in a range of dosages that include, but are not limited to, once every day, every two, days, every three days, once every four days, once every five days, once every six days, once every seven days, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, and once every two weeks.
  • the frequency of administration of the various combination compositions contemplated herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors.
  • the present disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account.
  • the amount of combination dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • Compound A is administered once, twice, three times, four times, five times, or six times a day. In some embodiments, Compound A is administered once, twice, three times, four times, five times, or six times a week. In some embodiments, Compound A is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks.
  • Compound B is administered once, twice, three times, four times, five times, or six times a day. In some embodiments, Compound B is administered once, twice, three times, four times, five times, or six times a week. In some embodiments, Compound B is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks.
  • Compound A and Compound B are administered once, twice, three times, four times, five times, or six times a day. In some embodiments, Compound A and Compound B administered once, twice, three times, four times, five times, or six times a week. In some embodiments, Compound A and Compound B are administered every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks.
  • the electrolyte supplementation is administered once, twice, three times, four times, five times, or six times a day. In some embodiments, the electrolyte supplementation is administered once, twice, three times, four times, five times, or six times a week. In some embodiments, the electrolyte supplementation is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks.
  • the administration of the combination contemplated herein may be optionally administered continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a length of time (i.e., a“drug holiday”).
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the combinations provided herein reduce side effects and/or toxicity effects of the administered TKI such that a drug holiday and/or dose reduction is not needed.
  • the combinations provided herein reduce side effects and/or toxicity effects of the administered Compound A such that a drug holiday and/or dose reduction is not needed. In some embodiments, the combinations provided herein reduce side effects and/or toxicity effects of the administered Compound B such that a drug holiday and/or dose reduction is not needed. In some embodiments, the combinations provided herein reduce side effects and/or toxicity effects of the administered Compound A and Compound B such that a drug holiday and/or dose reduction is not needed.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the disease or disorder, to a level at which the improved disease is retained. In some embodiments, the subject requires intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.
  • the combinations for use in the method disclosed herein may be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the combinations contemplated herein are formulated in a pharmaceutical composition using one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions contemplated herein comprise a therapeutically effective amount of a combination contemplated herein and a pharmaceutically acceptable carrier.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like.
  • it isotonic agents are included, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • either effective concentrations of the TKI or the electrolyte supplementation are each separately mixed with a suitable pharmaceutical carrier or vehicle.
  • effective combined concentrations of the TKI or the electrolyte supplementation are mixed with a suitable pharmaceutical carrier or vehicle.
  • the combined concentrations of the TKI or the electrolyte supplementation in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and/or progression of cancer, including haematological cancers and solid tumours.
  • separate concentrations of the TKI or the electrolyte supplementation in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and/or progression of cancer, including haematological cancers and solid tumours.
  • separate concentrations of the TKI or the electrolyte supplementation in the compositions are effective for delivery of an amount, upon administration, that treats or ameliorates one or more of the symptoms and/or progression of cancer, including haematological cancers and solid tumours.
  • the compositions can be formulated for single dosage administration.
  • the TKI or the electrolyte supplementation are dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective combined concentration such that the treated condition is relieved or ameliorated.
  • the TKI alone is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle and the electrolyte supplementation alone is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle.
  • the TKI or the electrolyte supplementation are then administered, simultaneously or sequentially, at an effective combined concentration such that the treated condition is relieved or ameliorated.
  • Pharmaceutical carriers or vehicles suitable for administration of the TKI or the electrolyte supplementation provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the present disclosure is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound contemplated herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder contemplated in the present disclosure.
  • the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound contemplated herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat or reduce one or more symptoms of a disease or disorder contemplated in the present disclosure.
  • formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for any suitable mode of administration known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • the pharmaceutical preparations may also be combined where desired with other active agents, e.g., analgesic agents.
  • Additional dosage forms include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790, incorporated herein by reference. Additional dosage forms also include dosage forms as described in U.S. Patent Applications Nos. 2003/0147952; 2003/0104062; 2003/0104053; 2003/0044466; 2003/0039688; and 2002/0051820, incorporated herein by reference. Further dosage forms include dosage forms as described in PCT Applications Nos.
  • the formulations of the present disclosure may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds.
  • the compounds for use in the methods disclosed herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.
  • the compounds of the present disclosure are administered to a subject, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • reaction conditions including, but not limited to, reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions (e.g., nitrogen atmosphere), and reducing/oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present disclosure.
  • Example 1 Effect of tarloxotinib (Compound A), alone or combined with KC1, on the ECG intervals measured from adult male guinea pigs.
  • the guinea pig is widely considered one of the most sensitive species to drug-induced QTc prolongation; it expresses large amounts of hERG channels (Kv 11.1), as well as the full complement of cardiac ion channels found in humans. As such, adult male Hartley guinea pigs (Charles River Canada) weighing between 300 and 400 g were used to monitor the effect of tarloxotinib alone or in combination with KC1.
  • Tarloxotinib was administered as an intravenous infusion, over 30 minutes at a flow rate of 200 pL per minute. This aimed at reproducing the intended clinical route and method of administration for tarloxotinib. Doses of 1 mg/kg, 3 mg/kg, 5 mg/kg, and 10 mg/kg of tarloxotinib were administered to determine dose-dependent conditions under which tarloxotinib caused a prolongation (approximately 30 ms) in corrected QT intervals of the testing (see Table 1).
  • ECG leads were placed on the animal in a 3-lead configuration. Prior to the first administration of tarloxotinib, ECGs were obtained from the conscious animals. The animals were then connected to the infusion line of a Harvard apparatus syringe pump set to deliver 200 pL per minute. After 30 minutes, at the end of the infusion, the first of a series of ECGs was obtained in labeled: IPD (Immediately Post-Dose). The animals were then returned to their cages. The ECG recording procedure was repeated 3 hours following the initiation of the infusion, and 6 hours following the initiation of the infusion. A 72-hour washout period was observed before the animals were exposed to another dose of the tarloxotinib.
  • the ECG signals were acquired at a frequency of 500 Hz using a Warner Instruments DP-311 ECG amplifier and digitized at a sampling rate of 2.0 kHz using a Digidata 1440A interface (Axon Instruments Inc., Foster City, CA, USA, now Molecular Devices Inc.). 5 minutes of continuous ECG recording were acquired at each time point.
  • the digital recording of the ECG was stored on a corporate server located at the IPS Therapeutique facility
  • QT intervals were measured both manually and automatically using pattern-recognition algorithms programmed into the analysis software. In all cases, manual verification of the automated analysis was conducted as follows: The QT intervals were measured in millisecond using cursor readings in the Clampfit 10.2.0.14 module of the pClamp 10.2.0.14 software (Axon Instrument Inc., Foster City, California, USA, [now Molecular Devices Inc.]). Three QT intervals were measured for each condition and then averaged in Microsoft Excel 2007. The QT interval depends on the heart rate. To isolate the effect of a drug on the QT interval from an effect on the heart rate, the QT interval must be corrected for the heart rate. The RR intervals were measured as was done for the QT intervals and used to correct the QT intervals Fridericia's correction formula. The corrected QT value is labelled the QTc interval (corrected QT interval) in this report.
  • tarloxotinib exhibited its maximal effect on the ECG intervals immediately following the end of the 30 minute infusion (IPD). This corresponds to the expected time of maximal exposure (TMax). The changes in ECG intervals measured at 3 hours and 6 hours post-dose were less than those measured IPD.
  • tarloxotinib The effects of tarloxotinib on PR interval duration may be attributed to multiple mechanisms. While not wishing to be bound by theory, in some embodiments, ion channel inhibition may contribute to a slower polarization/repolarization across the atrial tissue. A slower polarization/repolarization across the atrial tissue may lead to a slight delay in atrial conduction. Given the amplitude of ventricular mechanisms involving potassium channels, it is possible that tarloxotinib delayed atrial repolarization via inhibition of atrial potassium channels. Additionally, while not wishing to be bound by theory, in some embodiments, is also possible that tarloxotinib induced atrial effects via a direct action of tarloxotinib on the autonomous nervous system.
  • Tarloxotinib at doses ranging from 1 mg/kg to 10 mg/kg, did not cause statistically significant changes in QRS duration. Variability in the interval duration fell within the expected physiological range for guinea pigs (FIG. 2A). Intravenous doses of tarloxotinib of 1 mg/kg to 10 mg/kg and 6 mEq KC1 induced slight changes in QRS duration (increase IPD, decrease after 3 hours for 5 mg/kg). This finding appears to be inconsistent due to the dose-independent nature and reversibility. 3 mg/kg did not produce the prior effect of 5 mg/kg, nor did 10 mg/kg. The effect was reversible and disappeared after 6 hours post infusion (FIG. 2B).
  • Tarloxotinib alone or in combination with KC1, did not cause changes in QRS duration. This may suggest that tarloxotinib has little to no affinity for the rapid sodium channels responsible for ventricular depolarization. The consequences of a potential autonomic nervous system effect was not observed on the QRS complex. QRS signal amplitude was unchanged, suggesting that tarloxotinib has no acute cardiac toxicity leading to a loss of functionality by the ventricular tissue.
  • Tarloxotinib at doses ranging from 1 mg/kg to 10 mg/kg, caused a dose-dependent, statistically significant increase in QT interval 30 minutes post-start-of-the-infusion.
  • QT intervals increased from 146 to 196 ms in animals dosed with 10 mg/kg tarloxotinib.
  • the increase in QT interval was approximately 15 ms.
  • the effect was reversible and QT intervals were back to normal within 3 hours post infusion (FIG 3A).
  • Intravenous doses of tarloxotinib of 1 mg/kg to 10 mg/kg and 6 mEq KC1 caused QT prolongations ranging from 9 ms to 30 ms.
  • the prolongations were statistically significant, dose-dependent, and reversible within 3 hours.
  • the maximal effect was observed at the presumed moment of maximal exposure. 3 mg/kg, when co-administered with 6 mEq KC1, and did not exceed the upper limit for pro- arrhythmicity. Doses of 1 mg/kg, 5 mg/kg, and 10 mg/kg exceeded the upper limit for pro- arrhythmicity (FIG. 3B).
  • QTc values Correcting QT intervals for changes in heart rate associated with treatment yielded QTc values (“corrected” QT values). QTc values are considered more valuable in a clinical setting due to the removal of the impact of bradycardia or tachycardia on the duration of ventricular repolarization. In this study, correcting QT intervals for changes in heart rate yielded the same patterns as observed for uncorrected QT intervals. Administration of tarloxotinib caused a dose-dependent increase in QTc intervals ranging from 56 to 82 ms. The effect was reversible within 3 hours of administration (FIG 4 A).
  • the QTc prolongations measured when tarloxotinib was combined with KC1 ranged from 20 to 40 ms. Prolongations of 25 to 30 ms represent the highest tolerable QTc prolongation (10% of predose QTc intervals). Doses of 1 and 3 mg/kg tarloxotinib combined with 6 mEq KC1 would not be considered to contribute to pro- arrhythmicity (FIG 4B).
  • FIG. 5 asterisks (*) above a data point indicates that the QTc value is different from the pre-dose value recorded. Daggers ( ⁇ ) compare data points to the same time point measure in the presence of tarloxotinib alone. Therefore, a ⁇ indicates that the data point is different from the data point measured in tarloxotinib-administered animals at the same time point.
  • FIG. 5 was compiled with data measured at the time of highest exposure, i.e. 30 minutes following the initiation of the tarloxotinib infusion. This follows international regulatory guidelines ICH S7A and B, which state that potential safety liability are to be assessed at the moment of greatest systemic exposure (European medicines agency, 2000).
  • FIG. 7A depicts the correlation between serum K+ levels and QTcF change from the baseline post 180 min after Tarloxotinib infusion to NSCLC patients on cycle 1 day 1)
  • FIG. 7B depicts the effect of tarloxotinib (line“A”) and tarloxotinib + KC1 (line“B”) on dQTc, based on the QTc values depicted in FIG. 4.
  • FIG. 7A and FIG. 7B supports potassium supplementation when administering tarloxotinib.
  • KCl 6 mEq KCl was administered intravenously in combination with the same doses of tarloxotinib (1 mg/kg, 3 mg/kg, 5 mg/kg, or 10 mg/kg).
  • the effects of tarloxotinib administered with KCl were similar to the effects of tarloxotinib administered alone, with the exception that KCl mitigated part of the electrophysiological impact of tarloxotinib.
  • KCl decreased the QTc prolongation associated with 10 mg/kg tarloxotinib from 81 to 39 ms immediately post-dose. This improvement allowed the QTc prolongations caused by 1 and 3 mg/kg tarloxotinib to be maintained below the regulatory limit.
  • KC1 (Spectrum, Lot No. 2HA0220) was weighed out directly into a beaker. Deionized water was added q.s. to the beaker along with a stir bar and placed on a stir plate to mix until complete dissolution. Following dissolution, the contents of the beaker were transferred into an amber glass bottle and sealed with the corresponding cap, and retained at room temperature until needed for dosing.
  • Tarloxotinib concentration was acceptable for the nominal 2.5 mg/mL dose formulation. Tarloxotinib concentration measured 98.8%. The formulation was homogeneous and the %CV value was 10.2% (homogeneity acceptance criterion was a %CV value of ⁇ 15%).
  • the vehicle was devoid of Tarloxotinib.
  • Animals were administered an oral dose of saline or 0.5 mEq/kg of KC1 30 minutes prior to tarloxotinib infusion. 1 Horn following the completion of tarloxotinib infusion, the animals were administered an oral dose of saline, 1 mEq/kg of KC1 or 1.5 mEq/kg of KC1.
  • Oral dose 1 was administered 30 minutes prior to tarloxotinib infusion.
  • Oral dose 2 was administered 1 hour following completion of tarloxotinib infusion.
  • Blood samples were collected for serum potassium levels at 1 and 4.5 hours following completion of tarloxotinib infusion.
  • HR - heart rate (beats/min); DAP - diastolic arterial pressure (mmHg); MAP - mean arterial pressure (mmHg); SAP - systolic arterial pressure (mmHg); %A - percent change from corresponding vehicle value; Represents the mean value for 15 minutes prior to dose; b Represents the mean value for during infusion; Represents the mean value for 15 minutes prior to the indicated time; and Represents the mean value for 60 minutes prior to the indicated time.
  • HR heart rate (beats/min); DAP - diastolic arterial pressure (mmHg); MAP - mean arterial pressure (mmHg); SAP - systolic arterial pressure (mmHg); %A - percent change from corresponding vehicle value; Represents the mean value for 15 minutes prior to dose; Represents the mean value for during infusion; Represents the mean value for 15 minutes prior to the indicated time; and Represents the mean value for 60 minutes prior to the indicated time.
  • Tarloxotinib (5 mg/kg) administered intravenously in combination with the oral administration of one (1.5 mEq/kg) or two (0.5 and 1.0 mEq/kg) doses of KC1 appeared to inhibit the increase in QTc(F) observed following the administration of tarloxotinib after saline.
  • Tarloxotinib at 5 mg/kg administered after single (1.5 mEq/kg) oral dose of KC1 produced a greater inhibition with the QTc(F) significantly lower (p ⁇ 0.05) at 120 minutes after the tarloxotinib dose.
  • Sinus rhythm was maintained in all dogs throughout the study. A second-degree atrioventricular block was noted in animal #1 at 12 hours post-dose of treatment 3. This rhythm disturbance is occasionally seen in normal dogs and was not related to tarloxotinib.
  • ECG parameters are depicted in Tables 14-17.
  • Changes in QTc (F) caused by tarloxotinib (intravenous) alone and in combination with one (1.5 mEq/kg) or two (0.5 and 1.0 mEq/kg) oral doses of KC1 doses were analyzed for potential effects of KC1 on tarloxotinib effects.
  • Tarloxotinib-induced increases in QTc(F) were lower when KC1 was administered in combination with tarloxotinib. Exposure to Tarloxotinib was confirmed in all dogs.
  • a method of treating cancer in a subject comprising:
  • electrolyte supplementation comprises at least one of potassium ion, magnesium ion, and calcium ion.
  • the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer.
  • cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • the additional agent is an anti cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thiogu
  • a pharmaceutical combination comprising:
  • a pharmaceutical composition comprising the pharmaceutical combination of any one of Enumerated Embodiments 34-43 and a pharmaceutically acceptable excipient.
  • a method of reducing or preventing QT prolongation in a subject suffering from cancer comprising administering to the subject a therapeutically effective amount of tarloxotinib, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • electrolyte supplementation comprises at least one of potassium ion, magnesium ion, and calcium ion.
  • any one of Enumerated Embodiments 44-56 wherein the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer. 58.
  • the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • the additional agent is an anti cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thi
  • a method of reducing or preventing cardiotoxicity in a subject suffering from cancer comprising administering to the subject a therapeutically effective amount of tarloxotinib, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation.
  • electrolyte supplementation comprises at least one of potassium ion, magnesium ion, and calcium ion.
  • the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer.
  • the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • the additional agent is an anti cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,
  • a method of increasing tolerance to a dose of tarloxotinib in a subject comprising: administering to the subject a dose of tarloxotinib, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation;
  • a method for treating cancer in a subject comprising:
  • a electrolyte supplementation comprising the electrolyte if the determined serum concentration of the electrolyte is below a normal serum concentration.
  • electrolyte supplementation comprises at least one of potassium, magnesium, calcium, sodium, bicarbonate, chloride, and phosphate ion.
  • electrolyte supplementation comprises at least one of potassium ion, magnesium ion, and calcium ion.
  • the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer.
  • the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • the additional agent is an anti cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,
  • a method for treating cancer in a subject comprising:
  • electrolyte supplementation comprises at least one of potassium, magnesium, calcium, sodium, bicarbonate, chloride, and phosphate ion.
  • the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer.
  • the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • the additional agent is an anti cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,
  • the compound of Enumerated Embodiment 160, wherein the electrolyte supplementation comprises at least one of potassium ion, magnesium ion, and calcium ion.
  • the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer.
  • the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • the additional agent is an anti-cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,
  • a pharmaceutical combination comprising tarloxotinib, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for use in the treatment of cancer.
  • Embodiments 185-202 The pharmaceutical combination of any one of Enumerated Embodiments 185-202, wherein the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer.
  • the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal
  • any one of Enumerated Embodiments 185-202 wherein the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem gli
  • the additional agent is an anti-cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,
  • electrolyte supplementation comprises at least one of potassium ion, magnesium ion, and calcium ion.
  • electrolyte supplementation comprises at least one of potassium ion, magnesium ion, and calcium ion.
  • electrolyte supplementation is selected from the group consisting of potassium ion, magnesium ion, and calcium ion.
  • any one of Enumerated Embodiments 210-227 wherein the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer.
  • the additional agent is an anti-cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxif
  • any one of Enumerated Embodiments 235-252 wherein the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, or testicular cancer.
  • any one of Enumerated Embodiments 235-252 wherein the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • Embodiment 256 wherein the additional agent is an anti-cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen
  • an anti-cancer agent selected from
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition of Enumerated Embodiment 260 wherein the electrolyte supplementation comprises at least one of potassium, magnesium, calcium, sodium, bicarbonate, chloride, and phosphate ion. 262.
  • a pharmaceutical composition comprising the pharmaceutical combination of any one of Enumerated Embodiments 260-268 and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising tarloxotinib, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation for use in the treatment of cancer.
  • the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal
  • the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease,
  • composition comprising a therapeutically effective amount of tarloxotinib, or a pharmaceutically acceptable salt or solvate thereof, and an electrolyte supplementation in the manufacture of a medicament for the treatment of cancer in a patient.
  • any one of Enumerated Embodiments 295-312 wherein the cancer is bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland and testicular cancer. 314.
  • any one of Enumerated Embodiments 295-312 wherein the cancer is chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin’s Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, retinoblastoma, or non-small cell lung cancer.
  • Embodiment 316 wherein the additional agent is an anti-cancer agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen
  • an anti-cancer agent selected from

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Abstract

L'invention concerne des combinaisons et des compositions comprenant un inhibiteur de tyrosine kinase (TKI) et un supplément d'électrolyte, des formulations et des procédés de traitement du cancer les comprenant.
PCT/US2019/061121 2018-11-13 2019-11-13 Combinaison d'un inhibiteur de kinase et d'un électrolyte, compositions et procédés la comprenant WO2020102304A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170360790A1 (en) * 2014-12-03 2017-12-21 Auckland Uniservices Limited Kinase inhibitor prodrug for the treatment of cancer
WO2018031922A1 (fr) * 2016-08-11 2018-02-15 Sulfilatec, Inc. Compositions médicales et nutritionnelles et méthodes d'utilisation
US20180193274A1 (en) * 2014-12-24 2018-07-12 Principia Biopharma Inc. Compositions for ileo-jejunal drug delivery

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170360790A1 (en) * 2014-12-03 2017-12-21 Auckland Uniservices Limited Kinase inhibitor prodrug for the treatment of cancer
US20180193274A1 (en) * 2014-12-24 2018-07-12 Principia Biopharma Inc. Compositions for ileo-jejunal drug delivery
WO2018031922A1 (fr) * 2016-08-11 2018-02-15 Sulfilatec, Inc. Compositions médicales et nutritionnelles et méthodes d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COPPOLA ET AL.: "Management of QT prolongation induced by anti-cancer drugs: Target therapy and old agents. Different algorithms for different drugs", CANCER TREATMENT REVIEWS, vol. 63, no. 2018, February 2018 (2018-02-01), pages 135 - 143, Retrieved from the Internet <URL:https://doi.org/10.1016/j.ctrv.2017.11.009> *
MARKETWATCH: "Threshold Pharmaceuticals Initiates Phase 2 Clinical Trial of Tarloxotinib Bromide", TH -4000) IN PATIENTS WITH RECURRENT OR METASTATIC SQUAMOUS CELL CARCINOMAS OF THE HEAD AND NECK OR SKIN, 27 August 2015 (2015-08-27), Retrieved from the Internet <URL:https://www.marketwatch.com/press-releaselthreshold-pharmaceuticals-initiates-phase-2-clinical-trial-of-tarloxotinib-bromide-th-4000-in-patients-with-recurrent-or-metastatic-squamous-cell-carcinomas-of-the-head-and-neck-or-skin-2015-08-27> [retrieved on 20200106] *

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