Microcrystalline polymorphs of LMP744 and uses thereof

Abstract

Disclosed herein are crystalline polymorphs of LMP744 that can be used in the treatment of cancers associated with dysregulation of Top1 and / or MYC activity, such as, for example, a sarcoma, (e.g., Ewing's sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). This abstract is intended as a scanning tool for purposes of searching m the particular art and is not intended to be limiting of the present invention.

Description

Attorney Docket No.38373.0002P1 MICROCRYSTALLINE POLYMORPHS OF LMP744 AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Provisional Application No.63 / 677,115, filed on July 30, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Topoisomerases are ubiquitous enzymes that resolve the topological problems associated with DNA supercoiling during replication, transcription, and other nuclear processes. Human topoisomerase 1 (Top1) cleaves a single DNA strand by nucleophilic attack of the enzyme on a DNA phosphodiester to form a “cleavage complex” in which the 3′ end of the broken DNA strand is covalently linked to the enzyme (Staker, B. L., et al., The Mechanism of Topoisomerase 1 Poisoning by a Camptothecin Analog, Proc. Natl. Acad. Sci. U.S.A.2002, 99, 15387-15392). The broken (scissile) strand then undergoes “controlled rotation” around the unbroken strand to relax the DNA superhelical tension and remove supercoils. The catalytic cycle ends when the 5′ end of the scissile strand carries out a nucleophilic attack on the phosphotyrosyl-DNA phosphodiester to religate the DNA and release the enzyme.

[0003] Top1 inhibitors are classified as Top1 suppressors, which inhibit the DNA cleavage reaction, and Top1 poisons, which inhibit the DNA religation reaction. Top1 is overexpressed in cancer cells and DNA damage responses are defective in some human tumors. Top1 poisons that stabilize the “cleavage complex” have therefore been developed as chemotherapeutic agents. The mechanism of cancer cell death produced by Top1 poisons involves collision of the DNA replication fork with the DNA cleavage site in the ternary DNA-drug-Top1 complex leading to double-strand breaks and cell death (Pommier, Y., Topoisomerase I Inhibitors: Camptothecins and Beyond, Nat. Rev. Cancer 2006, 6, 789-802).

[0004] LMP744 is a novel selective and potent topoisomerase 1 inhibitor that has successfully completed Phase I clinical trials at the National Institutes of Health (Coyne, G. O., Phase 1 Studies of the Indenoisoquinolines LMP776 and LMP744 in Patients with Solid Tumors and Lymphomas, Cancer Chemother. Pharmacol.2025, 95:58). LMP744 has shown promising results for use in treating malignant glioma, a cancer of the brain that begins in glial cells (cells that surround and support nerve cells). Additionally, LMP744 has shownAttorney Docket No.38373.0002P1 promising activity for the treatment of pediatric cancers, such as Ewing’s sarcoma and solid tumors.

[0005] A limitation of the currently developed form of LMP744 is its limited solubility inwater, which reduces its bioavailability and makes its practical application difficult. One strategy to resolve this problem is polymorphism. The higher solubility and bioavailability of polymorphous modifications are generally associated with the formation of crystals that change the properties of the original compound. Unfortunately, the controlled synthesis of polymorphous forms continues to be an ongoing challenge. Thus, there remains a need for more soluble forms of LMP744, such as soluble crystalline polymorph forms, as well as methods of making and using same. These needs and others are met by the disclosure herein. SUMMARY

[0006] In accordance with the purpose(s) of the invention, as embodied and broadlydescribed herein, the invention, in one aspect, relates to crystalline polymorphs of LMP744, which can be useful in, for example, treating cancers associated with dysregulation of Top1 and / or MYC activity, such as, for example, a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

[0007] Thus, disclosed are crystalline polymorphs of a pharmaceutically acceptable salt of acompound having a structure:.

[0008] Also disclosed are pharmaceutical compositions comprising an effective amount of acrystalline polymorph as described herein and a pharmaceutically acceptable carrier.Attorney Docket No.38373.0002P1

[0009] Also disclosed are methods for modifying topoisomerase 1 (Top1) and / or MYC signaling in a subject, the method comprising the step of administering to the subject an effective amount of a crystalline polymorph as described herein.

[0010] Also disclosed are methods for modifying topoisomerase 1 (Top1) and / or MYC signaling in at least one cell, the method comprising the step of contacting the cell with an effective amount of a crystalline polymorph as described herein.

[0011] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a crystalline polymorph as described herein. Examples of cancer include, but are not limited to, a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

[0012] Also disclosed are kits comprising a crystalline polymorph as described herein and one or more selected from: (a) an agent associated with the treatment of cancer; (b) instructions for administering the crystalline polymorph in connection with treating cancer; and (c) instructions for treating cancer.

[0013] Additional aspects of the disclosed crystalline polymorphs, pharmaceutical compositions, and methods will be set forth, in part, in the detailed description, and claims which follow, and in part will be derived from the detailed description, or can be learned by practice of the disclosed crystalline polymorphs, pharmaceutical compositions, and methods. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosed crystalline polymorphs, pharmaceutical compositions, and methods. BRIEF DESCRIPTION OF THE FIGURES

[0014] These and other features of the aspects of the disclosed crystalline polymorphs, pharmaceutical compositions, and methods will become more apparent in the detailed description in which reference is made to the appended drawings wherein:

[0015] FIG.1 shows a representative1H NMR spectra obtained in DMSO-d6for a crystalline polymorph of LMP744.Attorney Docket No.38373.0002P1

[0016] FIG.2 shows a representative powder XRD pattern for a crystalline polymorph of LMP744.

[0017] FIG 3. shows a representative plot for the crystal size particle distribution measured using laser diffraction. DETAILED DESCRIPTION

[0018] The present invention can be understood more readily by reference to the following detailed description, examples, drawings, and claims, and their previous and following description. However, before the present crystalline polymorphs, pharmaceutical compositions, and / or methods are disclosed and described, it is to be understood that inventions described and claimed herein are not limited to the specific crystalline polymorphs, pharmaceutical compositions, and / or methods disclosed unless otherwise specified, as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0019] The following description of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods are provided as an enabling teaching of the invention in its best, currently known embodiment. To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various aspects of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods, while still obtaining the beneficial results of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods. It will also be apparent that some of the desired benefits of the present crystalline polymorphs, pharmaceutical compositions, and / or methods can be obtained by selecting some of the features of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods are possible and can even be desirable in certain circumstances and are a part of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods. Thus, the following description is provided as illustrative of the principles of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods and not in limitation thereof.Attorney Docket No.38373.0002P1 A. DEFINITIONS

[0020] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural forms unless the context clearly dictates otherwise. Thus, for example, reference to “a peak,” “a pharmaceutically acceptable salt,” or “a pharmaeceutically acceptable carrier” includes mixtures of two or more such peaks, pharmaceutically acceptable salts, or pharmaceutically acceptable carriers, and the like.

[0021] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0022] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0023] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0024] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship betweenAttorney Docket No.38373.0002P1 the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0025] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0026] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0027] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0028] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is aAttorney Docket No.38373.0002P1 mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0029] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0030] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0031] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0032] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in theAttorney Docket No.38373.0002P1 medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0033] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage form can comprise a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0034] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kitAttorney Docket No.38373.0002P1 comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0035] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form, which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0036] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0037] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) andAttorney Docket No.38373.0002P1 poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0038] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma-Aldrich Chemical Co. (Burlington, MA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1994); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 8th Edition, 2020); and Larock’s Comprehensive Organic Transformations (Wiley-VCH Publishers Inc., 2nd Edition, 1999).

[0039] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0040] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations,Attorney Docket No.38373.0002P1 subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C- E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods.

[0041] As used herein, the term “microcrystalline” means a crystallized material in which the crystals are small in size. For example, in various aspects, the median particle diameter, which can be determined by laser diffraction as is known in the art, of the crystals can be about 200 microns or less, about 180 microns or less, about 160 microns or less, about 140 microns or less, about 120 microns or less, about 100 microns or less, about 80 microns or less, about 60 microns or less, about 40 microns or less, about 20 microns or less, or about 15 microns or less. In further aspects, the median particle diameter of the crystals is from about 10 microns to about 200 microns, such as about 10 microns to about 180 microns, about 10 microns to about 150 microns, about 10 microns to about 120 microns, about 10 microns to about 100 microns, about 10 microns to about 50 microns, about 20 microns to about 200 microns, about 20 microns to about 180 microns, about 20 microns to about 150 microns, about 20 microns to about 120 microns, about 20 microns to about 100 microns, about 20 microns to about 80 microns, about 50 microns to about 200 microns, or about 100 microns to about 200 microns.

[0042] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same functionAttorney Docket No.38373.0002P1 that are related to the disclosed structures, and that these structures will typically achieve the same result.B. CRYSTALLINE POLYMORPHS

[0043] In one aspect, disclosed herein are crystalline polymorphs of LMP744, which can beuseful in, for example, treating cancers associated with dysregulation of Top1 and / or MYC activity, such as, for example, a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

[0044] In one aspect, disclosed are crystalline polymorphs of a pharmaceutically acceptablesalt of a compound having a structure:.

[0045] In a further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD)pattern that contains a peak at each of about 8.0 ± 0.2º 2θ, 12.0 ± 0.2º 2θ, 25.8 ± 0.2º 2θ, and about 26.7 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at each of about 7.8, 7.9, 8.0, 8.1, or 8.2º 2θ, and at about 11.8, 11.9, 12.0, 12.1, or 12.2º 2θ, and at about 25.6, 25.7, 25.8, 25.9, or 26.0º 2θ, and at about 26.5, 26.6, 26.7, 26.8, or 26.9º 2θ.

[0046] In a further aspect, the powder XRD pattern further contains a peak at each of about6.7 ± 0.2º 2θ and about 7.1 ± 0.2º 2θ. For example, the powder XRD pattern can further contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ.

[0047] In a further aspect, the powder XRD pattern further contains two or more peaks atpositions selected from about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, aboutAttorney Docket No.38373.0002P1 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or about 4.2º 2θ, and at about 8.1, 8.2, 8.3, 8.4, or about 8.5º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or about 4.2º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or 10.6º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or about 4.2º 2θ, and at about 12.3, 12.4, 12.5, 12.6, or about 12.7º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or about 4.2º 2θ, and at about 24.5, 24.6, 24.7, 24.8, or about 24.9º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or about 10.6º 2θ, and at about 14.2, 14.3, 14.4, 14.5, or about 14.6º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or about 10.6º 2θ, and at about 18.3, 18.4, 18.5, 18.6, or about 18.7º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or about 10.6º 2θ, and at about 23.5, 23.6, 23.7, 23.8, or about 23.9º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or about 10.6º 2θ, and at about 19.1, 19.2, 19.3, 19.4, or about 19.5º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 12.3, 12.4, 12.5, 12.6, or about 12.7º 2θ, and at about 16.4, 16.5, 16.6, 16.7, or about 16.8º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 12.3, 12.4, 12.5, 12.6, or about 12.7º 2θ, and at about 18.3, 18.4, 18.5, 18.6, or about 18.7º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 14.2, 14.3, 14.4, 14.5, or about 14.6º 2θ, and at about 20.6, 20.7, 20.8, 20.9, or 21.0º 2θ. For example, the powder XRD pattern can contain a peakAttorney Docket No.38373.0002P1 at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 14.2, 14.3, 14.4, 14.5, or about 14.6º 2θ, and at about 22.9, 23.0, 23.1, 23.2, or 23.3º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 18.3, 18.4, 18.5, 18.6, or 18.7º 2θ, and at about 21.5, 21.6, 21.7, 21.8, or 21.9º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 18.3, 18.4, 18.5, 18.6, or 18.7º 2θ, and at about 24.5, 24.6, 24.7, 24.8, or 24.9º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 20.6, 20.7, 20.8, 20.9, or 21.0º 2θ, and at about 22.9, 23.0, 23.1, 23.2, or 23.3º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 23.5, 23.6, 23.7, 23.8, or 23.9º 2θ, and at about 24.5, 24.6, 24.7, 24.8, or 24.9º 2θ.

[0048] In a further aspect, the powder XRD pattern further contains five or more peaks at positions selected from about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or 4.2º 2θ, and at about 8.1, 8.2, 8.3, 8.4, or 8.5º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or 10.6º 2θ, and at about 12.1, 12.2, 12.3, 12.4, or 12.5º 2θ, and at about 12.3, 12.4, 12.5, 12.6, or 12.7º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or 4.2º 2θ, and at about 8.1, 8.2, 8.3, 8.4, or 8.5º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or 10.6º 2θ, and at about 23.5, 23.6, 23.7, 23.8, or 23.9º 2θ, and at about 24.5, 24.6, 24.7, 24.8, or 24.9º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 21.5, 21.6, 21.7, 21.8, or 21.9º 2θ, and at about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ, and at about 22.9, 23.0, 23.1, 23.2, or 23.3º 2θ, and at about 23.5, 23.6, 23.7, 23.8, or 23.9º 2θ, and at about 24.5, 24.6, 24.7, 24.8, or 24.9º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 19.1, 19.2, 19.3, 19.4, or 19.5º 2θ, and at about 20.6, 20.7, 20.8, 20.9, or 21.0º 2θ, and at about 21.5, 21.6, 21.7, 21.8, or 21.9º 2θ, andAttorney Docket No.38373.0002P1 at about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ, and at about 22.9, 23.0, 23.1, 23.2, or 23.3º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 13.4, 13.5, 13.6, 13.7, or 13.8º 2θ, and at about 14.2, 14.3, 14.4, 14.5, or 14.6º 2θ, and at about 15.6, 15.7, 15.8, 15.9, 16.0, or 16.1, and at about 15.8, 15.9, 16.0, 16.1, or 16.2º 2θ, and at about 16.4, 16.5, 16.6, 16.7, or 16.8. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 13.4, 13.5, 13.6, 13.7, or 13.8º 2θ, and at about 14.2, 14.3, 14.4, 14.5, or 14.6º 2θ, and at about 16.4, 16.5, 16.6, 16.7, or 16.8º 2θ, and at about 18.5, 18.6, 18.7, 18.8, or 18.9º 2θ, and at about 23.5, 23.6, 23.7, 23.8, or 23.9º 2θ.

[0049] In a further aspect, the powder XRD pattern further contains ten or more peaks at positions selected from about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or 4.2º 2θ, and at about 8.1, 8.2, 8.3, 8.4, or 8.5º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or 10.6º 2θ, and at about 12.1, 12.2, 12.3, 12.4, or 12.5º 2θ, and at about 12.3, 12.4, 12.5, 12.6, or 12.7º 2θ, and at about 13.4, 13.5, 13.6, 13.7, or 13.8º 2θ, and at about 14.2, 14.3, 14.4, 14.5, or 14.6º 2θ, and at about 15.6, 15.7, 15.8, 15.9, or 16.0º 2θ, and at about 15.8, 15.9, 16.0, 16.1, or 16.2º 2θ, and at about 16.4, 16.5, 16.6, 16.7, or 16.8º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 16.4, 16.5, 16.6, 16.7, or 16.8º 2θ, and at about 18.3, 18.4, 18.5, 18.6, or 18.7º 2θ, and at about 18.5, 18.6, 18.7, 18.8, or 18.9º 2θ, and at about 19.1, 19.2, 19.3, 19.4, or 19.5º 2θ, and at about 20.6, 20.7, 20.8, 20.9, or 21.0º 2θ, and at about 21.5, 21.6, 21.7, 21.8, or 21.9º 2θ, and at about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ, and at about 22.9, 23.0, 23.1, 23.2, or 23.3º 2θ, and at about 23.5, 23.6, 23.7, 23.8, or 23.9º 2θ, and at about 24.5, 24.6, 24.7, 24.8, or 24.9º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or 4.2º 2θ, and at about 8.1, 8.2, 8.3, 8.4, or 8.5º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or 10.6º 2θ, and at about 12.1, 12.2, 12.3, 12.4, or 12.5º 2θ, and at about 12.3, 12.4, 12.5, 12.6, or 12.7º 2θ, and at about 21.5, 21.6, 21.7, 21.8, or 21.9º 2θ, and at about 21.6, 21.7, 21.8, 21.9, orAttorney Docket No.38373.0002P1 22.0º 2θ, and at about 22.9, 23.0, 23.1, 23.2, or 23.3º 2θ, and at about 23.5, 23.6, 23.7, 23.8, or 23.9º 2θ, and at about 24.5, 24.6, 24.7, 24.8, or 24.9º 2θ.

[0050] In a further aspect, the powder XRD pattern further contains fifteen or more peaks at positions selected from about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 3.8, 3.9, 4.0, 4.1, or 4.2º 2θ, and at about 8.1, 8.2, 8.3, 8.4, or 8.5º 2θ, and at about 10.2, 10.3, 10.4, 10.5, or 10.6º 2θ, and at about 12.1, 12.2, 12.3, 12.4, or 12.5º 2θ, and at about 12.3, 12.4, 12.5, 12.6, or 12.7º 2θ, and at about 13.4, 13.5, 13.6, 13.7, or 13.8º 2θ, and at about 14.2, 14.3, 14.4, 14.5, or 14.6º 2θ, and at about 15.6, 15.7, 15.8, 15.9, or 16.0º 2θ, and at about 15.8, 15.9, 16.0, 16.1, or 16.2º 2θ, and at about 16.4, 16.5, 16.6, 16.7, or 16.8º 2θ, and at about 18.3, 18.4, 18.5, 18.6, 18.7, or 18.8º 2θ, and at about 18.5, 18.6, 18.7, 18.8, or 18.9º 2θ, and at about 19.1, 19.2, 19.3, 19.4, or 19.5º 2θ, and at about 20.6, 20.7, 20.8, 20.9, or 21.0º 2θ, and at about 21.5, 21.6, 21.7, 21.8, or 21.9º 2θ. For example, the powder XRD pattern can contain a peak at each of about 6.5, 6.6, 6.7, 6.8, or 6.9º 2θ and at about 6.9, 7.0, 7.1, 7.2, or 7.3º 2θ, and at about 12.3, 12.4, 12.5, 12.6, or 12.7º 2θ, and at about 13.4, 13.5, 13.6, 13.7, or 13.8º 2θ, and at about 14.2, 14.3, 14.4, 14.5, or 14.6º 2θ, and at about 15.6, 15.7, 15.8, 15.9, or 16.0º 2θ, and at about 15.8, 15.9, 16.0, 16.1, or 16.2º 2θ, and at about 16.4, 16.5, 16.6, 16.7, or 16.8º 2θ, and at about 18.3, 18.4, 18.5, 18.6, 18.7, or 18.8º 2θ, and at about 18.5, 18.6, 18.7, 18.8, or 18.9º 2θ, and at about 19.1, 19.2, 19.3, 19.4, or 19.5º 2θ, and at about 20.6, 20.7, 20.8, 20.9, or 21.0º 2θ, and at about 21.5, 21.6, 21.7, 21.8, or 21.9º 2θ, and at about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ, and at about 22.9, 23.0, 23.1, 23.2, or 23.3º 2θ, and at about 23.5, 23.6, 23.7, 23.8, or 23.9º 2θ, and at about 24.5, 24.6, 24.7, 24.8, or 24.9º 2θ.

[0051] In a further aspect, the powder XRD pattern further contains a peak at each of about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ.

[0052] In a further aspect, the crystalline polymorph has an XRD pattern as shown in FIG.1.Attorney Docket No.38373.0002P1

[0053] In a further aspect, the pharmaceutically acceptable salt is selected from a halide salt, an acetate salt, an alginate salt, an ascorbate salt, a benzene sulfonate salt, a benzoate salt, a carbonate salt, a cinnamate salt, a citrate salt, a diphosphate salt, a fumarate salt, a gluconate salt, a lactate salt, a laurate salt, a malate salt, a maleate salt, a mesylate salt, a myristate salt, a nitrate salt, a palmitate salt, a perchlorate salt, a phenolate salt, a phosphate salt, a propionate salt, a sorbate salt, a succinate salt, a sulfate salt, and a tartrate salt. In a further aspect, the pharmaceutically acceptable salt is a halide salt. In a yet further aspect, the pharmaceutically acceptable salt is a hydrochloride salt.

[0054] In some aspect, the crystalline polymorph can be present as a crystalline particulate material, wherein the crystalline particulate material is a plurality of particles having a median particle diameter. The median particle diameter can be measured using any technique known in the art for measuring crystal size, such as, for example, light scattering, laser diffraction, and electron microscopy.

[0055] In some aspects, the median particle diameter is measured using laser diffraction. An exemplary instrument, which can be used to measure the median particle diameter is a Mastersizer, commercially produced by Malvern. This measurement calculates a volume distribution from the LASER diffraction pattern of a suspension of particles. The raw scatter data is processed using a complex algorithm and presented on the basis of equivalent spherical diameter. Dv(10), Dv(50), and Dv(90) are size values which indicate the median particle diameter in which 10%, 50%, or 90% particles within the particle volume distribution, respectively, are smaller. A Dv(90) value of 140 μm, for example, indicates that 90% of the total volume of the sample is in particles smaller than 140 μm.

[0056] In some aspects, the plurality of particles has a Dv(10) value of from about 0.5 μm to about 5.0 μm. The plurality of particles can have a Dv(10) value of, for example, from about 0.5 μm to about 4.5 μm, about 0.5 μm to about 4.0 μm, about 0.5 μm to about 3.5 μm, about 0.5 μm to about 3.0 μm, about 0.5 μm to about 2.5 μm, about 0.5 μm to about 2.0 μm, about 0.5 μm to about 1.5 μm, about 0.5 μm to about 1.0 μm, about 1.0 μm to about 4.5 μm, about 1.0 μm to about 4.0 μm, about 1.0 μm to about 3.5 μm, about 1.0 μm to about 3.0 μm, about 1.0 μm to about 2.5 μm, about 1.0 μm to about 2.0 μm, about 1.0 μm to about 1.5 μm, about 1.5 μm to about 5.0 μm, about 1.5 μm to about 4.5 μm, about 1.5 μm to about 4.0 μm, about 1.5 μm to about 3.5 μm, about 1.5 μm to about 3.0 μm, about 1.5 μm to about 2.5 μm, about 1.5 μm to about 2.0 μm, about 2.0 μm to about 4.0 μm, about 2.5 to μm about 3.5 μm, or about 3.0 μm to about 5.0 μm. The plurality of particles can have, for example, a Dv(10) value of about 1.0 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0Attorney Docket No.38373.0002P1 μm, 4.5 μm, or about 5.0 μm. In some aspects, the plurality of particles has a Dv(10) value of about 1.5 μm.

[0057] In some aspects, the plurality of particles has a Dv(50) value of from about 5.0 μm to about 15 μm. The plurality of particles can have a Dv(50) value of, for example, from about 5.0 μm to about 13 μm, about 5.0 μm to about 10 μm, about 5.0 to about 7.0 μm, about 7.0 μm to about 15 μm, about 7.0 μm to about 13.0 μm, about 7.0 μm to about 11 μm, about 7.0 μm to about 10 μm, about 8.0 μm to about 15 μm, about 8.0 μm to about 13.0 μm, about 8 μm to about 10 μm, or about 10 μm to about 15 μm. The plurality of particles can have, for example, a Dv(50) value of about 5.0 μm, 6.0 μm, 7.0 μm, 8.0 μm, 9.0 μm, 10 μm, 11 μm, or about 15 μm. In some aspects, the plurality of particles has a Dv(50) value of about 10 μm.

[0058] In some aspects, the plurality of particles has a Dv(90) value of from about 20 μm to about 60 μm. The plurality of particles can have a Dv(90) value of, for example, from about 20 μm to about 55 μm, about 20 μm to about 50 μm, about 20 μm to about 45 μm, about 30 μm to about 60 μm, about 30 μm to about 55 μm, about 30 μm to about 50 μm, about 20 μm to about 40 μm, about 20 μm to about 38 μm, about 20 μm to about 37 μm, about 20 μm to about 35 μm, about 25 μm to about 45 μm, about 25 μm to about 40 μm, about 25 μm to about 38 μm, about 25 μm to about 37 μm, about about 25 μm to about 35 μm, about 30 μm to about 45 μm, about 30 μm to about 40 μm, about 30 μm to about 38 μm, about 30 μm to about 37 μm, about 30 μm to about 35 μm, about 35 μm to about 45 μm, about 35 μm to about 38 μm, or about 37 μm to about 40 μm. The plurality of particles can have, for example, a Dv(90) value of about 20 μm, 25 μm, 30 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, 40 μm, or about 45 μm. In some aspects, the plurality of particles has a Dv(90) value of about 38 μm.

[0059] In some aspects, the plurality of particles has a Dv(10) value of from about 0.5 μm to about 5.0 μm, a a Dv(50) value of from about 5.0 μm to about 15 μm, and a Dv(90) value of from about 20 μm to about 60 μm. C. PHARMACEUTICAL COMPOSITIONS

[0001] In one aspect, disclosed are pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of a disclosed crystalline polymorph or a pharmaceutically acceptable salt thereof.Attorney Docket No.38373.0002P1

[0002] In a further aspect, disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of a crystalline polymorph of a compound having a structure:.

[0003] In various aspects, the compounds and compositions can be administered inpharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, intravenous, topical, or oral administration.

[0004] The nature of the pharmaceutical compositions for administration is dependent on themode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The crystalline polymorphs disclosed herein can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0005] In various aspects, the disclosed pharmaceutical compositions comprise the disclosedcrystalline polymorphs (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeuticAttorney Docket No.38373.0002P1 ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0006] In various aspects, the pharmaceutical compositions can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the crystalline polymorphs described herein. The crystalline polymorphs, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0007] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0008] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0009] A tablet containing the composition can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0010] The pharmaceutical compositions comprise a crystalline polymorph disclosed herein (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. TheAttorney Docket No.38373.0002P1 instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0011] Pharmaceutical compositions suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0012] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0013] Pharmaceutical compositions can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouthwashes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a crystalline polymorph as described herein, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0014] Pharmaceutical compositions can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.Attorney Docket No.38373.0002P1

[0015] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a crystalline polymorph, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0016] In various aspects, the effective amount is a therapeutically effective amount. In a further aspect, the effective amount is a prophylactically effective amount.

[0017] In various aspects, the pharmaceutical composition is administered to a mammal. In a further aspect, the mammal is a human. In yet further aspect, the human is a patient.

[0018] In a further aspect, the pharmaceutical composition is used to treat cancer. In a yet further aspect, the cancer is associated with dysregulation of Top1 and / or MYC activity. In a still further aspect, the cancer is selected from a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In yet a further aspect, the cancer is Ewing’s sarcoma. In an even further aspect, the cancer is glioblastoma.

[0019] It is understood that the disclosed compositions can be prepared from the disclosed crystalline polymorphs. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. D. METHODS FOR MODIFYING TOPOISOMERASE 1 AND / OR MYC SIGNALING IN A SUBJECT

[0060] In one aspect, disclosed are methods for modifying topoisomerase 1 (Top1) and / or MYC signaling in a subject, the method comprising the step of administering to the subject an effective amount of a crystalline polymorph as described herein. In a further aspect, the crystalline polymorph is a pharmaceutically acceptable salt of a compound having a structure:Attorney Docket No.38373.0002P1.

[0061] In a further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD)pattern that contains a peak at each of about 8.0 ± 0.2º 2θ, 12.0 ± 0.2º 2θ, 25.8 ± 0.2º 2θ, and about 26.7 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 7.8, 7.9, 8.0, 8.1, or 8.2º 2θ, and also at 11.8, 11.9, 12.0, 12.1, or 12.2º 2θ, and also at 25.6, 25.7, 25.8, 25.9, or 26.0º 2θ, and also at 26.5, 26.6, 26.7, 26.8, or 26.9º 2θ.

[0062] In a further aspect, modifying topoisomeraise I (Top1) and / or MYC signaling in asubject is decreasing Top1 and / or MYC signaling in a subject. In a still further aspect, modifying topoisomerase 1 (Top1) and / or MYC signaling in a subject is inhibiting Top1 and / or MYC signaling in a subject.

[0063] In various aspects, the subject has been diagnosed with a need for modifying Top1and / or MYC signaling prior to the administering step.

[0064] In a further aspect, the subject has been diagnosed with a need for treatment of adisease or disorder associated with Top1 signaling dysfunction prior to the administering step. In a yet still further aspect, the method comprises the step of identifying a subject in need of treatment of a disease or disorder associated with Top1 and / or MYC signaling dysfunction. In an even further aspect, the disease or disorder is a cancer such as, for example, a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

[0065] In some aspects, the subject has been diagnosed with cancer prior to the administeringstep.Attorney Docket No.38373.0002P1E. METHODS FOR MODIFYING TOPOISOMERASE 1 AND / OR MYC SIGNIALING IN ACELL

[0066] In one aspect, disclosed are methods for modifying topoisomerase 1 (Top1) and / orMYC signaling in at least one cell, the method comprising the step of contacting the cell with an effective amount of the crystalline polymorph as described herein. In a further aspect, the crystalline polymorph is a pharmaceutically acceptable salt of a compound having a structure:.

[0067] In a further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD)pattern that contains a peak at each of about 8.0 ± 0.2º 2θ, 12.0 ± 0.2º 2θ, 25.8 ± 0.2º 2θ, and about 26.7 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 7.8, 7.9, 8.0, 8.1, or 8.2º 2θ, and also at 11.8, 11.9, 12.0, 12.1, or 12.2º 2θ, and also at 25.6, 25.7, 25.8, 25.9, or 26.0º 2θ, and also at 26.5, 26.6, 26.7, 26.8, or 26.9º 2θ.

[0068] In a further aspect, modifying topoisomeraise I (Top1) and / or MYC signaling in asubject is decreasing Top1 and / or MYC signaling in at least one cell. In a still further aspect, modifying topoisomerase 1 (Top1) and / or MYC signaling in a subject is inhibiting Top1 and / or MYC signaling in at least one cell.

[0069] In a further aspect, the cell is a human cell. In a still further aspect, the cell has beenisolated from a human prior to the administering step.

[0070] In a further aspect, contacting the cell is via administration to a subject.

[0071] In a further aspect, the subject has been diagnosed with a need for modification ofTop1 and / or MYC signaling prior to the administering step.

[0072] In a further aspect, the subject has been diagnosed with a need for treatment of adisease or disorder associated with Top1 and / or MYC signaling dysfunction. In a still further aspect, the disease or disorder is a cancer such as, for example, a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer,Attorney Docket No.38373.0002P1 liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).F. METHODS FOR TREATING CANCER IN A SUBJECT

[0073] In one aspect, disclosed are methods of treating cancer in a subject in need thereof,the method comprising administering to the subject an effective amount of a crystalline polymorph described herein. In a further aspect, the crystalline polymorph is a pharmaceutically acceptable salt of a compound having a structure:.

[0074] In a further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD)pattern that contains a peak at each of about 8.0 ± 0.2º 2θ, 12.0 ± 0.2º 2θ, 25.8 ± 0.2º 2θ, and about 26.7 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 7.8, 7.9, 8.0, 8.1, or 8.2º 2θ, and also at 11.8, 11.9, 12.0, 12.1, or 12.2º 2θ, and also at 25.6, 25.7, 25.8, 25.9, or 26.0º 2θ, and also at 26.5, 26.6, 26.7, 26.8, or 26.9º 2θ.

[0075] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is ahuman.

[0076] In a further aspect, the subject has been diagnosed with a need for treatment of cancerprior to the administering step.

[0077] In a further aspect, the method further comprises the step of identifying a subject inneed of treatment of cancer.

[0078] In various aspects, the effective amount is a therapeutically effective amount. In afurther aspect, the effective amount is a prophylactically effective amount.

[0079] In various aspects, the cancer is associated with dysregulation of Top1 and / or MYCactivity. In a further aspect, the cancer is associated with an increase in Top1 and / or MYC activity.Attorney Docket No.38373.0002P1

[0080] In a further aspect, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In a still further aspect, the cancer is a solid tumor or a lymphoma. In a yet still further aspect, the cancer is a glioma. In a yet still further aspect, the cancer is leukemia.

[0081] In various aspects, the cancer is a pediatric cancer. In a further aspect, the pediatric cancer is a Ewing’s sarcoma or a solid tumor.

[0082] In various aspects, the crystalline polymorph is administered at a dose of from about 6 mg / m2to about 190 mg / m2. The crystalline polymorph can be administered, for example, at a dose of from about 6 mg / m2to about 180 mg / m2, about 6 mg / m2to about 150 mg / m2, about 6 mg / m2to about 120 mg / m2, about 6 mg / m2to about 100 mg / m2, about 6 mg / m2to about 80 mg / m2, about 6 mg / m2to about 50 mg / m2, about 6 mg / m2to about 40 mg / m2, about 6 mg / m2to about 30 mg / m2, about 6 mg / m2to about 20 mg / m2, about 6 mg / m2to about 10 mg / m2, about 10 mg / m2to about 190 mg / m2, about 10 mg / m2to about 180 mg / m2, about 10 mg / m2to about 150 mg / m2, about 10 mg / m2to about 120 mg / m2, about 10 mg / m2to about 100 mg / m2, about 10 mg / m2to about 80 mg / m2, about 10 mg / m2to about 50 mg / m2, about 10 mg / m2to about 40 mg / m2, about 10 mg / m2to about 30 mg / m2, about 10 mg / m2to about 20 mg / m2, about 20 mg / m2to about 190 mg / m2, about 20 mg / m2to about 190 mg / m2, about 20 mg / m2to about 180 mg / m2, about 20 mg / m2to about 150 mg / m2, about 20 mg / m2to about 120 mg / m2, about 20 mg / m2to about 100 mg / m2, about 20 mg / m2to 80 mg / m2, about 20 mg / m2to 50 mg / m2, about 20 mg / m2to about 40 mg / m2, about 20 mg / m2to about 30 mg / m2, about 30 mg / m2to about 190 mg / m2, about 30 mg / m2to about 180 mg / m2, about 30 mg / m2to about 150 mg / m2, about 30 mg / m2to about 120 mg / m2, about 30 mg / m2to about 100 mg / m2, about 30 mg / m2to about 80 mg / m2, about 30 mg / m2to about 50 mg / m2, about 30 mg / m2to about 40 mg / m2, about 40 mg / m2to about 190 mg / m2, about 40 mg / m2to about 180 mg / m2, about 40 mg / m2to about 150 mg / m2, about 40 mg / m2to about 120 mg / m2, about 40 mg / m2to about 100 mg / m2, about 40 mg / m2to about 80 mg / m2, about 40 mg / m2to about 50 mg / m2, about 50 mg / m2to about 190 mg / m2, about 50 mg / m2to about 180 mg / m2, about 50 mg / m2to about 150 mg / m2, about 50 mg / m2to about 120 mg / m2, about 50 mg / m2to about 100 mg / m2, about 50 mg / m2to about 80 mg / m2, about 80 mg / m2to about 190 mg / m2, about 80 mg / m2to about 180 mg / m2, about 80 mg / m2to about 150 mg / m2, about 80 mg / m2to about 120 mg / m2, aboutAttorney Docket No.38373.0002P1 80 mg / m2to about 100 mg / m2, about 100 mg / m2to about 190 mg / m2, about 100 mg / m2to about 150 mg / m2, about 100 mg / m2to about 120 mg / m2, about 120 mg / m2to about 190 mg / m2, about 120 mg / m2to about 180 mg / m2, about 120 mg / m2to about 150 mg / m2, about 150 mg / m2to about 190 mg / m2, about 150 mg / m2to about 180 mg / m2, or about 180 mg / m2to about 190 mg / m2.

[0083] In various aspects, the crystalline polymorph is administered once daily at a dose of from about 6 mg / m2to about 90 mg / m2. The crystalline polymorph can be administered once daily, for example, at a dose of from about 6 mg / m2to about 80 mg / m2, about 6 mg / m2to about 70 mg / m2, about 6 mg / m2to about 60 mg / m2, about 6 mg / m2to about 50 mg / m2, about 6 mg / m2to about 40 mg / m2, about 6 mg / m2to about 30 mg / m2, about 6 mg / m2to about 20 mg / m2, about 6 mg / m2to about 10 mg / m2, about 10 mg / m2to about 90 mg / m2, about 10 mg / m2to about 80 mg / m2, about 10 mg / m2to about 70 mg / m2, about 10 mg / m2to about 60 mg / m2, about 10 mg / m2to about 50 mg / m2, about 10 mg / m2to about 40 mg / m2, about 10 mg / m2to about 30 mg / m2, about 10 mg / m2to about 20 mg / m2, about 20 mg / m2to about 90 mg / m2, about 20 mg / m2to about 80 mg / m2, about 20 mg / m2to about 70 mg / m2, about 20 mg / m2to about 60 mg / m2, about 20 mg / m2to about 50 mg / m2, about 20 mg / m2to about 40 mg / m2, about 20 mg / m2to about 30 mg / m2, about 30 mg / m2to about 90 mg / m2, about 30 mg / m2to about 80 mg / m2, about 30 mg / m2to about 70 mg / m2, about 30 mg / m2to about 60 mg / m2, about 30 mg / m2to about 50 mg / m2, about 30 mg / m2to about 40 mg / m2, about 40 mg / m2to about 90 mg / m2, about 40 mg / m2to about 80 mg / m2, about 40 mg / m2to about 70 mg / m2, about 40 mg / m2to about 60 mg / m2, about 40 mg / m2to about 50 mg / m2, about 50 mg / m2to about 90 mg / m2, about 50 mg / m2to about 80 mg / m2, about 50 mg / m2to about 70 mg / m2, about 50 mg / m2to about 60 mg / m2, about 60 mg / m2to about 90 mg / m2, about 60 mg / m2to about 80 mg / m2, about 60 mg / m2to about 70 mg / m2, about 70 mg / m2to about 90 mg / m2, about 70 mg / m2to about 80 mg / m2, or about 80 mg / m2to about 90 mg / m2.

[0084] In various aspects, the crystalline polymorph is administered once daily at a dose of from about 6 mg / m2to about 190 mg / m2for a time period of from 1 to 5 days. The crystalline polymorph can be administered once daily at a dose of from about 6 mg / m2to about 190 mg / m2for a time period of from 1 to 4 days, 1 to 3 days, 1 to 2 days, 2 to 5 days, 2 to 4 days, 2 to 3 days, 3 to 5 days, 3 to 4 days, or 4 to 5 days.Attorney Docket No.38373.0002P1 KITS

[0085] In one aspect, disclosed are kits comprising a crystalline polymorph as describedherein and one or more selected from: (a) an agent associated with the treatment of cancer; (b) instructions for administering the crystalline polymorph in connection with treating cancer; and (c) instructions for treating cancer. In a further aspect, the crystalline polymorph is a pharmaceutically acceptable salt of a compound having a structure:.

[0086] In a further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD)pattern that contains a peak at each of about 8.0 ± 0.2º 2θ, 12.0 ± 0.2º 2θ, 25.8 ± 0.2º 2θ, and about 26.7 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 7.8, 7.9, 8.0, 8.1, or 8.2º 2θ, and also at 11.8, 11.9, 12.0, 12.1, or 12.2º 2θ, and also at 25.6, 25.7, 25.8, 25.9, or 26.0º 2θ, and also at 26.5, 26.6, 26.7, 26.8, or 26.9º 2θ.

[0087] In various aspects, the agent is a chemotherapeutic agent. In a further aspect, thechemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a PARP inhibitor, and an mTOR inhibitor agent.

[0088] In various aspects, the antineoplastic antibiotic agent is selected from doxorubicin,mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

[0089] In various aspects, the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0090] In various aspects, the alkylating agent is selected from carboplatin, cisplatin,cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.Attorney Docket No.38373.0002P1

[0091] In various aspects, the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[0092] In various aspects, the PARP inhibitor is selected from olaparib, niraparib, and rucaparib.

[0093] In various aspects, the mTOR inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0094] In a further aspect, the compound and the agent are co-packaged.

[0095] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls. H. EXAMPLES

[0096] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods described and aspected herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions. 1. SYNTHESIS OF LMP744 POLYMORPH

[0097] The LMP744 polymorph was prepared according to the synthesis outlined in Scheme 1 below. See also Cushman et al. (2000) J. Med. Chem. 43: 3688-3698.Attorney Docket No.38373.0002P1Attorney Docket No.38373.0002P1 a. PREPARATION OF 6,7-DIMETHOXY-ISOCHROMAN-3-ONE (COMPOUND 2) Step-1Molecular Weight: 196.20 Molecular Weight: 208.21Compound 1 Compound 2

[0098] To a stirred solution of (3,4-Dimethoxy-phenyl)-acetic acid (3.0 kg, 15.29 mol) in acetic acid (11.0 L, 3.66 vol) at room temperature, formaldehyde (3.0 L, 81.41 mol) was added at 25 °C to 30 °C. The reaction mixture was stirred for 15 min at room temperature. To the reaction mixture was added a solution of H2SO4(3.1 L, 1.03 vol) in water (6.6 L, 2.2 vol) at 25 °C to 45 °C. During the addition of H2SO4, the temperature was raised up to 45 C. The reaction mixture was heated to 50 °C for 18 h. The progress of reaction was monitored by TLC using ethyl acetate in n-hexane (1:1). The reaction mixture was cooled to room temperature and then poured to ice:water (30.0 kg:30.0 L). The aqueous layer was extracted four times with dichloromethane (DCM) (4 x 30.0 L). The combined organic layer was washed with water (30.0 L), twice with aqueous sodium bi carbonate solution (2 x 25.0 L), and brine (30.0 L) and concentrated under vacuum at 45-50oC. Hot residue was suspended in n-heptane (15.0 L) and the suspension was cooled to 20 °C to 30 °C. The solid was collected by filtration and the wet solid was washed with n-heptane (3.0 L). The solid was then dried in vacuo at room temperature to furnish 6,7-dimethoxy-isochroman-3-one (Compound 2) (1.81 kg, 56.92%) as a white solid. b. PREPARATION OF 2-CARBOXYMETHYL-4,5-DIMETHOXY-BENZOIC ACID (COMPOUND 3)Molecular Weight: 208.21Molecular Weight: 240.21 Compound 2 Compound 3

[0099] 6,7- Dimethoxy-isochroman-3-one (Compound 2) (1.8 kg, 8.64 mol) was added to a stirred solution of KOH (776.9 kg, 13.8 mol) in DM water (9.1 L) at room temperature, followed by water (9.1 L). The reaction mixture was cooled to 0 °C-10 °C and KMnO4(2.53Attorney Docket No.38373.0002P1kg, 16.0 mol) was added slowly at 0 °C to 10 °C, and stirred at RT for 18 h. The progress ofthe reaction was monitored by TLC using 65 % ethyl acetate, 25 % IPA, and 10 % water. IPA (2.7 L) was added to the reaction mixture at room temperature and heated to 60 °C to 65 °C for 2.5 h. The hot reaction mixture was passed through a celite pad to remove MnO2.and the celite pad was washed with water (5.4 L). The filtrate was extracted twice with toluene (2 x 17.0 L) to remove impurities and the toluene layer was discarded. The aqueous layer was cooled to 0 °C to 10 °C and concentrated HCl (3.25 L) was added slowly to the reaction mixture at 0 °C to 10 °C. The reaction mixture was stirred at 0 °C to 10 °C for 1 to 2 h. The solid was collected by filtration, washed twice with water (2 x 10.0 L), and dried in vacuo at 50 °C to 55 °C to furnish 2-carboxymethyl-4,5-dimethoxy-benzoic acid (Compound 3) (1.485 kg, 71.53%) as a white solid. c. PREPARATION OF 6,7-DIMETHOXYISOCHROMANE-1,3-DIONE(COMPOUND 4)

[0100] A mixture of 2-carboxymethyl-4,5-dimethoxy-benzoic acid (Compound 3)(1.48 kg, 6.1 mol) in acetyl chloride (13.3 L, 9.0 vol) under nitrogen atmosphere was stirred at RT for 24 h. The reaction mixture was cooled to 0 °C under nitrogen atmosphere, then diluted with n-heptane (14.8 L, 10.0 vol). After stirring at 0 °-5 °C for 1 h, the solid was collected on a filter then washed with n-heptane (2 x 2 L). The solid was then dried under vacuum at 40 ° to 45 °C to furnish 6,7-dimethoxy-isochroman-1,3-dione (Compound 4) 1.1 kg (80.29 %) as a light yellow solid.Attorney Docket No.38373.0002P1 d. PREPARATION OF (E)-1-(BENZO[D][1,3]DIOXOL-5-YL)-N-(3-BROMOPROPYL)METHANIMINE (COMPOUND 6)

[0101] To a stirred solution of 3-bromo-1-propylamine hydrobromide (1176.0 g, 5.37mol) in DCM (4.7 L, 4.0 vol ) under nitrogen atmosphere, Et3N (1646.0 mL, 11.81 mol.) in DCM (1176.0 mL) was added over 30 min at 5 °C. After stirring for 1 h, piperonal (Compound 5) (645.0 gm, 4.29 mol) in DCM (2352 mL, 2.0 vol) was added, followed byaddition of MgSO4 (1411.0 g) below 5 °C. The reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was filtered through celite and washed by DCM (2 x 1200 mL). The combined filtrate was washed with water (2 x 2000.0 mL) and brine (1 x 3000 mL). The filtrate was dried over Na2SO4, filtered, and concentrated under vacuum to furnish benzo[1,3]dioxol-5-ylmethylene-(2-bromo-ethyl)-amine (Compound 6) (1145.0 g, 78.89%) as a red viscous liquid. e. PREPARATION OF CIS-3-(BENZO[D][1,3]DIOXOL-5-YL)-2-(3-BROMOPROPYL)-6,7-DIMETHOXY-1-OXO-1,2,3,4- TETRAHYDROISOQUINOLINE-4-CARBOXYLIC ACID (COMPOUND 7)

[0102] To a stirred solution of 6,7-dimethoxy-isochroman-1,3-dione (Compound 4)(900.0 g, 4.05 mol) in chloroform (9.0 L) (E)-5-(((3- bromopropyl)imino)methyl)benzo[d][1,3]dioxol-2-ylium was added (Compound 6) (1140.0 g, 4.22 mol) in CHCl3(4.5 L) over 20 min below 10 °C. The reaction mixture was stirred at room temperature for 2 h. The solid was collected by filtration and washed with DCM (2 xAttorney Docket No.38373.0002P1 2000 mL) and MTB ether (2 x 1000 mL). The solid was dried under vacuum at 40 °C to 45 °C to furnish cis-3-benzo[1,3]dioxol-5-yl-2-(3-bromo-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4- tetrahydro-isoquinoline-4-carboxylic acid (Compound 7) (1160.0 g, 58.17%) as a light yellow solid. f. PREPARATION OF 6-(3-BROMOPROPYL)-2,3-DIMETHOXY-5H-[1,3]DIOXOLO[4',5':5,6]INDENO[1,2-C]ISOQUINOLINE-5,12(6H)-DIONE (COMPOUND 8)

[0103] A stirred solution of 3-benzo[1,3]dioxol-5-yl-2-(3-bromo-propyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid (Compound 7) (1.2 Kg,2.43 mol) in SOCl2 (26.4 L, 22.0 vol) was stirred at room temperature for 4 h. The reactionmixture color changed from a yellow to a red suspension. Toluene (18.0 L, 15.0 vol) was added to reaction mixture at room temperature. The red suspension was concentrated under vacuum to remove the bulk of SOCl2 and co-distilled with toluene (3 x 15.0 L) below 45° C. Toluene (15.0 L) was added to the suspension, filtered through a Buckner funnel, washed with toluene (2 x 5.0 L), and dried under vacuum to furnish crude Compound 8 (wet, 0.9 kg) as a red solid.

[0104] The wet crude product (0.9 kg) from above was suspended in a mixture of hot(50 °C) CHCl3 / MeOH (24 L: 24 L) for 2.0 h and filtered in the hot condition and washed with a hot mixture of 50 °C CHCl3 / MeOH (16 L : 16 L) . The product was dried under vacuum to furnish (Compound 8) (wet 0.560 kg, 50.38%) as a red solid. g. PURIFICATION OF COMPOUND 8

[0105] Compound 8 (20.0 g) was suspended in a methanol and chloroform mixture(20.0 vol : 20.0 vol) at room temperature. The reaction mixture was heated to 50 °C and the reaction temperature was maintained at 50 °C for 2 h. The mixture was then filtered andAttorney Docket No.38373.0002P1 washed with a hot 50 °C methanol and chloroform mixture (20.0 vol :20.0 vol) to obtain pure compound 8 (15.4 g). 2. PREPARATION OF LMP744 POLYMORPH

[0106] 6-(3-Bromopropyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione (50.0 g, 105.86 mmol) was added to ethanol amine (1000.0 mL) at RT and the mixture was heated up to 85 °C. The reaction temperature was maintained at 85 ± 2 °C for 24 h. The reaction mixture was cooled to room temperature, and then chloroform (7.5 L) was added to the reaction mixture. The reaction mixture was washed with water (2 x 4.0 L) and concentrated under vacuum to obtain 6-(3-((2- hydroxyethyl)amino)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2- c]isoquinoline-5,12(6H)-dione (40.0 g, 83.51%) as a free base .

[0107] 6-(3-((2-Hydroxyethyl)amino)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione free base (40.0 g, 88.40 mmol) was added to ethanol (500.0 mL). A solution of 10 % ethanolic HCl (748.0 mL) was added slowly to the reaction mixture at room temperature. The reaction mixture was stirred for 2 h at room temperature, filtered, and the wet cake was washed with ethanol (1000.0 mL). The solid was dried in the oven at 50 ± 2 °C for 19 h to obtain 6-(3-((2- hydroxyethyl)amino)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione hydrochloride (LMP744) (32.0 g, 74.04 %) as a reddish brownsolid. A representative1H NMR spectrum obtained in DMSO-d6is shown in FIG.1. 3. POWDER X-RAY DIFFRACTION (XRD) PATTERNAttorney Docket No.38373.0002P1

[0108] Powder XRD patterns were collected on a PANalytical Empyreandiffractometer using a Cu K incident beam of radiation generated at 45 kV / 40 mA. Asilicon standard was analyzed to verify the observed position of the Si 111 peak is consistentwith the NIST-certified position. Powder samples were sandwiched between 3- m-thickEtnom films and analyzed in transmission geometry. The X-ray source was configured with Soller slits of 0.02 radians, a fixed anti-scatter slit of 1 / 2°, a mask of 10 mm, and a fixed divergence slit of 1 / 2°. The diffracted beam passed through a 3.0 mm anti-scatter extension and Soller slits of 0.02 radians to the detector. A beam-stop was used to minimize the background generated by air. Diffraction pattern was collected with Data Collector software using a PIXcel3D-Medipix3 detector located 240 mm from the specimen. The data wasacquired using one scan from 2-2-40 2 with the sample spinning at a revolution time of 2seconds.

[0109] The powder XRD pattern obtained for the crystalline polymorph is shown in FIG.2. The pattern shows predominantly broad peaks indicative of a crystalline material or possible mixtures thereof.

[0110] The observed peaks for the powder XRD pattern are shown below in Table 1. TABLE 1.Attorney Docket No.38373.0002P14. PARTICLE SIZE ANALYSIS

[0111] Particle size analysis was performed using a Malvern Panalytical Mastersizer 3000 using LASER Diffraction – Liquid Dispersion in a non-aqueous carrier and a Hydro MV accessory. The system default values were set as detailed in Table 2 below. TABLE 2.

[0112] The analysis settings were set according to Table 3. TABLE 3.Attorney Docket No.38373.0002P1

[0113] A plot showing the size distribution of the crystals is shown in FIG.3. The Dv(10), Dv(50), and Dv(90) were determined to be 1.51, 10.3, amd 37.6 μm, respectively. The full table of results is shown below in Table 4. TABLE 4.Attorney Docket No.38373.0002P1Attorney Docket No.38373.0002P1Attorney Docket No.38373.0002P1

[0114] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other aspects of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

Attorney Docket No.38373.0002P1 CLAIMS What is claimed is:

1. A crystalline polymorph of a pharmaceutically acceptable salt of a compound havinga structure:.

2. The crystalline polymorph of claim 1, wherein the crystalline polymorph has apowder X-ray diffraction (XRD) pattern that contains a peak at each of about 8.0 ± 0.2º 2θ, 12.0 ± 0.2º 2θ, 25.8 ± 0.2º 2θ, and about 26.7 ± 0.2º 2θ.

3. The crystalline polymorph of claim 2, wherein the powder XRD pattern furthercontains a peak at each of about 6.7 ± 0.2º 2θ and about 7.1 ± 0.2º 2θ.

4. The crystalline polymorph of claim 3, wherein the powder XRD pattern furthercontains two or more peaks at positions selected from about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ.

5. The crystalline polymorph of claim 3, wherein the powder XRD pattern furthercontains five or more peaks at positions selected from about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ.Attorney Docket No.38373.0002P1 6. The crystalline polymorph of claim 3, wherein the powder XRD pattern further contains ten or more peaks at positions selected from about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ.

7. The crystalline polymorph of claim 3, wherein the powder XRD pattern further contains fifteen or more peaks at positions selected from about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ.

8. The crystalline polymorph of claim 3, wherein the powder XRD pattern further contains a peak at each of about 4.0 ± 0.2º 2θ, about 8.3 ± 0.2º 2θ, about 10.4 ± 0.2º 2θ, about 12.3 ± 0.2º 2θ, about 12.5 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 14.4 ± 0.2º 2θ, about 15.8 ± 0.2º 2θ, about 16.0 ± 0.2º 2θ, about 16.6 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.7 ± 0.2º 2θ, about 19.3 ± 0.2º 2θ, about 20.8 ± 0.2º 2θ, about 21.7 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.1 ± 0.2º 2θ, about 23.7 ± 0.2º 2θ, and about 24.7 ± 0.2º 2θ.

9. The crystalline polymorph of claim 2, wherein the crystalline polymorph has an XRD pattern as shown in FIG.

1.

10. The crystalline polymorph of claim 1, wherein the pharmaceutically acceptable salt is selected from a halide salt, an acetate salt, an alginate salt, an ascorbate salt, a benzene sulfonate salt, a benzoate salt, a carbonate salt, a cinnamate salt, a citrate salt, a diphosphate salt, a fumarate salt, a gluconate salt, a lactate salt, a laurate salt, a malate salt, a maleate salt, a mesylate salt, a myristate salt, a nitrate salt, a palmitate salt, a perchlorate salt, a phenolate salt, a phosphate salt, a propionate salt, a sorbate salt, a succinate salt, a sulfate salt, and a tartrate salt.

11. The crystalline polymorph of claim 1, wherein the pharmaceutically acceptable salt is a halide salt.Attorney Docket No.38373.0002P1 12. The crystalline polymorph of claim 11, wherein the halide salt is a hydrochloride salt.

13. A pharmaceutical composition comprising an effective amount of the crystalline polymorph of claim 1 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13, wherein the effective amount is a pharmaceutically effective amount.

15. A method for modifying topoisomerase 1 (Top1) and / or MYC signaling in a subject, the method comprising the step of administering to the subject an effective amount of the crystalline polymorph of claim 1.

16. The method of claim 15, wherein modifying is decreasing.

17. The method of claim 15, wherein modifying is inhibiting.

18. The method of claim 15, wherein the subject has been diagnosed with a need for modifying Top1 and / or MYC signaling prior to the administering step.

19. The method of claim 15, wherein the subject has been diagnosed with a need for treatment of a disease or disorder associated with Top1 signaling dysfunction prior to the administering step.

20. The method of claim 19, further comprising the step of identifying a subject in need of treatment of a disease or disorder associated with Top1 and / or MYC signaling dysfunction.

21. The method of claim 15, wherein the subject has been diagnosed with cancer prior to the administering step.

22. A method for modifying topoisomerase 1 (Top1) and / or MYC signaling in at least one cell, the method comprising the step of contacting the cell with an effective amount of the crystalline polymorph of claim 1.

23. The method of claim 22, wherein modifying is decreasing.

24. The method of claim 22, wherein modifying is inhibiting.

25. The method of claim 22, wherein the cell is human.Attorney Docket No.38373.0002P1 26. The method of claim 25, wherein the cell has been isolated from a human prior to the administering step.

27. The method of claim 22, wherein contacting is via administration to a subject.

28. The method of claim 27, wherein the subject has been diagnosed with a need for modification of Top1 and / or MYC signaling prior to the administering step.

29. The method of claim 27, wherein the subject has been diagnosed with a need for treatment of a disease or disorder associated with Top1 and / or MYC signaling dysfunction.

30. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the crystalline polymorph of claim 1.

31. The method of claim 30, wherein the subject is a mammal.

32. The method of claim 31, wherein the mammal is a human.

33. The method of claim 30, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

34. The method of claim 30, further comprising the step of identifying a subject in need of treatment of cancer.

35. The method of claim 30, wherein the effective amount is a therapeutically effective amount.

36. The method of claim 30, wherein the effective amount is a prophylactically effective amount.

37. The method of claim 30, wherein the cancer is associated with dysregulation of Top1 and / or MYC activity.

38. The method of claim 30, wherein the cancer is associated with an increase in Top1 and / or MYC activity.

39. The method of claim 30, wherein the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cellAttorney Docket No.38373.0002P1 lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

40. The method of claim 30, wherein the cancer is a solid tumor or a lymphoma.

41. The method of claim 30, wherein the cancer is a glioma.

42. The method of claim 41, wherein the glioma is a malignant glioma.

43. The method of claim 30, wherein the cancer is leukemia.

44. The method of claim 30, wherein the cancer is a pediatric cancer.

45. The method of claim 44, wherein the pediatric cancer is a Ewing’s sarcoma or a solid tumor.

46. The method of claim 30, wherein the crystalline polymorph is administered at a dose of from about 6 mg / m2to about 190 mg / m2.

47. The method of claim 46, wherein the crystalline polymorph is administered once daily at a dose of from about 6 mg / m2to about 90 mg / m2.

48. The method of claim 46, wherein the crystalline polymorph is administered once daily at a dose of from about 6 mg / m2to about 190 mg / m2for a time period of from 1 to 5 days.

49. A kit comprising the crystalline polymorph of claim 1 and one or more selected from: (a) an agent associated with the treatment of cancer; (b) instructions for administering the crystalline polymorph in connection with treating cancer; and (c) instructions for treating cancer.

50. The kit of claim 49, wherein the agent is a chemotherapeutic agent.Attorney Docket No.38373.0002P1 51. The kit of claim 50, wherein the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a PARP inhibitor, and an mTOR inhibitor agent.

52. The kit of claim 51, wherein the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

53. The kit of claim 51, wherein the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

54. The kit of claim 51, wherein the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

55. The kit of claim 51, wherein the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

56. The kit of claim 51, wherein the PARP inhibitor is selected from olaparib, niraparib, and rucaparib.

57. The kit of claim 51, wherein the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

58. The kit of claim 49, wherein the compound and the agent are co-packaged.

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