DIOXOPIPERAZINES

Technical Field

[001] The technology is directed to compositions and methods to improve the therapeutic efficiency of Jb/s-dioxopiperazine compounds such as razoxane. In particular, the compositions and methods improve the therapeutic efficiency of razoxane for the treatment of cancers and dermatological conditions.

Cross reference to related application

[002] This application claims priority to US provisional patent application No 62/902,256 filed 18 September 2019 which is incorporated by reference in its entirety.

Background

[003] Razoxane and dexrazoxane are Jb/s-dioxopiperazines initially used for a variety of applications including pharmaceuticals and jet fuel additives. Later it was also suggested that they might be anti-tumor agents.

[004] However, razoxane and dexrazoxane were neither cytotoxic nor selective for tumor cells. Both compounds are now known to be cytostatic due to the ability to block the cell cycle at G2/M without any discernible inhibitory, toxic, or destructive effect at any other phase of the cell cycle. The mechanism of the cytostatic effect has yet to be fully elucidated although it has been postulated that it is at least partly due to the inhibition of topoisomerase II.

[005] Razoxane and dexrazoxane have a number of pharmacologic activities including blocking the cell cycle at G2/M, normalizing tumor neovasculature, anti-inflammatory activity, antineoplastic activity, topoisomerase lla inhibition and metal chelating activity (e.g. Pb ²⁺ , Cu ²⁺ , Fe ²⁺ , Zn ²⁺ , and Mg ²⁺ ). These activities have led razoxane and dexrazoxane to be investigated for use in potentiation of irradiation in cancer treatments, potentiation of chemotherapy, prevention of spontaneous metastases, cytoprotection for myocardium, pulmonary epithelium, gastrointestinal tract and kidney. Dexrazoxane is used as a cytoprotectant against doxorubicin, daunorubicin, bleomycin, mitoxantrone, etoposide and cisplatin.

[006] Dexrazoxane hydrochloride is marketed under the name Zinecard® in the USA and Cardioxane® in Europe and is approved for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in subjects with metastatic breast cancer. Dexrazoxane is approved to treat accidental extravasation of anthracyclines. [007] Shortly after the discovery of razoxane as a antineoplastic agent, a number of phase I and phase II studies were performed with an emphasis on inducing remission in leukemias and solid tumors. Clinical trials to assess the efficacy of razoxane for the treatment of acute leukemia (AML, AMML, CML), non-Hodgkin lymphomas, colorectal cancer, breast cancer, lung cancer, cervical carcinoma, soft tissue sarcoma, osteosarcoma and malignant melanomas have been performed. These trials showed that razoxane is ineffective in terms of inducing remission in solid tumors and demonstrated only short responses in leukemia and lymphomas. In addition the activity of drug combinations was less than that reported for either drug alone in comparable subject populations, particularly for the combination of cisplatin and razoxane given concomitantly. In contrast, an initial pretreatment with razoxane enhanced the activity of a subsequent cis-platinum-radiation combinations. Thus, the ability of razoxane to potentiate cytotoxic drugs can not be generalized. Further, administration of razoxane can induce neutropenia and thrombocytopenia.

[008] There is a need for compositions and methods to improve the efficacy and/or reduce the side effects of the administration of Jb/s-dioxopiperazine compounds such as razoxane, particularly for the treatment of malignancies and dermatological conditions.

Summary

[009] There is described herein methods to improve the therapeutic efficacy or reduce the side effects of Jb/s-dioxopiperazine compounds such as razoxane and dexrazoxane in subjects suffering from malignancies or dermatological conditions.

[010] In a first aspect there is provided a method for improving the efficacy and/or reducing the side effects of the administration of a compound of Formula I or a pharmaceutically acceptable salt, chelate, hydrate or solvate thereof, or a derivative, analog, or prodrug thereof in a subject suffering from a malignancy or a dermatological condition; wherein

R ¹ is independently selected from H, optionally substituted Ci-e alkyl, optionally substituted C cycloalkyl, and benzyl group; R ² is selected from an optionally substituted Ci-e alkyl group; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the method comprising the steps of:

(1) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the administration of the compound to the subject; and

(2) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the administration of the therapeutic agent to the subject.

In one embodiment n is 1 , R ¹ is H, and R ² is CF The compound of Formula I may be a racemic mixture.

The factor or parameter may be selected from the group consisting of: a. dose modification; b. route of administration; c. schedule of administration; d. indication for use; e. disease stage; f. subject selection; g. subject genotype or phenotype; h. malignancy or dermatological condition phenotype; i. malignancy or dermatological condition genotype; j. pre/post treatment preparation; k. toxicity management;

L. pharmacokinetic/pharmacodynamic monitoring; m. chemosensitization; n. chemopotentiation; o. post-treatment subject management; p. the use of a herbal medication; q. a bulk drug product improvement; r. diluent system; s. solvent system; t. excipient; u. dosage kit and packaging; v. drug delivery system; w. drug conjugate form; x. compound analog; y. prodrug; z. multiple drug system; aa. biotherapeutic enhancement; bb. biotherapeutic resistance modulation; cc. radiation therapy enhancement; dd. use of selective target cell population therapeutic; ee. multidrug resistance reversal agents; ff. antibody directed conjugate; gg. adjuvant; and hh. additional therapeutic agent.

The dose modification is dose escalation regimen, for example the dose escalation regimen may comprise;

(a) administering the compound to the subject at a dosage from about 1.5 mg/kg to about 50 mg/kg (or an equivalent dose in mg/m ² units) and then further administering the compound one or more times to the subject at increased dosages up to a maximum dose of about 50 mg/kg until a response is observed; and

(b) when the subject experiences a response, administering at least one further dose of the compound at the dosage level that resulted in the response.

In a second aspect there is provided a dose escalation regimen for treating a malignancy or dermatological condition in a subject, the regimen comprising;

(a) administering a compound of Formula I or a pharmaceutically acceptable salt, chelate, hydrate or solvate thereof to the subject at a dosage from about 1.5 mg/kg to about 50 mg/kg and then administering the compound to the subject one or more additional times at increased dosages up to a maximum dose of about 50 mg/kg until a response is observed; wherein R ¹ is independently selected from H, optionally substituted Ci-e alkyl, optionally substituted C3-6 cycloalkyl, and benzyl group;

R ² is selected from an optionally substituted C alkyl group; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

(b) when the subject experiences a response, administering at least one further dose of the compound at the dosage level that resulted in the response.

In step (a) the dosage may be about 3 mg/kg or about 5mg/kg.

The regimen may be a linear increase in razoxane dosage, or a stepwise increase in razoxane dosage.

The regimen may comprise administering a razoxane dosage every one to seven days, for example daily.

In a third aspect there is provided use of a compound of a compound of Formula I or a pharmaceutically acceptable salt, chelate, hydrate or solvate thereof, for the manufacture of a medicament for the treatment of a malignancy or a dermatological condition in a subject using a dose escalation regimen; wherein

R ¹ is independently selected from H, optionally substituted C _1-6 alkyl, optionally substituted C _3-6 cycloalkyl, and benzyl group;

R ² is selected from an optionally substituted C alkyl group; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In one embodiment n is 1 , R ¹ is H, and R ² is CH3.

The compound of Formula I is a racemic mixture.

In a fourth aspect there is provided a composition to improve the efficacy and/or reduce the side effects of the administration of a compound of Formula I or a pharmaceutically acceptable salt, chelate, hydrate or solvate thereof, or a derivative, analog, or prodrug thereof to in subject suffering from a malignancy or dermatological condition; wherein

R ¹ is independently selected from H, optionally substituted Ci-e alkyl, optionally substituted C3-6 cycloalkyl, and benzyl group;

R ² is selected from an optionally substituted C alkyl group; and n is 1, 2, 3, 4, 5, 6, 7, 8,9 or 10; wherein the composition: a. is formulated for use in a program of dose modification; b. is formulated for use in a program of alteration or modification of route of administration; c. is formulated for use in a program of alteration or modification of schedule of administration; d. is formulated for use in a program of selecting appropriate indications for use; e. is formulated for use in a program of selecting appropriate disease stages for use; f. is formulated for use in a program of selecting appropriate additional indications for use; g. is formulated for use in a program of selecting appropriate subject or disease phenotypes for use of the composition; h. is formulated for use in a program of selecting appropriate subject or disease genotypes for use of the composition; i. is formulated for use in a program of toxicity management; j. is formulated for use in a program of pre-treatment management; k. is formulated for use in a program of post-treatment management;

L. is formulated for use in a program of biotherapeutic enhancement; m. is formulated for use in a program of biotherapeutic resistance modulation; n. is formulated for use in a program of radiation therapy enhancement; o. is formulated for use in a program of selective target cell population therapeutics; p. is formulated for use in a program of inhibiting telomerase or inducing telomere dysfunction; q. further comprises a diluent; r. further comprises a solvent system; s. further comprises an excipient; t. is incorporated into a dosage kit and packaging; or u. comprises a drug delivery system.

[011] In one embodiment the compound of Formula I is a S isomer, an R isomer or a mixture thereof. In another embodiment the compound of Formula I is a mixture of S and R isomers. In a preferred embodiment the compound of Formula I is a racemic mixture of S and R isomers. The racemic mixture may be razoxane.

[012] Typically, the unmodified compound is dexrazoxane or razoxane or a pharmaceutically acceptable salt, chelate, hydrate or solvate thereof, or a derivative, analog, or prodrug thereof , the modified compound is a modification of dexrazoxane or razoxane or a pharmaceutically acceptable salt, chelate, hydrate or solvate thereof, or a derivative, analog, or prodrug thereof.

[013] The malignancy may be selected from the group consisting of breast cancer, cancer of the female reproductive system, cancer of the male reproductive system, cancer of the cardiac system, cancer of the respiratory system, cancer of the lung, cancer of the gastrointestinal tract, cancer of the urinary system, cancer of muscle, bone, or soft tissue, soft tissue cancer. In one embodiment the malignancy is osteosarcoma.

[014] The dermatological condition may be selected from the group consisting of psoriasis, solar keratosis, onychomycosis, and/or fungal infections, impetigo, epidermolysis bullosa, eczema, neurodermatitis, pruritis, erythema, hidradenitis suppurativa, warts, diaper rash, jock itch, acne vulgaris, acne conglobate, acne necrotica miliaris.chorance, rosacea, rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, meibomian gland dysfunction, mitogenic alopecia, perioral dermatitis, acneiform rashes and transient acantholytic dermatosis.

[015] The subject may be a human. In some embodiments the subject may be an infant, child, adolescent, adult or geriatric subject.

[016] The compound may be administered by a route of administration selected from the group consisting of intravenous, parenteral, intraperitoneal, transcutaneous, subcutaneous, intramuscular, intraurethral, intrarectal, ocular, intraocular, intra-articular, oral or topical administration. [017] Preferably, the compound is administered orally, intravenously, intraperitoneally, topically or transcutaneously.

[018] In one embodiment the compound is in the form of a salt. In particular, the compound may be an acid salt for example of hydrochloric acid, sulfuric acid, methanesulfonic, maleic, oxalic and phosphoric acid referred to as hydrochloride, sulfate, mesylate, maleate, oxalate and phosphate salts, respectively.

[019] In one embodiment the compound is a chelate of a metal ion selected from the group consisting of calcium, manganese, magnesium, iron, zinc, copper, molybdenum, silver, gold, and cobalt.

Definitions

[020] The following are some definitions of terms used in the art that may be helpful in understanding the description. These are intended as general definitions and should in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following description.

[021] Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements described herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements. For example as used herein, 'a’, ‘an ¹ and 'the' include singular and plural referents unless the context clearly dictates otherwise. Thus, for example, reference to 'a compound' or 'a pharmacologically active compound' includes a single active agent as well as two or more different active agents in combination.

[022] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, methods, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps, features, methods, compositions and compounds.

[023] The term 'optionally substituted' as used throughout the specification denotes that a particular functional group may or may not be further substituted with one or more non hydrogen substituent groups. Suitable chemically viable optional substituents for a particular functional group will be apparent to those skilled in the art. Typical optional substituents include C1-C4 alkyl, C2-C4 alkenyl, OH, halogen, 0(Ci-C ₄ alkyl), NR ^a R ^b wherein R ^a and R ^b are independently selected from H and C1-C3 alkyl, CONH2, SH, S(Ci-C ₃ alkyl), -CH ₂ 0(C _I - ₃ alkyl), -C^phenyl, hydroxy(Ci- ₃ alkyl), halo(Ci-3 alkyl), mesylate and tosylate. Presently preferred optional substituents include C1-3 alkyl, C1-3 alkoxy, -CH2(Ci-3)alkoxy, -CH2-phenyl, halogen, OH, hydroxy(Ci-3)alkyl, halo(Ci-3)alkyl, e.g., CF3, CH2CF3, and mesylate.

[024] The term 'alkyl' as used herein means a group or part of a group and refers to a straight or branched aliphatic hydrocarbon group having 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms. Thus, the term alkyl includes, but is not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, amyl, 1,2- dimethylpropyl, 1 , 1 -dimethylpropyl, pentyl, isopentyl, hexyl, and the like. The group may be a terminal group or a bridging (alkylene) group.

[025] The term 'C1-6 alkyl' as used herein means a group or part of a group and refers to a straight or branched aliphatic hydrocarbon group having 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms. Thus, the term alkyl includes, but is not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, amyl, 1,2- dimethylpropyl, 1,1 -dimethylpropyl, pentyl, isopentyl, hexyl, and the like. The group may be a terminal group or a bridging (alkylene) group.

[026] The term 'cycloalkyl' as used herein refers to a saturated monocyclic, fused or spiro polycyclic, carbocycle having from 3 to 9 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The group may be a terminal group or a bridging group. [027] Certain compounds disclosed herein may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are within the scope of the subject matter disclosed herein. [028] The term 'pharmaceutically acceptable salt' refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. The salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base function with a suitable organic acid. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, fumaric, maleic, pyruvic, alkyl sulfonic, arylsulfonic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, ambonic, pamoic, pantothenic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, b-hydroxybutyric, galactaric, and galacturonic acids. Suitable pharmaceutically acceptable base addition salts of the compounds described herein include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Alternatively, organic salts made from N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, ammonium salts, quaternary salts such as tetramethylammonium salt, amino acid addition salts such as salts with glycine and arginine. In the case of compounds that are solids, it will be understood by those skilled in the art that the compounds described herein may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.

[029] A 'pharmaceutical carrier, diluent or excipient' includes, but is not limited to, any physiological buffered (i.e. , about pH 7.0 to 7.4) medium comprising a suitable water soluble organic carrier, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. Suitable water soluble organic carriers include, but are not limited to saline, dextrose, corn oil, dimethylsulfoxide, and gelatin capsules. Other conventional additives include lactose, mannitol, corn starch, potato starch, binders such as crystalline cellulose, cellulose derivatives, acacia, gelatins, disintegrators such as sodium carboxymethyl-cellulose, and lubricants such as talc or magnesium stearate.

[030] As used herein, the term 'solvate' means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute), or an aggregate that consists of a solute ion or molecule, i.e., a compound described herein, with one or more solvent molecules. When water is the solvent, the corresponding solvate is a 'hydrate'. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and other hydrated forms. It should be understood by one of ordinary skill in the art that the pharmaceutically acceptable salt and/or prodrug of the present compound may also exist in a solvate form. The solvate is typically formed via hydration which is either part of the preparation of the compound or through natural absorption of moisture by the anhydrous compound of the present invention.

[031] The terms 'treating' and 'treatment' refer to any and all uses which remedy a condition or symptoms, prevent the establishment of a condition or disease, or otherwise prevent, hinder, retard, or reverse the progression of a condition or disease or other undesirable symptoms in any way whatsoever. [032] The term 'effective amount' includes within its meaning a non-toxic but sufficient amount of a compound to provide the desired effect. The exact amount required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, the severity of the condition being treated, the particular agent being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact 'effective amount'. However, for any given case, an appropriate 'effective amount' may be determined by one of ordinary skill in the art using only routine experimentation.

[033] Except where the context dictates otherwise, the term “subject” is used to refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Animals include all vertebrates, e.g., mammals and non-mammals, such as sheep, dogs, cows, chickens, amphibians, and reptiles. In a preferred embodiment the subject is a human.

[034] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[035] Throughout this specification, the term 'consisting essentially of means the inclusion of the stated element(s), integer(s) or step(s), but other element(s), integer(s) or step(s) that do not materially alter or contribute to the working of the invention may also be included.

[036] In each embodiment of the invention 'consisting essentially of may be used in place of 'comprising'.

[037] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this specification.

Description

[038] Disclosed herein are compositions, methods and dosage regimes to improve the therapeutic benefit or efficiency of Jb/s-dioxopiperazine compounds, such as razoxane in subjects with a malignancy or dermatological condition such as psoriasis. [039] Also disclosed herein are dosage forms, excipients, solvents, diluents, drug delivery systems, preservatives, agents to potentiate the activity of the razoxane and induce cell death (e.g. by inducing apoptosis).

Compounds

[040] There is provided Jb/s-dioxopiperazines compounds useful for the treatment of various diseases and conditions, including treatment of malignancies and dermatological conditions.

[041] The compounds are compounds of Formula I or pharmaceutically acceptable salts, chelates, hydrates or solvates thereof, or derivatives, analogs, or prodrugs thereof, wherein

R ¹ is independently selected from H, optionally substituted Ci-e alkyl, optionally substituted C cycloalkyl, and benzyl group,

R ² is selected from an optionally substituted C alkyl group, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[042] Preferably, where n=1 the compounds are a mixture of S and R isomers. In particular the mixture is a racemic mixture of S and R isomers. Where n > 1 the compounds are a mixture of isomers where the number of isomers is calculated by n!. In particular, the mixture of is an equimolar mixture of n! isomers.

[043] In one embodiment the compound of Formula I has the following structure: , wherein R ¹ is H and R ² is CH ₃ .

The S-isomer of this structure (1,2-bis(3,5- dioxopiperazin-l-yl)-propane) is dexrazoxane. The racemic mixture of the S and R isomer of the above structure is razoxane (also known as ICRF 159, or (±)1,2-di(3,5-dioxopiperazin-1-yl) propane. As used herein the term razoxane refers to this racemic mixture. [044] Under physiological conditions dexrazoxane hydrolyzes into one-ring open intermediates, and then to its fully ring opened metal ion-binding form, which has a structure similar to EDTA.

[045] When the compound possesses a sufficiently acidic, a sufficiently basic, or both a sufficiently acidic and a sufficiently basic functional group, these group or groups can react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[046] For example, pharmaceutically acceptable salts of compounds of Formula I can be formed with the following positively-charged ions: sodium, potassium, aluminum, lithium, calcium, magnesium, zinc, ammonium, caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine, ethanolamine, diethanolamine, N- methylglucamine, or tris(hydroxymethyl)aminomethane.

[047] In other embodiments pharmaceutically acceptable salts can also be formed with the following negatively-charged ions: chloride, bromide, iodide, carbonate, nitrate, sulfate, bisulfate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, formate, acetate, adipate, butyrate, propionate, succinate, glycolate, gluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, mesylate, 4'-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, ethanedisulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, p- toluenesulfonate, sulfanilate, cyclohexylaminosulfonate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfonate, glucoheptanoate, glycerophosphonate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, nicotinate, isonicotinate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfurate, 2-phenylpropionate, picrate, pivalate, thiocyanate, mesylate, undecanoate, stearate, algenate, p-hydroxybutyrate, salicylate, galactarate, galacturonate, caprylate, isobutyrate, malonate, suberate, sebacate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, phenylacetate, isethionate, lactobionate, p-aminobenzoate, sulfamate, diethylacetate, pimelate, aminosulfonate, acrylate, g-hydroxybutyrate, and methoxybenzoate.

[048] If the pharmacologically active compound of Formula I has one or more basic functional groups, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with a suitable inorganic acid or a suitable organic acid. If the pharmacologically active compound has one or more acidic functional groups, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free acid with an inorganic or organic base.

[049] In the case of compounds of Formula I that are solids, it is understood by those skilled in the art that the compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of this disclosure.

[050] In some embodiments the compound forms a chelate with a metal. The term “chelate” as used herein means a compound of Formula I bound to at least one metal. The bonds between the compound of Formula I and the metal can include covalent bonds, ionic bonds, and/or coordinate covalent bonds.

[051] In particular embodiments, the metal is selected from alkaline, alkaline earth, transition, and rare earth, basic, and semi-metals. In more particular embodiments, the metal is selected from boron, calcium, chromium, cobalt, copper, iron, magnesium, manganese, molybdenum, potassium, selenium, vanadium, silver, gold and zinc.

Compositions, dosages and routes of administration

[052] In the clinical setting administration of the compounds (i.e. compounds of Formula I or pharmaceutically acceptable salts, chelates, hydrates or solvates thereof, or derivatives, analogs, or prodrugs thereof) will be an effective treatment for malignancies or dermatological conditions.

[053] In various aspects the compounds of the invention may be formulated as a pharmaceutical composition comprising the compound together with a pharmaceutically acceptable carrier, diluent or excipient. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

[054] The methods described herein are achieved by using a pharmaceutical composition comprising one or more of the compounds. Preferably administration of the compounds is via an oral route. In this context the compounds may be formulated in a variety of ways. In one embodiment the compounds are in a solid form, and may optionally be used in compositions containing a pharmaceutically inert carrier, including for example solid carriers such as lactose, starch, dextrin or magnesium stearate. The compounds described herein may also be used without pharmaceutical carriers for example when administered in a capsule form. [055] In some embodiments the compounds may be formulated for topical, transdermal or percutaneous administration. Typically, these formulations are in the form of a cream, gel, ointment, emulsion (e.g., oil-in-water, water-in-oil, silicone-in-water, water-in-silicone, water- in-oil-in-water, oil-in-water, oil-in-water-in-oil, oil-in-water-in-silicone, etc.), solutions (e.g., aqueous or hydro-alcoholic solutions), lotion or plaster. In some embodiments, the composition is formulated as topical skin composition. The composition can have a dermatologically acceptable vehicle or carrier for the plant, plant part, or extract thereof. The composition can further include a moisturizing agent or a humectant, a surfactant, a silicone containing compounds, a UV agent, an oil, and/or other ingredients identified in this specification or those known in the art.

[056] The appropriate concentration of a compound described herein in a formulation for topical use can be determined by a person of skill in the art. Suitable concentrations can include 0.01% to 20% by weight of a compound described herein. In some embodiments the formulation may contain 0.1, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 99 weight percent of a compound described herein.

[057] The composition can be formulated for topical skin application at least 1, 2, 3, 4, 5,

6, 7, or more times a day during use.

[058] It is also contemplated that the viscosity of the composition can be selected to achieve a desired result, e.g., depending on the type of composition desired, the viscosity of such composition can be from about 1 cps (centipoise) to well over 1 million cps or any range or integer derivable therein (e.g., 2 cps, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 200000, 300000, 400000, 500000, 600000, 700000, 800000, 900000, 1000000, 2000000, 3000000, 4000000, 5000000, at least about 10000000.

[059] Formulations for topical use can also include any one of, any combination of, or all of the following additional ingredients: water, a chelating agent, a moisturizing agent, a preservative, a thickening agent, a silicone containing compound, an essential oil, a structuring agent, a vitamin, or an antioxidant, or any combination thereof.

[060] The topical formulations may by way of example contain conventional carriers. For example, the ointments may contain water and one or more hydrophobic carriers selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol and white vaseline. The carrier compositions of the creams are typically based on water and white vaseline, in combination with glycerol and more minor components, e.g. one or more of glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. The gels may by way of example be formulated using isopropyl alcohol and water, suitably in combination with minor components, for example one or more of glycerol and hydroxyethyl cellulose.

[061] Compounds described herein may be used in combination therapy, for example with a non-steroidal anti-inflammatory drug, a TNF inhibitor or a vitamin.

[062] In other embodiments the compounds described herein may be formulated for injection in a liquid carrier such as water or any pharmaceutically acceptable liquid known in the art. Suitable carriers may include for example water, ethanol, polyols (e.g. glycerol, propylene glycol), and vegetable oils. The compounds described herein may be provided as dispersions or powders for the preparation of injectable solutions or dispersions.

[063] While oral administration is preferred it is envisaged that the compounds described herein may be administered parenterally for example by intravenous, subcutaneous or intramuscular injection. The compounds can also be administered transdermally or topically.

[064] A skilled person, by routine experimentation will determine an effective dose of the compounds or compositions described herein. The effective dose may often be determined on a case-by-case basis. Preferably, the effective dose will be non-toxic.

[065] The effective dose for any subject will be dependent upon a variety of pharmacokinetic factors including the activity of the particular therapeutic agent, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the stage or severity of the condition, other health considerations affecting the subject, and the status of liver and kidney function of the subject. Other factors influencing the selection of an effective dose include: the condition being treated; the composition used; the age, body weight, general health, sex, diet and prior medical history of the subject; the time of administration; the route of administration; the half-life of the compounds; the rate of sequestration of compounds; the duration of the treatment; drugs used in combination or coincidental with the treatment, together with other related factors well known in medicine.

[066] It will be appreciated that the actual dosages of the agents used in the compositions described herein will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, the disease and/or condition being treated, and the particular drug combination selected.

[067] Methods for determining optimal dosages are described in the art, e.g., Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent. [068] In some embodiments it is expected that useful doses are expected to be from less than about 0.1 mg/kg/day, about 0.1 to about 1000 mg/kg/day, or about 0.1 to 900 mg/kg/day, or about 0.1 to 850, or about 0.1 to 800 mg/kg/day, 0.1 to 750 mg/kg/day, or 0.1 to 700 mg/kg/day, or about 0.1 to 650 mg/kg/day, or about 0.1 to 600 mg/kg/day, or about 0.1 to 550 mg/kg/day, or about 0.1 to 500 mg/kg/day, or about 0.1 to 450 mg/kg/day, or about 0.1 to 400 mg/kg/day, or about 0.1 to 350 mg/kg/day, or about 0.1 to 300 mg/kg/day, or about 0.1 to 250 mg/kg/day, or about 0.1 to 200 mg/kg/day, or about 0.1 to 150 mg/kg/day, or about 0.1 to 100 mg/kg/day, or about 0.1 to 50 mg/kg/day, or about 0.1 to 10 mg/kg/day, or about 0.1 to 5 mg/kg/day.

[069] It will be understood by the skilled person that the optimal number of doses and time between doses will be dependent on the nature and the severity of the condition to be treated, the route and site of administration.

[070] The dosage and schedule of administration may vary depending on the particular compound used and considerations such as the severity of disease of the subject.

[071] Compounds and compositions described herein may be administered therapeutically or preventively. In the context of a therapeutic application, compounds and compositions are administered to a subject already suffering from an autoimmune condition, in an amount sufficient to at least partially arrest the condition and its symptoms and/or complications.

The compound or composition should provide a quantity of the compound sufficient to effectively treat the subject. In a preventive application, administration of the compound or compositions described herein prior to the onset of clinically significant condition will be useful in preventing the onset of that condition, for example in subjects predisposed to a dermatological condition such as psoriasis.

[072] Therapeutic advantages may be achieved through the use of combination regimens. In combination therapy, the compounds and compositions described herein and one or more known therapeutic agents may be administered simultaneously or sequentially in any order. Accordingly, methods of treatment described herein may be applied in conjunction with conventional therapy, such as chemotherapy or with the use of immuno-oncological agents.

[073] The amount of a compound of Formula I included in a unit dose of a pharmaceutical composition will vary depending upon factors such as the particular compound, the malignancy or dermatological condition, the severity of the condition, the characteristics of the subject (e.g., weight). The amount of the compound to be used can nevertheless be routinely determined by one skilled in the art. Such pharmaceutical compositions include a therapeutically effective quantity of the pharmacologically active agent and an inert pharmaceutically acceptable carrier or diluent.

[074] These compositions are prepared in unit dosage form appropriate for the chosen route of administration, such as oral administration or parenteral administration. A compound of Formula I as described above can be administered in any conventional dosage form prepared by combining a therapeutically effective amount of such a compound as an active ingredient with appropriate pharmaceutical carriers or diluents according to procedures known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The pharmaceutical carrier employed may be either a solid or liquid. Examples of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.

[075] A variety of pharmaceutical forms can be employed. For example, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.

[076] To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of a pharmacologically active agent as described above is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.

[077] The compositions may be manufactured using techniques generally known for preparing pharmaceutical compositions, e.g., by conventional techniques such as mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing. [078] Pharmaceutical compositions may be formulated in manner known in the art using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations, which can be used pharmaceutically.

[079] Proper formulation is dependent upon the route of administration chosen. For injection, the compounds described herein may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.

[080] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[081] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds described herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, solutions, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[082] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

[083] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[084] Pharmaceutical formulations for parenteral administration can include aqueous solutions or suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or modulators that increase the solubility or dispersibility of the composition to allow for the preparation of highly concentrated solutions, or can contain suspending or dispersing agents. Pharmaceutical preparations for oral use can be obtained by combining the pharmacologically active agent with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). Disintegrating modulators may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[085] Other ingredients such as stabilizers, for example, antioxidants such as sodium citrate, ascorbyl palmitate, propyl gallate, reducing agents, ascorbic acid, vitamin E, sodium bisulfite, butylated hydroxytoluene, BHA, acetylcysteine, monothioglycerol, phenyl-a- naphthylamine, or lecithin can be used. Also, chelators such as EDTA can be used. Other ingredients that are conventional in the area of pharmaceutical compositions and formulations, such as lubricants in tablets or pills, coloring agents, or flavoring agents, can be used. Also, conventional pharmaceutical excipients or carriers can be used. The pharmaceutical excipients can include, but are not necessarily limited to calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. Other pharmaceutical excipients are well known in the art. Exemplary pharmaceutically acceptable carriers include, but are not limited to, any and/or all of solvents, including aqueous and non-aqueous solvents, dispersion media, coatings, antibacterial and/or antifungal agents, isotonic and/or absorption delaying agents, and/or the like. The use of such media and/or agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional medium, carrier, or agent is incompatible with the active ingredient or ingredients, its use in a composition is contemplated.

[086] Supplementary active ingredients can also be incorporated into the compositions, particularly as described above. For administration of any of the compounds described herein, preparations should meet sterility, pyrogenicity, general safety, and purity standards as required by the FDA Office of Biological Standards or by other regulatory organizations regulating drugs.

[087] For administration intranasally or by inhalation, the compounds for use described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[088] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain agents such as suspending, stabilizing and/or dispersing agents.

[089] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[090] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[091] In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[092] An exemplary pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD (vapor phase drying) co solvent system. VPD is a solution of 3% w/v (weight/volume) benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.

[093] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained- release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[094] The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[095] A pharmaceutical composition can be administered by a variety of methods known in the art. The routes and/or modes of administration vary depending upon the desired results. Depending on the route of administration, the pharmacologically active agent may be coated in a material to protect the targeting composition or other therapeutic agent from the action of acids and other compounds that may inactivate the agent. Conventional pharmaceutical practice can be employed to provide suitable formulations or compositions for the administration of such pharmaceutical compositions to subjects. Any appropriate route of administration can be employed, for example, but not limited to, intravenous, parenteral, intraperitoneal, intravenous, transcutaneous, subcutaneous, intramuscular, intraurethral, or oral administration. Depending on the severity of the malignancy or other disease, disorder, or condition to be treated, as well as other conditions affecting the subject to be treated, either systemic or localized delivery of the pharmaceutical composition can be used in the course of treatment. The pharmaceutical composition as described above can be administered together with additional therapeutic agents intended to treat a particular disease or condition, which may be the same disease or condition that the pharmaceutical composition is intended to treat, which may be a related disease or condition, or which even may be an unrelated disease or condition.

[096] Pharmaceutical compositions according to the present invention can be prepared in accordance with methods well known and routinely practiced in the art. See, e.g.,

Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000; and Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. Pharmaceutical compositions are preferably manufactured under GMP conditions. Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds described herein include ethylene-vinyl acetate copolymer particles, osmotic pumps, and implantable infusion systems. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, e.g., polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or can be oily solutions for administration or gels. Pharmaceutical compositions described herein are usually administered to the subjects on multiple occasions. Intervals between single dosages can be weekly, monthly or yearly. Intervals can also be irregular as indicated by therapeutic response or other parameters well known in the art. Alternatively, the pharmaceutical composition can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life in the subject of the pharmacologically active agent included in a pharmaceutical composition. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some subjects may continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the subject can be administered as part of a prophylactic regimen.

[097] For the purposes of the present application, treatment can be monitored by observing one or more of the improving symptoms associated with the disease, disorder, or condition being treated, or by observing one or more of the improving clinical parameters associated with the disease, disorder, or condition being treated, as described above.

[098] Sustained-release formulations or controlled-release formulations are well-known in the art. For example, the sustained-release or controlled-release formulation can be: (1) an oral matrix sustained-release or controlled-release formulation; (2) an oral multilayered sustained-release or controlled-release tablet formulation; (3) an oral multiparticulate sustained-release or controlled-release formulation; (4) an oral osmotic sustained-release or controlled-release formulation; (5) an oral chewable sustained-release or controlled-release formulation; or (6) a dermal sustained-release or controlled-release patch formulation.

[099] The pharmacokinetic principles of controlled drug delivery are described, for example, in B.M. Silber et al., "Pharmacokinetic/Pharmacodynamic Basis of Controlled Drug Delivery" in Controlled Drug Delivery: Fundamentals and Applications (J.R. Robinson & V.H.L. Lee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 5, pp. 213-251, incorporated herein by this reference.

[0100] One of ordinary skill in the art can readily prepare formulations for controlled release or sustained release comprising a compound described herein by modifying the formulations described above, such as according to principles disclosed in V.H.K. Li etal, "Influence of Drug Properties and Routes of Drug Administration on the Design of Sustained and Controlled Release Systems" in Controlled Drug Delivery: Fundamentals and Applications (J.R. Robinson & V.H.L. Lee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 1 , pp. 3-94, incorporated herein by this reference. This process of preparation takes into account physicochemical properties of the pharmacologically active agent such as aqueous solubility, partition coefficient, molecular size, stability, and nonspecific binding to proteins and other biological macromolecules. This process of preparation also takes into account biological factors such as absorption, distribution, metabolism, duration of action, the possible existence of side effects, and margin of safety, for the pharmacologically active agent. Accordingly, one of ordinary skill in the art could modify the formulations into a formulation having the desirable properties described above for a particular application. Methods to improve therapeutic efficiency or reduce side effects [0101] The methods described herein can incorporate additional adaptations and improvements intended to provide further advantages. These adaptations or improvements can accomplish one or more of the following: reduce side effects, reduce pain, increase the therapeutic index of the compound, and improve the efficiency of the compound administered in suppressing the growth of a malignancy and/or inducing killing of cells of the malignancy.

[0102] The methods are to improve the efficacy or reduce the side effects of the administration of a compound of Formula I or a pharmaceutically acceptable salt, chelate, hydrate or solvate thereof, or a derivative, analog, or prodrug thereof to a subject suffering from a malignancy or dermatological condition. The methods typically comprise the steps of:

(1) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the administration of the compound to the subject; and

(2) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the administration of the compound to the subject.

[0103] In one embodiment the factor or parameter may be selected from one of more of the group consisting of: a. dose modification (including dosage escalation regimens); b. route of administration; c. schedule of administration; d. indications for use; e. disease stage; f. subject selection; g. subject genotype or phenotype; h. malignancy or dermatological condition phenotype; i. malignancy or dermatological condition genotype; j. pre/post treatment preparation; k. toxicity management;

L. pharmacokinetic/pharmacodynamic monitoring; m. chemosensitization; n. chemopotentiation; o. post-treatment subject management; p. the use of a herbal medication created either synthetically or through extraction; q. a bulk drug product improvement; r. diluent system; s. solvent system; t. excipient; u. dosage kits and packaging; v. drug delivery system. w. drug conjugate form; x. compound analogs; y. prodrugs; z. multiple drug system; aa. biotherapeutic enhancement; bb. biotherapeutic resistance modulation; cc. radiation therapy enhancement; dd. use of selective target cell population therapeutics; ee. multidrug resistance reversal agents; ff. antibody directed conjugates; or gg. adjuvants;

Dose Modification (including Dose Escalation)

[0104] In some embodiments the methods are to improve the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein.

[0105] In some embodiments improvements in the efficacy or reduction of side effects of the compounds described herein are made by alterations to the time that the compound is administered, the use of dose-modifying agents that control the rate of metabolism of the compound, tissue protective agents, and other alterations.

[0106] Examples of dose modifications include variations of infusion schedules (e.g., bolus intravenous versus continuous infusion), the use of lymphokines (e.g., G-CSF, M-CSF, GM- CSF, EPO) to increase leukocyte count for improved immune response or for preventing anemia. Other examples include: continuous intravenous infusion for hours to days; biweekly administration; progressive escalation of dosing based on subject tolerance; doses less than 250 mg/m ² for greater than 14 days; selected and intermittent boost dose administrations; bolus single and multiple doses of 100-1000 mg/m ² ; oral dosing including multiple daily dosing; micro dosing, immediate release dosing; slow release dosing; or controlled release dosing.

[0107] In one example, a compound of Formula I (for example razoxane) is used in a method of treating a cancer or dermatological condition in a subject, the method comprising administering the compound to the subject according to a dosage escalation regimen wherein the dosage escalation regimen comprises: (a) administering a dosage of from about 1.5 mg/kg to about 50 mg/kg and then administering one or more increased dosages of the compound to the subject at a maximum dose of about 50 mg/kg until a response is observed. The response may be disappearance or reduction of the cancer or dermatological condition for greater than or equal to one month; and (b) when the subject experiences a response, giving two additional administrations of the compound at the dosage level that resulted in the response.

[0108] The normal daily dosage of a suitable compound of Formula I lies in the range from about 10 mg to about 3 grams, from about 25 mg to about 3 grams, from about 50 mg to about 500 mg, from about 100 mg to about 400 mg, and/or from about 125 mg to about 175 mg. For example, for use in treating cancer or a dermatological condition, dosages of razoxane from between about 10 mg to about 200 mg, or from about 10 mg/kg to about 35 mg/kg can be used. In one embodiment the daily dose of razoxane for administration over an extended period of time (i.e. more than two weeks) is 125 mg.

[0109] It will be appreciated that these daily dosages can be divided into two or more portions, for example three or five, and the administration during the day of several smaller doses can prove advantageous as compared with a single larger dose.

[0110] In other embodiments the dose of razoxane may be up to about 3,000 mg/m ² , for example about 500, about 750, about 1,000, about 1,250, about 1,500, about 1,750, about 2,000, about 2,250, about 2,500, about 2,750, or about 3,000 mg/m ² . In these embodiments the dose can be divided into two or more portions for administration in one day. Additionally or alternatively, the dose may be administered weekly, once every two weeks or once every three weeks.

[0111] Furthermore, the daily dosage will vary somewhat according to the particular subject and the mode of administration. Thus, doses as indicated herein can be given orally or as a solution for intravenous injection, by the intramuscular route, or in small volumes subcutaneously.

[0112] As used herein, an “escalating dosage regimen” or “dosage escalation regimen” is a dosage regimen administered to a subject wherein dosages in a series can be increased in a stepwise (i.e., a subsequent dosage is either greater than or equal to the immediately preceding dosage, but at least one increase in dosage occur over the length of the regimen) or linear fashion (i.e., each subsequent dosage is greater than its immediately preceding dosage).

[0113] In one example of a linear dosage regimen, a subject is initially administered about 3 mg/kg of the compound. If the subject does not achieve a partial or complete response after a 3 week period, then the subject is administered about 5 mg/kg of the compound.

[0114] In one example of a stepwise dosage regimen, a subject is initially administered about 3 mg/kg of a compound of Formula I (e.g. razoxane) followed by a second dose at 3 mg/kg. Subsequent doses of the compound, in order, include about 5 mg/kg, about 5 mg/kg, about 9 mg/kg, and about 9 mg/kg. A dosage according to this example is administered every 1-4 weeks. The subject is monitored throughout the regimen to determine whether a partial or complete response has been achieved. If the subject does not achieve a partial or complete response before the next scheduled dosage, the next scheduled dosage is administered. If the subject does achieve a partial response, the subject may be administered a dosage approximately equal to the immediately preceding dosage.

Route of Administration

[0115] In some embodiments improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations in the route by which the compound is administered. For example one compound described herein, razoxane is administered by injection and improvements can include: changing route from intravenous to oral; or the use of subcutaneous, intramuscular, intra-arterial, intraocular, intraperitoneal, intra-lesional, intralymphatic, intratumoral, intrathecal, intravesicular, intra-articular, intracranial, ocular, transcutaneous, transdermal, or topical administration. Specific examples for compounds described herein include: central venous administration; intraperitoneal administration; intravenous administration; intravesicular administration for bladder cancer; intrathecal administration; intra-arterial administration; continuous infusion; or intermittent infusion. Topical or transdermal administration is preferred for the administration of the compounds in the treatment of dermatological conditions. For the treatment of malignancies preferred routes of administration are oral, central venous administration, intraperitoneal administration, and intravenous administration.

Schedule of Administration

[0116] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations to the time that the compound is administered. For example, administration of the compounds changing from a monthly administration to a weekly or daily dosing or variations. Other examples include: daily administration; weekly administration for three weeks; weekly administration for two weeks; biweekly administration; biweekly administration for three weeks with a 1-2 week rest period; intermittent boost dose administration; or administration daily for one week then once per week for multiple weeks. Preferably, schedules of administration for compounds described herein include schedules to avoid at least one of leukopenia, anemia, neutropenia, thrombocytopenia, and gastrointestinal distress.

Indications for Use

[0117] In other embodiments improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations in the types of condition or disease or the clinical stage of the condition or disease for which the compound is administered. For example, the use of compounds described herein for the treatment of dermatological conditions such as psoriasis or pityriasis rubra pilaris, breast cancer; use for the treatment of acute leukemias, including, but not limited to, acute myelocytic leukemia (AML); use for treatment of acute leukemias of childhood, including acute myelocytic leukemia (AML) and acute lymphocytic leukemia (ALL); use for treatment of myelodysplastic syndrome; use for treatment of chronic myelocytic leukemia (CML), either subsequent to or in combination with the administration of tyrosine kinase inhibitors or homoharringtonine (omacetaxine mepesuccinate); use for treatment of chronic lymphocytic leukemia; use for treatment of ovarian cancer; use for treatment of lymphoma including Hodgkin's lymphoma and non-Hodgkin's lymphoma; use for treatment of prostate cancer, especially androgen-resistant prostate cancer; use for treatment of lung small-cell carcinoma, either subsequent to or in combination with the administration of epidermal growth factor receptor (EGFR) inhibitors such as erlotinib (Tarceva®) or gefitinib (Iressa®), wherein the lung small cell carcinoma is characterized by either wild-type or mutated EGFR; use for treatment of lung non-small cell carcinoma, subsequent to or in combination with EGFR inhibitors such as erlotinib or gefitinib, wherein the lung non-small cell carcinoma is characterized by either wild-type or mutated EGFR; use for treatment of breast cancer characterized by overexpressed Her-2-neu; use for treatment of glioblastoma that is resistant to one or both of the following therapeutic agents: temozolomide (Temodar) or bevacizumab (Avastin), or is characterized by EGFR variant III, either alone or in combination with other therapeutic agents; use for treatment of malignancies characterized by overexpressed topoisomerase II; or use for treatment of malignancies characterized by overexpressed and/or mutated EGFR; use for treatment of Kaposis sarcoma; or use for the treatment of osteosarcoma. [0118] The osteosarcoma may be any variant of osteosarcoma including those selected from the group consisting of: conventional (intramedullary) osteosarcoma, osteoblastic osteosarcoma, chondroblastic osteosarcoma, fibroblastic osteosarcoma, epithelioid osteosarcoma, giant-cell rich osteosarcoma, small cell osteosarcoma, telangiectatic osteosarcoma, cortex-associated osteosarcoma, parosteal osteosarcoma, dedifferentiated parosteal osteosarcoma, periosteal osteosarcoma, high-grade surface osteosarcoma, intracortical osteosarcoma, low-grade (central) osteosarcoma, osteoblastoma-like osteosarcoma, disease-associated osteosarcoma, osteosarcoma in Paget's disease, osteosarcoma in fibrous dysplasia, osteosarcoma in Mazabraud's disease, multicentric osteosarcoma, post-irradiation osteosarcoma, and osteosarcoma of the gnathic bones. Disease Stages

[0119] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by selecting that the stage of disease at which the compounds may be administered. For example, the compounds may be administered the use of chemotherapy for non-resectable local disease, prophylactic use to prevent metastatic spread or inhibit disease progression or conversion to more malignant stages, treatment of dermatological conditions that are refractory to standard therapy, (e.g. psoriasis that is not responsive to methotrexate treatment) or treatment of early stages of a dermatological condition.

Subject Selection

[0120] In other embodiments improvements to the efficacy of a compound described herein or a reduction in the side effects of the administration of the compound are made by alterations to the type of subject that would best tolerate or benefit from the use of the compound. For example, a pediatric dose can be used for elderly subjects. Other examples include subject selection on the basis of one or any combination of the following criteria:

(a) a high or low levels of histone deacetylase, protein kinases, or ornithine decarboxylase;

(b) a low or high susceptibility to a thrombocytopenia or neutropenia, in particular subjects with a high susceptibility benefit from lower doses;

(c) intolerance of gastro-intestinal toxicities;

(d) over- or under-expression of a gene selected from the group consisting of jun, GPCRs, signal transduction proteins, VEGF, prostate specific genes, protein kinases, and telomerase;

(e) immune screening;

(f) DNA methylation screening;

(g) the duration of their initial response; (h) without mutations in p53; and

(i) lack of extensive prior treatment, particularly with agents that induce multidrug resistance.

Subject/Disease Phenotype

[0121] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by a more precise identification of a subject's ability to tolerate, metabolize and exploit the use of the compound. For example, an analysis of subject or disease phenotype can be, carried out by a method selected from the group consisting of: a diagnostic tool, technique or assay to confirm a subject's phenotype; a method for measurement of histone deacetylase, ornithine decarboxylase, VEGF, a protein that is a gene product of a prostate specific gene, a protein that is a gene product of jun, and/or a protein kinase; surrogate compound dosing; low dose pre-testing for enzymatic status; determination of the multi-drug resistance activity of cells; determining expression or activation of a signalling or metabolic protein, where an alteration in the level of expression or activation of the signalling or metabolic protein indicates the therapeutic potential of a chemotherapeutic agent; detection or assay of expression of biomarkers indicating sensitivity to apoptosis-inducing agents; use of an in vitro human tumor clonal assay to determine subjects with enhanced responses; use of an immunohistochemical assay to determine overexpression of HIF-1a; and assessment of a p53 or APC (adenomatous polyposis coli) mutation. Other examples include mutations in IL36RN, IL1F5, IL12B, IL23R, RUNX3, TAGAP, STAT3, DDX58, ZC3H12C, CARD14 orCARMl Subject/Disease Genotype

[0122] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by testing and analyzing a subject's genotype for unique features that may be of value to predict efficacy, toxicity, metabolism, or other parameters relevant to therapeutic use of the compound. General examples include: biopsy samples of affected tumors or normal tissues (e.g., skin cell cells or blood cell) may be analyzed to specifically tailor or monitor the use of a particular drug against a gene target; analysis of unique tumor gene expression pattern, SNP's (single nucleotide polymorphisms), to enhance efficacy or to avoid particular drug-sensitive normal tissue toxicities. Examples include the use of a diagnostic tool, a diagnostic technique, a diagnostic kit, or a diagnostic assay to confirm a subject's particular genotype; use of a gene chip; use of gene expression analysis; use of single nucleotide polymorphism (SNP) analysis; measurement of the level of a metabolite or a metabolic enzyme; determination of the presence of one or more specific genetic variants of the MDR1 (multidrug resistance mutation 1) gene associated with increased efficacy of an antineoplastic drug transported by MDR1 protein; identification of one or more biomarkers associated with sensitivity or resistance to at least one of the compounds disclosed herein.

Pre-/Post-Treatment Preparation

[0123] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by preparation of a subject prior to or after the use of a compound described herein. General examples include: induction or inhibition of metabolizing enzymes, specific protection of sensitive normal tissues or organ systems. Other examples include the use of colchicine or an analog thereof; the use of a uricosuric; the use of uricase; the non-oral use of nicotinamide; the use of a sustained-release form of nicotinamide; the use of an inhibitor of poly-ADP ribose polymerase; the use of caffeine; the use of leucovorin rescue; infection control; the use of an anti-hypertensive agent; the use of a retinoid; the use of etanercept; the use of methotrexate; the use of a topical steroidal anti-inflammatory; the use of vitamin D or a vitamin D analog; the use of phototherapy; or the use of cyclosporin.

Toxicity Management

[0124] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by use of additional drugs or procedures to prevent or reduce potential side- effects or toxicities. Some examples are the use of anti-emetics, anti-nausea agents, hematological support agents to limit or prevent neutropenia, anemia, thrombocytopenia, vitamins, antidepressants, treatments for sexual dysfunction, or use of other agents or methods to reduce potential side effects or toxicities. Other examples include the use of colchicine or analogs; the use of uricosurics such as probenecid; the use of diuretics; the use of uricase; non-oral use of nicotinamide; use of sustained-release forms of nicotinamide; use of inhibitors of poly-ADP ribose polymerase; the use of caffeine; leucovorin rescue; the use of sustained release allopurinol; non-oral use of allopurinol; administration of bone marrow transplant stimulants, blood, platelet infusions, Neupogen, G-CSF; or GM-CSF; pain management; infection control; administration of anti inflammatories such as non-steroidal anti-inflammatories (e.g. diclofenac); administration of fluids; administration of corticosteroids; administration of insulin control medications; administration of antipyretics; administration of anti-nausea treatments; administration of anti-diarrhea treatments; administration of antihistamines as pre-treatment to prevent anaphylaxis; administration of agents for reduction of gastric toxicity; administration of steroids as pre-treatment to prevent anaphylaxis; administration of sympathomimetics as pre-treatment to prevent anaphylaxis; and administration of an agent to control or prevent chemotherapy-induced thrombocytopenia.

Pharmacokinetic/Pharmacodynamic Monitoring

[0125] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by the use of monitoring drug levels after dosing in an effort to maximize a subject's drug plasma level, to monitor the generation of toxic metabolites, or to monitor of ancillary medicines that could be beneficial or harmful in terms of drug-drug interactions. Examples include the monitoring of drug plasma protein binding, the monitoring of specific metabolites or breakdown products, or other products of biotransformation. Specific examples for the compounds disclosed herein include: multiple determinations of drug plasma levels; multiple determinations of metabolites in the blood or urine; monitoring of immune function; use of ELISPOT (enzyme-linked immune absorbent spot) to measure immune responses; determination of surface marker upregulation; or monitoring of checkpoint inhibition.

Drug Combinations

[0126] In other embodiments improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by exploiting unique drug combinations that may provide a more than additive or synergistic improvement in efficacy or side-effect management. Examples of drugs that can be used in combination with the compounds described herein are alkylating agents with anti metabolites, topoisomerase inhibitors with antitubulin agents. Additional examples include fraudulent nucleosides, fraudulent nucleotides; thymidylate synthetase inhibitors; signal transduction inhibitors; cisplatin or platinum analogs; alkylating agents; anti-tubulin agents; antimetabolites; use berberine; apigenin; colchicine and analogs thereof; genistein; etoposide; cytarabine; camptothecins; vinca alkaloids, including vincristine, vindesine, vinorelbine, vinflunine, and vinblastine; topoisomerase inhibitors; 5-fluorouracil; curcumin; rosmarinic acid; mitoguazone; meisoindigo; imatinib; dasatinib; use with nilotinib; epigenetic modulators; transcription factor inhibitors; taxol; homoharringtonine; pyridoxal; spirogermanium; caffeine; nicotinamide; methylglyoxalbisguanylhydrazone; epidermal growth factor receptor (EGFR) inhibitors; poly-ADP ribose polymerase (PARR) inhibitors; Bruton's tyrosine kinase (BTK) inhibitors; bis-[thio-hydrazide] amides; succinimide or maleimide derivatives as inhibitors of topoisomerase II; HDAC (histone deacetylase) inhibitors; immunostimulants; inhibitors of telomerase; agents that inhibit the expression or activity of Her2 (human epidermal growth factor receptor 2); agents that inhibit the expression or activity of estrogen receptors; agents that inhibit the expression or activity of antigens associated with specific tumor targets, such as CT (cancer/testis) antigens; G- quadruplex ligands; polycyclic lysophosphatidic receptor antagonists; anti-CTGF ( connective tissue growth factor) agents; myeloid differentiation inducing agents; covalent diabodies binding to a tumor-associated antigen; bispecific antibodies that have a cell- penetrating determinant and an intracellular target-binding determinant; multidomain molecules that comprise a cell binding ligand that binds to cells in the tumor stroma such as endothelial cells, fibroblasts, or immune cells and an oligonucleotide that inhibits the nonsense-mediated decay pathway; tumor-specific antibodies binding to a portion of the CD44 protein or a binding protein derived from the light-chain or heavy-chain complementary-determining regions of such antibodies; inhibitors of the chemokine co receptor CXCR4; pyruvate dehydrogenase kinase (PDK1) inhibitors; epherin receptor targeting agents; binding proteins for Axl; Wnt pathway inhibitors together with MAPK pathway inhibitors; TEC family kinase inhibitors; substituted macrocyclic compounds with proteasome activity; peptide-based PACE4 inhibitors; azaindole derivatives as JAK3 inhibitors; use with inhibitors of Myc; inhibitors of furin and other pro-protein convertases; GPBP-1 inhibitors, optionally together with a p21 inhibitor; a PGE2 inhibitor; a retinoid; etanercept; methotrexate; a topical steroidal anti-inflammatory; vitamin D or a vitamin D analog; phototherapy; or cyclosporin.

Chemosensitization

[0127] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by exploiting them as chemosensitizers where no measureable activity is observed when used alone but in combination with other therapeutics a more than additive or synergistic improvement in efficacy is observed. Some examples include use of a compound described herein as a chemosensitizer in combination with; a topoisomerase inhibitor; with a fraudulent nucleoside; a fraudulent nucleotide; a thymidylate synthetase inhibitor; a signal transduction inhibitor; cisplatin or a platinum analog; an alkylating agent; an anti-tubulin agent; an antimetabolite; berberine; apigenin; colchicine or an analog of colchicine; genistein; etoposide; cytarabine; a camptothecins; a vinca alkaloid; 5- fluorouracil; curcumin; rosmarinic acid; mitoguazone; a retinoid; etanercept; methotrexate; a topical steroidal anti-inflammatory; vitamin D or a vitamin D analog; phototherapy; or cyclosporin. Chemopotentiation

[0128] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by exploiting them as chemopotentiators where minimal therapeutic activity is observed alone but in combination with other therapeutics a more than additive or synergistic improvement in efficacy is observed. Some examples include use of a compound described herein as a chemopotentiator in combination with: a topoisomerase inhibitor; with a fraudulent nucleoside; a fraudulent nucleotide; a thymidylate synthetase inhibitor; a signal transduction inhibitor; cisplatin or a platinum analog; an alkylating agents; an anti-tubulin agent; an antimetabolite; berberine; apigenin; colchicine or an analog of colchicine; genistein; etoposide; cytarabine; a camptothecins; a vinca alkaloid; 5- fluorouracil; curcumin; rosmarinic acid; a mitoguazone; a retinoid; etanercept; methotrexate; a topical steroidal anti-inflammatory; vitamin D or a vitamin D analog; phototherapy; or cyclosporin.

Post-Treatment Subject Management

[0129] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by drugs, treatments and or diagnostics to allow for the maximum benefit to subjects treated with a compound. Examples include: pain management, nutritional support, anti-emetics, anti-nausea therapies, anti-anaemia therapy, anti-inflammatories, or growth factors.

Bulk Drug Product Improvements

[0130] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations in the pharmaceutical bulk substance. Examples include free base form; salt formation; homogeneous crystalline structure; amorphous structure; pure isomers; racemic mixtures; increased purity; or lower residual solvents and heavy metals.

Diluent Systems

[0131] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations in the diluents used to solubilize and deliver/present the compound for administration. Examples include: emulsions; dimethylsulfoxide (DMSO); N- methylformamide (NMF); dimethylformamide (DMF); dimethylacetamide (DMA); ethanol; benzyl alcohol; dextrose-containing water for injection; Cremophor; cyclodextrins; or PEG. Solvent Systems

[0132] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations in the solvents used or required to solubilize a compound for administration or for further dilution. Examples include emulsions; DMSO; NMF; DMF; DMA; ethanol; benzyl alcohol; dextrose-containing water for injection; Cremophor; PEG; or salt systems.

Excipients

[0133] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations in the materials/excipients, buffering agents, or preservatives required to stabilize and present a compound described herein for proper administration. Examples of suitable materials/excipients, buffering agents, or preservatives include: mannitol; albumin; EDTA; sodium bisulfite; benzyl alcohol; carbonate buffers; phosphate buffers; polyethylene glycol (PEG); vitamin A; vitamin D; vitamin E; esterase inhibitors; cytochrome P450 inhibitors; multi-drug resistance (MDR) inhibitors; organic resins; or detergents.

[0134] Examples of suitable excipients are selected from the group consisting of acacia gum; acesulfame potassium; acetone; acetophenone; acetyl tributyl citrate; acetylated monoglyceride; acetylcysteine; activated carbon; alginic acid; allantoin; benzoic acid; calcium carbonate; calcium phosphate; cellulose; cyclodextrin; kolliphor EL; canthaxanthin; croscarmellose sodium; crospovidone; DDAIP (dodecyl 2-dimethylaminopropanoate); denatured alcohol; ethyl cellulose; a feed additive; gelatin; glyceryl behenate; gum Arabic; a humectant; hydroxypropyl cellulose; hypromellose; iron(ll,lll) oxide; lactose; liquid paraffin; macrogol; magnesium stearate; maltitol; mannitol; methyl cellulose; N-Methyl-2-pyrrolidone; oleic acid; plaga (polylactic-co-glycolic acid); polyethylene glycol; a polysorbate; polyvinylpolypyrrolidone; polyvinylpyrrolidone; povidone; propylene glycol; purified water; shellac; silicon dioxide; sodium dodecyl sulfate; sorbitol; starch; succinic acid; sugar; talc; 1,1,1,2-Tetrafluoroethane; thimerasol; thiomersal; titanium dioxide; triacetin; 1,1,1- Trichloroethane; triethyl citrate; xanthan gum; and xylitol.

Dosage Forms

[0135] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations in the potential dosage forms of the compound dependent on the route of administration, duration of effect, plasma levels required, exposure to normal tissues potentially resulting in side effects, and exposure to metabolizing enzymes. Examples of suitable dosage forms include: tablets, capsules, topical gels, creams, patches, suppositories, lyophilized dosage fills, immediate-release formulations, controlled- release formulations, slow-release formulations, or liposomal formulations.

Dosage Kits and Packaging

[0136] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations in the dosage forms, container/closure systems, accuracy of mixing and dosage preparation and presentation. Examples include the use of amber vials to protect from light; and stoppers with specialized coatings to improve shelf-life stability. Other forms of dosage kits and packaging are also known in the art and can include, for example, vials, ampules, jars, intravenous bags, or other containers.

Drug Delivery Systems

[0137] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by the use of delivery systems to improve the potential attributes of a compound described herein such as convenience, duration of effect, or reduction of toxicities.

Examples of suitable delivery systems include: oral dosage form; nanocrystals; nanoparticles; a cosolvent; a slurry; a syrup; a bioerodible polymer; a liposome; a slow release injectable gel; a microsphere; an amphiphilic block copolymer system; an emulsion vehicle comprising an emulsion of a-tocopherol stabilized by a biocompatible surfactant; a biodegradable polymer composition containing phosphorus and desaminotyrosyl L-tyrosine linkages in the polymer backbone; a substantially anhydrous injectable semi-solid compositions comprising a water immiscible fatty acid matrix and a cytostatic agent; a lipophilic vehicle; a pH-dependent carrier that includes a compound that includes at least one ionizable group; a pH-dependent carrier that includes a monocarboxylic acid having at least 8 carbons and less than about 10% by weight of zwitterionic phospholipids; a liposome comprising a compound described herein followed by administration of a lipid nanoparticle comprising a triggering agent; or a non-pegylated liposome.

Drug Conjugate Forms

[0138] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations to a compound described herein with covalent, ionic, or hydrogen bonded moieties to alter the efficacy, toxicity, pharmacokinetics, metabolism, or route of administration. Examples include of moieties suitable for use with the compounds described herein include: a polymer system such as a polyethylene glycol; a polylactide; a polyglycolide; the use of amino acids; the use of peptides; the use of multivalent linkers; the use of conjugates to fatty acids; the use of conjugates to fatty alcohols; the use of conjugates to elastin-like peptide; the use of conjugates with polyclonal or monoclonal antibodies, proteins, or peptides; the use of conjugates with cell-binding agents through a charged or pro-charged cross-linker; the use of conjugates to antibodies targeted to tumor markers; the use of biodegradable polymer-bioactive moiety conjugates; the use of conjugates with 2-nitroimidazole compounds with a secondary basic nitrogen atom and a linker; the use of conjugates with ladder frame polyether compounds, including those derived from brevenal, brevisin, tamulamide, brevetoxins, hemibrevetoxins, gambierols, and gambieric acids; the use of conjugates to antibodies having one or more non-natural amino acid residues at specific positions in the heavy or light chains; the use of conjugates to a sialoadhesin binding moiety; the use of pheophorbide-a conjugates to a compound disclosed herein or a derivative or analog thereof; the use of conjugates to multi-component nanochains; the use of conjugates to activatable antibodies that include a masking moiety, a cleavable moiety, and an antibody binding specifically to interleukin-6; the use of conjugates including hydrophilic linkers; the use of conjugates to antibodies specific for p97; the use of conjugates including a modified amino acid incorporating an azido group; the use of albumin conjugates; or the use of conjugates to folate.

Compound Analogs

[0139] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations to a compound described herein by addition of chemical functionalities that may alter efficacy, reduce toxicity, improve pharmacological performance, be compatible with a particular route of administration, or alter the metabolism of the compound. Examples of suitable analogs include: alteration of side chains to increase or decrease lipophilicity; addition of an additional chemical functionality to alter a property selected from the group consisting of reactivity, electron affinity, chelating capacity; and alteration of salt form.

Prodrugs

[0140] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by alterations to a compound described herein such that improved pharmaceutical performance is gained with a variant of the compound in that after introduction into the body a portion of the molecule is altered (for example enzymatic ring opening or cleavage of a portion of the compound to reveal the preferred active molecule. Examples of suitable prodrug systems include: dimers; a Schiff base; a pyridoxal complex; a caffeine complex; a plasmin-activated prodrug; a drug targeting complex comprising a targeting carrier molecule that is selectively distributed to a specific cell type or tissue containing the specific cell type, a linker which is acted upon by a molecule that is present at an effective concentration in the environs of the specific cell type, and a therapeutically active agent to be delivered to the specific cell type; a prodrug molecule comprising a conjugate of a compound of Formula I, a protease-specific cleavable peptide; and optionally, a targeting peptide, with the prodrug molecule being substantially inactive prior to degradation of the protease-specific cleavable peptide by a proteolytic enzyme.

Multiple Drug Systems

[0141] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by the use of additional compounds, such as therapeutic or biological agents that when administered in the proper fashion, a unique and beneficial effect can be realized. Examples of suitable additional compounds include: an inhibitor of multi-drug resistance, a specific drug resistance inhibitor, a specific inhibitor of a selective enzyme, a signal transduction inhibitor, meisoindigo; imatinib; hydroxyurea; dasatinib; capecitabinenilotinib; a topoisomerase inhibitor with non-overlapping side effects; a PARR inhibitor; a EGFR inhibitor; or a HDAC inhibitor.

Biotherapeutic Enhancement

[0142] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by use of the compound as a sensitizer/potentiator in combination with a biological response modifier. Examples of suitable biological response modifiers include: a cytokine; a lymphokine; a therapeutic antibody; an antisense therapy; a gene therapy; a ribozyme; RNA interference; a vaccines (cellular or non-cellular); a stem cells; and an autologous cell transplant.

Resistance Modulation

[0143] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by exploiting their use to overcome developing or complete resistance to the efficient use of therapeutics. Examples of the use of compounds described herein for resistance modulation include: use against tumors resistant to the effects of biological response modifiers; use against a tumor resistant to the effects of a cytokine; use against a tumor resistant to the effects of a lymphokine; use against a tumor resistant to an effect of a therapeutic antibody; use against a tumor resistant to an effect of an antisense therapy; use against a tumor resistant to an effect of a gene therapy; use against a tumor resistant to the effects of a ribozyme; use against a tumor resistant to the effects of RNA interference; or use against a dermatological condition resistant to treatment with a folic acid antagonist such as methotrexate.

Radiation Therapy Enhancement

[0144] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by exploiting their use in a combination with ionizing radiation, phototherapy, heat therapy, or radio-frequency generated therapy. In particular, the therapy can be selected from the group consisting of: a hypoxic cell sensitizer; a radiation sensitizer/protector; a photosensitizer; a radiation repair inhibitor; thiol depletion; a vaso-targeted agent; a radioactive seed; a radionuclide; a radiolabeled antibody; brachytherapy; and a bioreductive alkylating agent.

[0145] In some embodiment the combination further comprises a known chemotherapy drug, for example as described above.

Selective Target Cell Population Therapeutics

In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by more precise identification and exposure of the compound to those select cell populations where the compounds effect can be maximally exploited. Examples of suitable cell types include: radiation sensitive cells; radiation resistant cells; energy depleted cells; endothelial cells; dermal cells; epidermal cells; or subcutaneous cells.

Use with Agents to Enhance Activity

[0146] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by use of agents to enhance activity of the compound. Examples of suitable agents to enhance the activity of the compounds described herein include: nicotinamide; caffeine; tetandrine; or berberine.

Use with Multidrug Resistance Reversal Agents [0147] In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by use of the compound thereof with a multidrug resistance reversal agent. Examples of suitable multidrug resistance reversal agents include: verapamil, N- myristoylated protein kinase C-a pseudo substrate peptides; dexverapamil (an enantiomer of verapamil); N-solanesyl-N,N'-bis(3,4-dimethylbenzyl)ethylenediamine, cepharanthine, quinidine, reserpine, chlorpromazine and trifluoperazine (S. Akiyama et ai, "Most Drugs That Reverse Multidrug Resistance Also Inhibit Photoaffinity Labeling of P-Glycoprotein by a Vinblastine Analog," Mol. Pharmacol. 33:144-147 1988)); triazine derivatives (A. Dhainaut et ai, "New Triazine Derivatives as Potent Modulators of Multidrug Resistance." J. Med. Chem. 35: 2481-2496 (1992)); terferadine; RU-486; dihydropyridine analogs (M. Kamiwatari et ai, "Correlation Between Reversing of Multidrug Resistance and Inhibiting of [3H]Azidopine Photolabeling of P-Glycoprotein by Newly Synthesized Dihydropyridine Analogues in a Human Cell Line." Cancer Res. 49: 3190-3195 (1989)); the staurosporine derivative NA-382 (K.-l. Miyamoto et ai, "Inhibition of Multidrug Resistance by a New Staurosporine Derivative, NA-382, in Vitro and in Vivo," Cancer Res. 53: 1555-1559 (1993); ningalin B analogs (United States Patent No. 7,250,409 to Boger); other agents (United States Patent No. 5,786,344 to Ratain et ai, cyclosporine A, verapamil, cefoperazone, N- ethoxycarbonyl-7-oxo-staurosporine (NA-382); nifedipine, nitrendipine, nicardipine and diltiazem; other dihydropyridines; tiapamil; nisoldipine; nimodipine; nitrendipine; phenothiazines; thioxanthenes; fluphenazine; chlorpromazine; triflupromazine; trifluoperazine; prochlorperazine; progesterone; metabolites of progesterone; tirilazad; vincristine; vinblastine; actinomycin D; colchicine; etoposide; daunorubicin; doxorubicin; taxotere; taxol; tamoxifen; reserpine; dipyramidole; chloroquine; propranolol; terfenadine; ivermectin; and quinidine. Additional multidrug resistance reversal agents are disclosed in United States Patent No. 8,673,914 to Chen etai:, these multidrug resistance reversal agents are phosphodiesterase inhibitors, such as PDE5 inhibitors, and include sildenafil, vardenafil, tadalafil, lodenafil, udenafil, benzamidenafil, mirodenafil, avanafil, zaprinast, SLX-2101, UK-371,800, UK-122764, icariin, DA-8159, and 3-[4-(2-hydroxyethyl)piperazin-1- yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b ]-pyrazin-2(1 H)-one.

Combination Regimens

In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by using the compound as a chemotherapeutic agent or as an agent having therapeutic activity against a dermatological condition in a combination regimen with a therapeutic agent. Examples therapeutic agents for use with a compound described herein include: at least one agent that induces immunoactivity; at least one agent that induces macrophage activation; at least one cytokine; at least one agent that inhibits telomerase; at least one agent that inhibits survivin; at least one agent that induces demethylation; at least one adjuvant; at least one antibody; at least one innate or adaptive immune stimulator; at least one checkpoint inhibitor; at least one mTOR antagonist; at least one Akt inhibitor; at least one notch inhibitor; at least one HSP inhibitor; at least one phosphatidylinositide 3-kinase inhibitor; at least one kinase inhibitor; cytarabine; taxane; or taxol.

Directed Antibody Conjugates

In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by use of the compound with directed antibody conjugates.

Adjuvants

In other embodiments, improvements to the efficacy of a compound described herein or to reduce the side effects of the administration of a compound described herein are made by use of the compound with an adjuvant. Examples of suitable adjuvants include GM-CSF, poly-ICLC (carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly L-lysine), nanoparticles, microparticles, aluminum salts, squalene, QS-21 (a plant extract from Quillaja saponaha containing water-soluble triterpene glycosides), virosomes, IL-2, IL-7, IL- 21, and type 1 interferons. Other adjuvants are known in the art.

Malignancies and Dermatological Conditions

[0148] The methods and compositions described herein improve the efficacy and/or reduce the side effects of the administration of a compound of Formula I or a pharmaceutically acceptable salt, chelate, hydrate or solvate thereof, or a derivative, analog, or prodrug thereof to a subject suffering from a malignancy or dermatological condition.

[0149] The methods and compositions described herein can be used to treat any form of malignancy forms of cancer, including, but not limited to:

(a) breast cancer, including: ductal carcinoma, including ductal carcinoma in situ

(DCIS) (comedocarcinoma, cribriform, papillary, micropapillary), infiltrating ductal carcinoma (IDC), tubular carcinoma, mucinous (colloid) carcinoma, papillary carcinoma, metaplastic carcinoma, and inflammatory carcinoma; lobular carcinoma, including lobular carcinoma in situ (LCIS) and invasive lobular carcinoma; Paget's disease of the nipple; Her2/neu+tumors; ER+ tumors; and triple negative tumors; (b) cancers of the female reproductive system, including: cancers of the cervix uteri, including cervical intraepithelial neoplasia (Grade I), cervical intraepithelial neoplasia (Grade II), cervical intraepithelial neoplasia (Grade III) (squamous cell carcinoma in situ), keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, verrucous carcinoma, adenocarcinoma in situ, adenocarcinoma in situ, endocervical type, endometrioid adenocarcinoma, clear cell adenocarcinoma, adenosquamous carcinoma, adenoid cystic carcinoma, small cell carcinoma, and undifferentiated carcinoma; cancers of the corpus uteri, including endometrioid carcinoma, adenocarcinoma, adenocanthoma (adenocarcinoma with squamous metaplasia), adenosquamous carcinoma (mixed adenocarcinoma and squamous cell carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, clear cell adenocarcinoma, squamous cell adenocarcinoma, and undifferentiated adenocarcinoma; cancers of the ovary, including serous cystadenoma. serous cystadenocarcinoma, mucinous cystadenoma, mucinous cystadenocarcinoma, endometrioid tumor, endometrioid adenocarcinoma, clear cell tumor, clear cell cystadenocarcinoma, and unclassified tumor; cancers of the vagina, including squamous cell carcinoma and adenocarcinoma; and cancers of the vulva, including vulvar intraepithelial neoplasia (Grade I), vulvar intraepithelial neoplasia (Grade II), vulvar intraepithelial neoplasia (Grade III) (squamous cell carcinoma in situ); squamous cell carcinoma, verrucous carcinoma, Paget's disease of the vulva, adenocarcinoma (NOS), basal cell carcinoma (NOS), and Bartholin's gland carcinoma;

(c) cancers of the male reproductive system, including: cancers of the penis, including squamous cell carcinoma; cancers of the prostate, including adenocarcinoma, sarcoma, and transitional cell carcinoma of the prostate; cancers of the testis, including seminomatous tumor, nonseminomatous tumor, teratoma, embryonal carcinoma, yolk sac tumor, and choriocarcinoma;

(d) cancers of the cardiac system, including sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

(e) cancers of the respiratory system, including squamous cell carcinoma of the larynx, primary pleural mesothelioma, and squamous cell carcinoma of the pharynx;

(f) cancers of the lung, including squamous cell carcinoma (epidermoid carcinoma), variants of squamous cell carcinoma, spindle cell carcinoma, small cell carcinoma, carcinoma of other cells, carcinoma of intermediate cell type, combined oat cell carcinoma, adenocarcinoma, acinar adenocarcinoma, papillary adenocarcinoma, bronchiolo-alveolar carcinoma, solid carcinoma with mucus formation, large cell carcinoma, giant cell carcinoma, clear cell carcinoma, and sarcoma;

(g) cancers of the gastrointestinal tract, including: cancers of the ampulla of Vater, including primary adenocarcinoma, carcinoid tumor, and lymphoma; cancers of the anal canal, including adenocarcinoma, squamous cell carcinoma, and melanoma; cancers of the extrahepatic bile ducts, including carcinoma in situ, adenocarcinoma, papillary adenocarcinoma, adenocarcinoma, intestinal type, mucinous adenocarcinoma, clear cell adenocarcinoma, signet-ring cell carcinoma, adenosquamous carcinoma, squamous cell carcinoma, small cell (oat) carcinoma, undifferentiated carcinoma, carcinoma (NOS), sarcoma, and carcinoid tumor; cancers of the colon and rectum, including adenocarcinoma in situ, adenocarcinoma, mucinous adenocarcinoma (colloid type; greater than 50% mucinous carcinoma), signet ring cell carcinoma (greater than 50% signet ring cell), squamous cell (epidermoid) carcinoma, adenosquamous carcinoma, small cell (oat cell) carcinoma, undifferentiated carcinoma, carcinoma (NOS), sarcoma, lymphoma, and carcinoid tumor; cancers of the esophagus, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the gallbladder, including adenocarcinoma, adenocarcinoma, intestinal type, adenosquamous carcinoma, carcinoma in situ, carcinoma (NOS), clear cell adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, signet ring cell carcinoma, small cell (oat cell) carcinoma, squamous cell carcinoma, and undifferentiated carcinoma; cancers of the lip and oral cavity, including squamous cell carcinoma; cancers of the liver, including hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; cancers of the exocrine pancreas, including duct cell carcinoma, pleomorphic giant cell carcinoma, giant cell carcinoma, osteoclastoid type, adenocarcinoma, adenosquamous carcinoma, mucinous (colloid) carcinoma, cystadenocarcinoma, acinar cell carcinoma, papillary carcinoma, small cell (oat cell) carcinoma, mixed cell typed, carcinoma (NOS), undifferentiated carcinoma, endocrine cell tumors arising in the islets of Langerhans, and carcinoid; cancers of the salivary glands, including acinic (acinar) cell carcinoma, adenoid cystic carcinoma (cylindroma), adenocarcinoma, squamous cell carcinoma, carcinoma in pleomorphic adenoma (malignant mixed tumor), mucoepidermoid carcinoma (well differentiated or low grade), and mucoepidermoid carcinoma (poorly differentiated or high grade); cancers of the stomach, including adenocarcinoma, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma, undifferentiated carcinoma, lymphoma, sarcoma, and carcinoid tumor; and cancers of the small intestine, including adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma;

(h) cancers of the urinary system, including: cancers of the kidney, including renal cell carcinoma, carcinoma of Bellini's collecting ducts, adenocarcinoma, papillary carcinoma, tubular carcinoma, granular cell carcinoma, clear cell carcinoma (hypernephroma), sarcoma of the kidney, and nephroblastoma; cancers of the renal pelvis and ureter, including transitional cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma; cancers of the urethra, including transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma; and cancers of the urinary bladder, including carcinoma in situ, transitional urothelial cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, undifferentiated;

(i) cancers of muscle, bone, and soft tissue, including: cancers of bone, including: bone-forming: osteosarcoma; cartilage-forming: chondrosarcoma and mesenchymal chondrosarcoma; giant cell tumor, malignant; Ewing's sarcoma; vascular tumors: hemangioendothelioma, hemangiopericytoma, and angiosarcoma; connective tissue tumors: fibrosarcoma, liposarcoma, malignant mesenchymoma, and undifferentiated sarcoma; and other tumors: chordoma and adamantinoma of long bones; and

(j) cancers of soft tissues, including: alveolar soft-part sarcoma, angiosarcoma, epithelioid sarcoma, extraskeletal chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant hemangiopericytoma, malignant mesenchymoma, malignant schwannoma, rhabdomyosarcoma, synovial sarcoma, and sarcoma (NOS); cancers of the nervous system, including cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), cancers of the meninges (meningioma, meningiosarcoma, gliomatosis), cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pilealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancers of the spinal cord neurofibroma, meningioma, glioma, sarcoma); hematologic cancers, including myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma; myelodysplastic syndrome), Hodgkin's disease, and non-Hodgkin's lymphoma (malignant lymphoma); cancers of the endocrine system, including: cancers of the thyroid gland, including papillary carcinoma (including those with follicular foci), follicular carcinoma, medullary carcinoma, and undifferentiated (anaplastic) carcinoma; and neuroblastomas, including sympathicoblastoma, sympathicogonioma, malignant ganglioneuroma, gangliosympathicoblastoma, and ganglioneuroma; cancers of the skin, including squamous cell carcinoma, spindle cell variant of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma developing from sweat or sebaceous gland, and malignant melanoma; cancers of the eye, including: cancers of the conjunctiva, including carcinoma of the conjunctiva; cancers of the eyelid, including basal cell carcinoma, squamous cell carcinoma, melanoma of the eyelid, and sebaceous cell carcinoma; cancers of the lacrimal gland, including adenocarcinoma, adenoid cystic carcinoma, carcinoma in pleomorphic adenoma, mucoepidermoid carcinoma, and squamous cell carcinoma; cancers of the uvea, including spindle cell melanoma, mixed cell melanoma, and epithelioid cell melanoma; cancers of the orbit, including sarcoma of the orbit, soft tissue tumor, and sarcoma of bone; and retinoblastoma.

[0150] In particular, the methods and compositions described herein are particularly suitable for the treatment of advanced soft tissue sarcoma. The methods and compositions described herein are also suitable for the treatment of melanoma; colon cancer; chronic lymphocytic leukemia; skin cancer; lung cancer, including small-cell lung cancer and non- small-cell lung cancer; throat cancer; stomach cancer; salivary gland cancer; breast cancer, including triple-negative breast cancer and breast cancer characterized by overexpression of Her-2-neu; prostate cancer, including androgen-resistant prostate cancer; pancreatic cancer; ovarian cancer; uterine cancer; endometrial cancer; other leukemias; renal cell carcinoma; multiple myeloma; liver cancer; pituitary gland cancer; acute myeloid leukemia; oophoroma; glioma; head and neck cancer; colorectal cancer; bladder cancer; HPV-induced papilloma; Hodgkin's lymphoma; non-Hodgkin's lymphoma; chronic myelocytic leukemia; mycosis fungoides; and myelodysplastic syndrome.

[0151] In a preferred embodiment, the osteosarcoma may be any variant of osteosarcoma including those selected from the group consisting of: conventional (intramedullary) osteosarcoma, osteoblastic osteosarcoma, chondroblastic osteosarcoma, fibroblastic osteosarcoma, epithelioid osteosarcoma, giant-cell rich osteosarcoma, small cell osteosarcoma, telangiectatic osteosarcoma, cortex-associated osteosarcoma, parosteal osteosarcoma, dedifferentiated parosteal osteosarcoma, periosteal osteosarcoma, high- grade surface osteosarcoma, intracortical osteosarcoma, low-grade (central) osteosarcoma, osteoblastoma-like osteosarcoma, disease-associated osteosarcoma, osteosarcoma in Paget's disease, osteosarcoma in fibrous dysplasia, osteosarcoma in Mazabraud's disease, multicentric osteosarcoma, post-irradiation osteosarcoma, and osteosarcoma of the gnathic bones.

[0152] In one embodiment the sarcoma is a soft tissue sarcoma for example leiomyosarcoma, liposarcoma, fibroblastic sarcoma, rhabdomyosarcoma, Ewing's sarcoma, synovial sarcoma, vascular sarcoma, malignant peripheral nerve sheath tumours, gastrointestinal stromal tumour, kaposi's sarcoma, and follicular dendritic cell sarcoma. The vascular sarcoma my be an angiosarcoma, hemangiosarcoma, lymphangiosarcoma, or a hemangioendothelioma.

[0153] In another embodiment, the liposarcoma may be a liposarcoma according to any one of the World Health Organization classification of soft tissue tumors which recognizes 5 categories of liposarcomas: (1) well differentiated, which includes the adipocytic, sclerosing, and inflammatory subtypes; (2) dedifferentiated; (3) myxoid; (4) round cell; and (5) pleomorphic. The liposarcoma may have a combination of morphologic types and be classified as a combined or mixed-type liposarcoma. In some embodiments, the liposarcoma may be a myxoid liposarcoma, or a pleomorphic liposarcoma .

[0154] In addition, the methods and compositions described herein are also particularly suitable for treatment of several non-malignant proliferative conditions, HSV-induced shingles and dermatological conditions including dermatitis, psoriasis, solar keratosis, onychomycosis, and/or fungal infections, impetigo, epidermolysis bullosa, eczema, neurodermatitis, pruritis, erythema, hidradenitis suppurativa, warts, diaper rash, jock itch, acne vulgaris, acne conglobate, acne necrotica miliaris, chorance, rosacea, rhinophyma- type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, meibomian gland dysfunction, mitogenic alopecia, perioral dermatitis, acneiform rashes, and transient acantholytic dermatosis.

[0155] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.