Methods of treating astrocytoma

Abstract

Described herein are compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for the treatment of conditions, diseases, or disorders, e.g., WHO 2021 grade 3 astrocytoma.

Description

WSGR Docket No.57339-709601 METHODS OF TREATING ASTROCYTOMA CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Application No.18 / 977,389, filed December11, 2024, and U.S. Provisional Application No.63 / 691,306, filed September 5, 2024, each of which is incorporated herein by reference. FIELD

[0002] Described herein are compounds, pharmaceutical compositions and medicamentscomprising such compounds, and methods of using such compounds for the treatment of conditions, diseases, or disorders that are characterized by certain genetic profiles, e.g., mutant IDH, no homozygous deletion of CDKN2A / B, etc. BACKGROUND

[0003] Cancer treatment is associated with multiple complex challenges, including lack ofefficacy and severe toxicities often experienced by patients. For example, gliomas, such as astrocytomas, are exceedingly difficult to treat, and patients have extremely low survival rates with very short life expectancies. In 2021, World Health Organization (WHO) re-reclassified gliomas based on the genetic profile of these malignancies. Specifically, grade 3 astrocytoma is characterized by IDH (e.g., IDH1, IDH2) mutation in combination with no homozygous deletion of CDKN2A / B. Most astrocytomas respond to cytotoxic chemotherapy to a variable extent. However, since chemotherapy agents vary in their ability to cross normal cerebral vasculature (blood-brain-barrier) as well as tumor capillary beds (blood-tumor barrier), many drugs tested over the years have failed to produce meaningful antitumor efficacy, because they were unable to reach invading tumor cells in sufficient dose and for sufficient time. Surgical intervention is rarely a viable interventional strategy on its own, as rapid growth into surrounding normal brain tissue can complicate surgical access; recurrence is high in cases where tumor removal is incomplete. The addition of radiation therapy has provided some improvement in survival outcomes following surgery but is infrequently curative. Combination chemotherapies have likewise shown modest to poor therapeutic effect thus far. A wide range of chemotherapeutic agents and combinations of chemotherapeutic agents have been employed with or without additional treatment (e.g., surgical intervention); however, no treatment regimen or strategy has succeeded in extending lifespan of subjects having advanced gliomas (e.g., grade 3 astrocytoma) beyond the modest benefits of treatments developed fourWSGR Docket No.57339-709601 decades ago. Worse even, to date, there is no approved nonsurgical treatment available for patients who have recurrent astrocytoma after receiving prior treatment, e.g., external beam radiation therapy (EBRT) and an adjuvant temozolomide regimen. There is an unmet need for new treatment strategies. SUMMARY

[0004] Among other things, the present disclosure provides an insight that effectiveness ofcancer treatment depends on the ability to select a patient population that has the best chance to respond to treatment with a particular anticancer agent. Genetic characterization of tumors based on biomarker research enables patient selection.

[0005] In one aspect, the present disclosure provides a method of treating cancer, comprisingadministering to a subject an ornithine decarboxylase inhibitor.

[0006] In one aspect, the present disclosure provides a method of treating cancer, comprisingadministering to a subject an ornithine decarboxylase inhibitor and a second therapeutic agent or treatment including a chemotherapeutic agent, an immunotherapy agent, or radiation therapy.

[0007] In one aspect, the present disclosure provides a method of treating cancer, comprisingadministering to a subject an ornithine decarboxylase inhibitor and a chemotherapeutic agent.

[0008] In one aspect, the present disclosure provides a method of treating cancer, comprisingadministering to a subject an ornithine decarboxylase inhibitor and an alkylating agent.

[0009] In one aspect, the present disclosure provides a method of treating cancer, comprisingadministering to a subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0010] In one aspect, the present disclosure provides a method of treating cancer,comprising administering to a subject eflornithine or a salt thereof and lomustine.

[0011] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0012] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH1 and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0013] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH2 and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.WSGR Docket No.57339-709601

[0014] In another aspect, the present disclosure provides a method of treating a cancercharacterized by mutant IDH (e,g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to a subject eflornithine or a salt thereof and lomustine.

[0015] In another aspect, the present disclosure provides a method of treating a cancercharacterized by mutant IDH1 and no homozygous deletion of CDKN2A / B genes, comprising administering to a subject eflornithine or a salt thereof and lomustine.

[0016] In another aspect, the present disclosure provides a method of treating a cancercharacterized by mutant IDH2 and no homozygous deletion of CDKN2A / B genes, comprising administering to a subject eflornithine or a salt thereof and lomustine.

[0017] In another aspect, the present disclosure provides a method of treating cancer ina subject with no homozygous deletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

[0018] In another aspect, the present disclosure provides a method of treating cancer ina subject with intact CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

[0019] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

[0020] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH1 and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

[0021] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH2 and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

[0022] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

[0023] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH1 and intact CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

[0024] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH2 and intact CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.WSGR Docket No.57339-709601

[0025] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0026] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH1 and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0027] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH2 and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0028] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0029] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH1 and intact CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0030] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH2 and intact CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0031] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with no homozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

[0032] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with intact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

[0033] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

[0034] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH1 and no homozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.WSGR Docket No.57339-709601

[0035] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH2 and no homozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

[0036] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

[0037] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH1 and intact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

[0038] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH2 and intact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

[0039] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0040] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH1 and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0041] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH2 and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0042] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0043] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH1 and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

[0044] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH2 and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.WSGR Docket No.57339-709601

[0045] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (2) selecting a subject who has no homozygous deletion of CDKN2A / B genes; and (3) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof.

[0046] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant and has no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and a chemotherapeutic agent, e.g., lomustine.

[0047] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) evaluating IDH1 genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH1 mutant and has no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and a chemotherapeutic agent, e.g., lomustine.

[0048] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) evaluating IDH2 genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH2 mutant and has no homozygous deletion of CDKN2A / B genes; andWSGR Docket No.57339-709601 (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and a chemotherapeutic agent, e.g., lomustine.

[0049] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) preparing an oral solution of eflornithine or a salt thereof comprising: adding the contents of a pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, wherein the pouch comprises: an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate; and (2) administering to a subject with the cancer characterized by mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes the oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate, and a chemotherapeutic agent, e.g., lomustine.

[0050] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) preparing an oral solution of eflornithine or a salt thereof comprising: adding the contents of a pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, wherein the pouch comprises: an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate; and (2) administering to a subject with the cancer characterized by mutant IDH1 and no homozygous deletion of CDKN2A / B genes the oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate, and a chemotherapeutic agent, e.g., lomustine.WSGR Docket No.57339-709601

[0051] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) preparing an oral solution of eflornithine or a salt thereof comprising: adding the contents of a pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, wherein the pouch comprises: an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate; and (2) administering to a subject with the cancer characterized by mutant IDH2 and no homozygous deletion of CDKN2A / B genes the oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate, and a chemotherapeutic agent, e.g., lomustine.

[0052] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes compared to a cancer subject having mutant IDH1 and homozygous deletion of CDKN2A / B genes.

[0053] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH1 and no homozygous deletion of CDKN2A / B genes compared to a cancer subject having mutant IDH1 and homozygous deletion of CDKN2A / B genes.

[0054] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH2 and no homozygous deletion of CDKN2A / B genes compared to a cancer subject having mutant IDH2 and homozygous deletion of CDKN2A / B genes.

[0055] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes compared to a cancer subject having mutant IDH (e.g., IDH1, IDH2) and homozygous deletion of CDKN2A / B genes.

[0056] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH1 and intact CDKN2A / BWSGR Docket No.57339-709601 genes compared to a cancer subject having mutant IDH1 and homozygous deletion of CDKN2A / B genes.

[0057] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH2 and intact CDKN2A / B genes compared to a cancer subject having mutant IDH2 and homozygous deletion of CDKN2A / B genes.

[0058] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes compared to a cancer subject having mutant IDH (e.g., IDH1, IDH2) and homozygous deletion of CDKN2A / B genes.

[0059] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH1 and no homozygous deletion of CDKN2A / B genes compared to a cancer subject having mutant IDH1 and homozygous deletion of CDKN2A / B genes.

[0060] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH2 and no homozygous deletion of CDKN2A / B genes compared to a cancer subject having mutant IDH2 and homozygous deletion of CDKN2A / B genes.

[0061] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes compared to a cancer subject having mutant IDH (e.g., IDH1, IDH2) and homozygous deletion of CDKN2A / B genes.

[0062] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH1 and intact CDKN2A / B genes compared to a cancer subject having mutant IDH1 and homozygous deletion of CDKN2A / B genes.

[0063] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH2 and intact CDKN2A / B genes compared to a cancer subject having mutant IDH2 and homozygous deletion of CDKN2A / B genes.

[0064] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) gene compared to a cancer subject having wildtype IDH (e.g., IDH1, IDH2) gene.WSGR Docket No.57339-709601

[0065] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH1 gene compared to a cancer subject having wildtype IDH1 gene.

[0066] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH2 gene compared to a cancer subject having wildtype IDH2 gene.

[0067] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) gene compared to a cancer subject having wildtype IDH (e.g., IDH1, IDH2) gene.

[0068] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH1 gene compared to a cancer subject having wildtype IDH1 gene.

[0069] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH2 gene compared to a cancer subject having wildtype IDH2 gene.

[0070] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine. In some embodiments, the present disclosure provides a method of treating cancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine.

[0071] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH1 and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine. In some embodiments, the present disclosure provides a method of treating cancer, comprising selecting a subject with mutant IDH1 and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine.

[0072] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH2 and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine. In some embodiments, the present disclosure provides a method of treating cancer, comprising selecting a subject with mutant IDH2 and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine.WSGR Docket No.57339-709601 INCORPORATION BY REFERENCE

[0073] All publications, patents, and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] The novel features of the disclosure are set forth with particularity in theappended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:

[0075] FIG. 1A and FIG. 1B show clinical pharmacokinetic data following oraladministration of eflornithine (n=6; doses 2.3 and 2.8 g / m2). FIG.1A and FIG.1B show plasma concentrations for D- and L-eflornithine on Days 1 and 14, respectively.

[0076] FIG. 2 shows overall survival (OS) results for all intension-to-treat (ITT)patients with further summary statistics in Table 5.

[0077] FIG. 3 shows progression free survival (PFS) results for all intension -to-treat(ITT) patients with further summary statistics in Table 6.

[0078] FIG. 4 shows overall survival (OS) results for patients with mutant IDH (IDH1or IDH2) and intact CDKN2A / B genes with further summary statistics in Table 9.

[0079] FIG. 5 shows progression free survival (PFS) results for patients with mutantIDH (IDH1 or IDH2) mutant and intact CDKN2A / B genes with further summary statistics in Table 10.

[0080] FIG. 6 shows overall survival (OS) results for patients with mutant IDH (IDH1or IDH2), intact CDKN2A / B and intact ATRX with further summary statistics in Table 11.

[0081] FIG. 7 shows progression free survival (PFS) results for patients with mutantIDH (IDH1 or IDH2), intact CDKN2A / B and intact ATRX with further summary statistics in Table 12. DETAILED DESCRIPTION DefinitionsWSGR Docket No.57339-709601

[0082] Unless defined otherwise, all technical and scientific terms used herein have thesame meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0083] In this application, the use of “or” means “and / or” unless stated otherwise. Theterms “and / or” and “any combination thereof” and their grammatical equivalents as used herein, can be used interchangeably. These terms can convey that any combination is specifically contemplated. Solely for illustrative purposes, the following phrases “A, B, and / or C” or “A, B, C, or any combination thereof” can mean “A individually; B individually; C individually; A and B; B and C; A and C; and A, B, and C.” The term “or” can be used conjunctively or disjunctively, unless the context specifically refers to a disjunctive use.

[0084] As used in this specification and claim(s), the words “comprising” (and anyform of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.

[0085] The term “about” or “approximately” can mean within an acceptable error rangefor the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. In some embodiments, “about” refers to a range of up to 10% of a given value. In some embodiments, “about” refers to a range of up to 5% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.

[0086] Reference in the specification to “some embodiments,” “an embodiment,”“certain embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosure.

[0087] The term “acceptable” with respect to a formulation, composition or ingredient,as used herein, means having no persistent detrimental effect on the general health of the subject being treated.WSGR Docket No.57339-709601

[0088] The term “modulate” as used herein, means to interact with a target eitherdirectly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. In some embodiments, “modulate” means to interact with a target either directly or indirectly so as to decrease or inhibit receptor activity. In some embodiments. modulation is an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., a positive allosteric modulator) of a G protein-coupled receptor (e.g., 5HT2A) are modulators of the receptor.

[0089] The term “modulator” as used herein, refers to a molecule that interacts with atarget either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, or combinations thereof. In some embodiments, a modulator is an antagonist. Receptor antagonists are inhibitors of receptor activity. Antagonists mimic ligands that bind to a receptor and prevent receptor activation by a natural ligand. Preventing activation may have many effects. If a natural agonist binding to a receptor leads to an increase in cellular function, an antagonist that binds and blocks this receptor decreases the function of the receptor.

[0090] The term “agonism,” as used herein, generally refers to the activation of areceptor or enzyme by a modulator, or agonist, to produce a biological response.

[0091] The term “agonist,” as used herein, generally refers to a modulator that binds toa receptor or enzyme and activates the receptor to produce a biological response. By way of example only, a “5HT2A agonist” can be used to refer to a compound that exhibits an EC50 with respect to 5HT2A activity of no more than about 100 μM. In some embodiments, the term “agonist” includes full agonists or partial agonists. “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor. “Partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.

[0092] The term “antagonism,” as used herein, generally refers to the inactivation of areceptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and blocks function of the receptor.

[0093] The term “antagonist” or “neutral antagonist,” as used herein, generally refersto a modulator that binds to a receptor or enzyme and blocks a biological response. AnWSGR Docket No.57339-709601 antagonist may have no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.

[0094] The terms “administer,” “administering,” “administration,” and the like, as usedherein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0095] The terms “effective amount” or “therapeutically effective amount,” as usedherein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0096] The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing- effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0097] The term “subject,” “individual,” or “patient” encompasses mammals.Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.

[0098] The terms “treat,” “treating,” or “treatment,” as used herein, include alleviating,abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease orWSGR Docket No.57339-709601 condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0099] The term “pharmaceutically acceptable,” as used herein, generally refers amaterial, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.[000100] A “pharmaceutically acceptable salt” suitable for the disclosure may be an acidor base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethyl sulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize from this disclosure and the knowledge in the art that further pharmaceutically acceptable salts include those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985). In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in an appropriate solvent. As used herein, In some embodiments, a salt is a pharmaceutically acceptable salt.[000101] The phrase “pharmaceutically acceptable excipient” or “pharmaceuticallyacceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serveWSGR Docket No.57339-709601 as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.[000102] Ranges provided herein are understood to be shorthand for all of the valueswithin the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.[000103] As used herein, the term “Adverse Event” (AE), is any untoward medicaloccurrence in a clinical study patient administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and / or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs may also include pre- or post-treatment complications that occur as a result of protocol specified procedures, lack of efficacy, overdose, drug abuse / misuse reports, or occupational exposure. Preexisting events that increase in severity or change in nature during or as a consequence of participation in the clinical study will also be considered AEs. An AE does not include the following: (1) Medical or surgical procedures such as non-CNS tumor surgery, endoscopy, tooth extraction, and transfusion. The condition that led to the procedure may be an adverse event and must be reported; (2) Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the screening visit that do not worsen; (3) Situations where anWSGR Docket No.57339-709601 untoward medical occurrence has not occurred (e.g., hospitalization for elective surgery, social and / or convenience admissions); (4) Overdose without clinical sequelae; or (5) Any medical condition or clinically significant laboratory abnormality with an onset date before the consent form is signed and not related to a protocol-associated procedure is not an AE. It is considered to be pre-existing and should be documented on the medical history eCRF. The severity of AEs will be graded using the CTCAE, Version 4.03. If a CTCAE criterion does not exist, the Investigator will use the grade or adjectives: grade 1 (Mild), grade 2 (Moderate), grade 3 (Severe), grade 4 (Life-threatening), or grade 5 (Fatal) to describe the maximum intensity of the adverse event.[000104] As used herein, the term “Serious Adverse Event” (SAE), is defined as an eventthat, at any dose, results in the following: (1) Death; (2) Life-threatening (Note: The term “life- threatening” in the definition of “serious” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.); (3) In-patient hospitalization or prolongation of existing hospitalization; (4) Persistent or significant disability / incapacity; (5) A congenital anomaly / birth defect; or (6) A medically important event or reaction: such events may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes constituting SAEs. Medical and scientific judgment must be exercised to determine whether such an event is a reportable under expedited reporting rules. Examples of medically important events include intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; and development of drug dependency or drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal product will be considered a medically important event and subject to expedited reporting requirements. Therapeutic Applications CDKN2A / B and IDH (e.g., IDH1, IDH2) genes[000105] Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) and Cyclin DependentKinase Inhibitor 2B (CDKN2B) genes reside on the short arm of chromosome 9 and are commonly expressed in many tissues and cell types. CDKN2A / B encode multiple proteins which are critical in cell-cycle regulation. The deletion of either CDKN2A / B or mutation of either CDKN2A / B is associated with various cancers, e.g., gliomas. The deletions of CDKN2A / B can occur in either a homozygous or heterozygous manner. Homozygous deletions refer to the loss of both copies of a gene (i.e., both alleles) in a cell. HeterozygousWSGR Docket No.57339-709601 deletions refer to the loss of a single copy of a gene (i.e., one allele) while the other copy remains intact in a cell. Typically, homozygous deletions lead to complete loss of function, whereas heterozygous deletions lead to partial loss of function.[000106] Isocitrate Dehydrogenase 1 (IDH1) gene is one of three isocitratedehydrogenase isozymes (the other being IDH2 and IDH3). IDH1 encodes an enzyme that catalyzes the reversible oxidative decarboxylation of isocitrate as part of the citric acid cycle where the enzyme generates an oncometabolite (i.e., 2-hydroxyglutarate) that affects cellular metabolism and redox homeostasis.[000107] Isocitrate Dehydrogenase 2 (IDH2) gene provides instructions for making anenzyme called isocitrate dehydrogenase 2. This enzyme is found in mitochondria, which are the energy-producing centers within cells. Within mitochondria, the enzyme participates in reactions that produce energy for cell activities. Specifically, isocitrate dehydrogenase 2 normally converts isocitrate to 2-ketoglutarate. A series of additional enzymes further process 2-ketoglutarate to produce energy. The conversion reaction also produces NADPH, which is necessary for many cellular processes and helps protect cells from potentially harmful molecules called reactive oxygen species. In some embodiments, a mutant IDH is a mutant IDH1. In some embodiments, a mutant IDH is a mutant IDH2.[000108] In some embodiments, a subject as described herein comprises mutant IDH (e.g.,IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes. In some embodiments, a subject as described herein comprises mutant IDH1 and no homozygous deletion of CDKN2A / B genes. In some embodiments, a subject as described herein comprises mutant IDH2 and no homozygous deletion of CDKN2A / B genes. In some embodiments, a subject as described herein comprises mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes. In some embodiments, a subject as described herein comprises mutant IDH1 and intact CDKN2A / B genes. In some embodiments, a subject as described herein comprises mutant IDH2 and intact CDKN2A / B genes. In some embodiments, a subject as described herein comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, and intact ATRX genes. In some embodiments, a subject as described herein comprises mutant IDH1, no homozygous deletion of CDKN2A / B, and intact ATRX genes. In some embodiments, a subject as described herein comprises mutant IDH2, no homozygous deletion of CDKN2A / B, and intact ATRX genes. In some embodiments, a subject as described herein comprises mutant IDH (e.g., IDH1, IDH2), intact CDKN2A / B, and intact ATRX genes. In some embodiments, a subject as described herein comprises mutant IDH1, intact CDKN2A / B, and intact ATRXWSGR Docket No.57339-709601 genes. In some embodiments, a subject as described herein comprises mutant IDH2, intact CDKN2A / B, and intact ATRX genes.[000109] Among other things, the present disclosure provides an insight that a populationof cancer subjects with no homozygous deletion of CDKN2A / B genes responds more favorably to a cancer treatment compared to a population with homozygous deletion of CDKN2A / B. Among other things, the present disclosure provides an insight that a population of cancer subjects with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes responds more favorably to a cancer treatment compared to a population with homozygous deletion of CDKN2A / B and / or IDH (e.g., IDH1, IDH2) wild type. In some embodiments, the present disclosure encompasses a finding that a cancer subject with certain genetic profiles as described herein (e.g., mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX, etc., or combinations thereof) responds more favorably to an ornithine decarboxylase inhibitor than a cancer subject with, e.g., one or more of the following: wild type IDH (e.g., IDH1, IDH2), homozygous deletion of CDKN2A / B and mutant ATRX. In some embodiments, an ornithine decarboxylase inhibitor is eflornithine or a salt thereof. In some embodiments, a more favorable response is demonstrated by an improved overall survival (OS). In some embodiments, a more favorable response is demonstrated by an improved progression free survival (PFS).[000110] In one aspect, the present disclosure provides a method of treating cancer in asubject with no homozygous deletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor. In one aspect, the present disclosure provides a method of treating cancer in a subject with intact CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor. In one aspect, the present disclosure provides a method of treating cancer in a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor. In one aspect, the present disclosure provides a method of treating cancer in a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor. In some embodiments, a provided method further comprises administering a second therapeutic agent or treatment including, e.g., a chemotherapeutic agent, an immunotherapy agent, or radiation therapy, or a combination thereof. In some embodiments, the second therapeutic agent is a chemotherapeutic agent. In some embodiments, chemotherapeutic agent is selected from an alkylating agent. In some embodiments, alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine,WSGR Docket No.57339-709601 fotemustine, ifosfamide, lomustine, mechlorethamine, melphalan, nimustine, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, streptozocin or uramustine, or a salt thereof where applicable. In some embodiments, alkylating agent is lomustine, carmustine, or semustine. In some embodiments, alkylating agent is altretamine. In some embodiments, alkylating agent is bendamustine. In some embodiments, alkylating agent is busulfan. In some embodiments, alkylating agent is carboplatin. In some embodiments, alkylating agent is carmustine. In some embodiments, alkylating agent is chlorambucil. In some embodiments, alkylating agent is cisplatin. In some embodiments, alkylating agent is cyclophosphamide. In some embodiments, alkylating agent is dacarbazine. In some embodiments, alkylating agent is fotemustine. In some embodiments, alkylating agent is ifosfamide. In some embodiments, alkylating agent is lomustine. In some embodiments, alkylating agent is mechlorethamine. In some embodiments, alkylating agent is melphalan. In some embodiments, alkylating agent is nimustine. In some embodiments, alkylating agent is oxaliplatin. In some embodiments, alkylating agent is procarbazine. In some embodiments, alkylating agent is temozolomide. In some embodiments, alkylating agent is thiotepa. In some embodiments, alkylating agent is trabectedin. In some embodiments, alkylating agent is streptozocin. In some embodiments, alkylating agent is uramustine. In some embodiments, the second therapeutic agent is immunotherapy agent. In some embodiments, a provided method further comprises radiation therapy.[000111] In one aspect, the present disclosure provides a method of treating cancer in asubject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.[000112] In another aspect, the present disclosure provides a method of treating a cancercharacterized by mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to a subject eflornithine or a salt thereof and lomustine.[000113] In another aspect, the present disclosure provides a method of treating cancer ina subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.[000114] In one aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with no homozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor. In one aspect, the present disclosure provides method of treating cancer, comprising selecting a subject with intact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor. InWSGR Docket No.57339-709601 one aspect, the present disclosure provides a method of treating cancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor. In one aspect, the present disclosure provides a method of treating cancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor. In some embodiments, a provided method further comprises administering a second therapeutic agent or treatment including a chemotherapeutic agent, an immunotherapy agent, or radiation therapy, or a combination thereof. In some embodiments, the second therapeutic agent is a chemotherapeutic agent. In some embodiments, chemotherapeutic agent is selected from an alkylating agent. In some embodiments, alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, mechlorethamine, melphalan, nimustine, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, streptozocin or uramustine. In some embodiments, alkylating agent is lomustine, carmustine, or semustine, or a salt thereof where applicable. In some embodiments, alkylating agent is altretamine. In some embodiments, alkylating agent is bendamustine. In some embodiments, alkylating agent is busulfan. In some embodiments, alkylating agent is carboplatin. In some embodiments, alkylating agent is carmustine. In some embodiments, alkylating agent is chlorambucil. In some embodiments, alkylating agent is cisplatin. In some embodiments, alkylating agent is cyclophosphamide. In some embodiments, alkylating agent is dacarbazine. In some embodiments, alkylating agent is fotemustine. In some embodiments, alkylating agent is ifosfamide. In some embodiments, alkylating agent is lomustine. In some embodiments, alkylating agent is mechlorethamine. In some embodiments, alkylating agent is melphalan. In some embodiments, alkylating agent is nimustine. In some embodiments, alkylating agent is oxaliplatin. In some embodiments, alkylating agent is procarbazine. In some embodiments, alkylating agent is temozolomide. In some embodiments, alkylating agent is thiotepa. In some embodiments, alkylating agent is trabectedin. In some embodiments, alkylating agent is streptozocin. In some embodiments, alkylating agent is uramustine. In some embodiments, the second therapeutic agent is immunotherapy agent. In some embodiments, a provided method further comprises radiation therapy.[000115] Immunotherapy agents are known in the art and as appreciated by those skilledin the art, various immunotherapy agents can be used in accordance with the present disclosure. In some embodiments, an immunotherapy agent includes the following: (1) IL-15 (T-cell growth factor); (2) Anti-Programmed Death-1 (PD1) and / or anti-B7-H1 (PD1 ligand) (T-cellWSGR Docket No.57339-709601 checkpoint blockade inhibitor); (3) IL-12 (vaccine adjuvant); (4) CD40 and / or CD40L (antigen presenting cell stimulator); (5) IL-7 (T-cell growth factor); (6) CpG (vaccine adjuvant); (7) 1- methyltryptophan (enzyme inhibitor); (8) Anti-CD137 (anti-4-1BB) (T-cell stimulator); (9) Anti-TGF-I3 (signaling inhibitor); (10) Anti-IL-10 Receptor or Anti-IL10 (suppression inhibitor; IL-10 is a suppressor cytokine); (11) Flt3L (dendritic cell growth factor / vaccine adjuvant); (12) Anti-Glucocorticoid-Induced TNF Receptor (GITR) (T-cell stimulator); (13) CCL21 Adenovirus (T-cell attracting chemokine); (14) Monophosphoryl Lipid A (MPL) (vaccine adjuvant); (15) Poly I:C and / or Poly ICLC (vaccine adjuvant); (16) Anti-0X40 (T-cell stimulator); (17) Anti-B7-H4 (T-cell checkpoint blockade inhibitor); (18) Resiquimod and / or 852A (vaccine adjuvant) (19) LIGHT and / or LIGHT vector (T-cell stimulator); (20) Anti- Lymphocyte Activation Gene-3 (LAG-3) (T-cell checkpoint blockade inhibitor); (21) Anti- CTLA4 (T-cell checkpoint blockade inhibitor).[000116] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.[000117] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.[000118] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (2) selecting a subject who has no homozygous deletion of CDKN2A / B genes; and (3) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof.[000119] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (2) selecting a subject who has no homozygous deletion of CDKN2A / B genes; and (3) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and a chemotherapeutic agent, e.g., lomustine.WSGR Docket No.57339-709601[000120] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant and has no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof.[000121] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant and has no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and a chemotherapeutic agent, e.g., lomustine.[000122] In another aspect, the present disclosure provides a method of treating cancer,comprising: (1) preparing an oral solution of eflornithine or a salt thereof comprising: adding the contents of a pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, wherein the pouch comprises: an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate; and (2) administering to a subject with the cancer characterized by mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes the oral solutionWSGR Docket No.57339-709601 of eflornithine, e.g., eflornithine hydrochloride hydrate and a chemotherapeutic agent, e.g., lomustine.[000123] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes compared to a cancer subject having mutant IDH (e.g., IDH1, IDH2) and homozygous deletion of CDKN2A / B genes.[000124] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes compared to a cancer subject having mutant IDH (e.g., IDH1, IDH2) and homozygous deletion of CDKN2A / B genes.[000125] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes compared to a cancer subject having mutant IDH (e.g., IDH1, IDH2) and homozygous deletion of CDKN2A / B genes.[000126] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes compared to a cancer subject having mutant IDH (e.g., IDH1, IDH2) and homozygous deletion of CDKN2A / B genes.[000127] In another aspect, the present disclosure provides a method that providesimproved overall survival (OS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) gene compared to a cancer subject having wildtype IDH (e.g., IDH1, IDH2) gene.[000128] In another aspect, the present disclosure provides a method that providesimproved progression free survival (PFS) in a cancer subject having mutant IDH (e.g., IDH1, IDH2) gene compared to a cancer subject having wildtype IDH (e.g., IDH1, IDH2) gene.[000129] In another aspect, the present disclosure provides a method of treating cancer,comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine. In some embodiments, the present disclosure provides a method of treating cancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine.[000130] Among other things, the present disclosure provides various methods of treatingcancers, e.g., those described above. As used herein, a provided method is referred to as a “Method of the Disclosure.”WSGR Docket No.57339-709601[000131] Among other things, the present disclosure provides a method of treating cancercharacterized by certain genetic profiles as described herein. In some embodiments, the present disclosure encompasses an insight that methods of treating cancers described herein provide improved treatment outcome in subject populations with certain genetic profiles compared to subject populations without such genetic profiles. In some embodiments, treatment outcome is improved in subject populations with certain IDH (e.g., IDH1, IDH2) and / or CDKN2A / B profiles. In some embodiments, treatment outcome is improved in subject populations with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes. In some embodiments, treatment outcome is improved in subject populations with mutant IDH (e.g., IDH1, IDH2) and no mutation of CDKN2A / B genes. In some embodiments, a cancer is a brain cancer. In some embodiments, a cancer is glioma. In some embodiments, a cancer is astrocytoma. In some embodiments, improvement of treatment outcome is statistically significant.[000132] In some embodiments, for a Method of the Disclosure, the subject has mutantIDH (e.g., IDH1, IDH2) gene. In some embodiments, for a Method of the Disclosure, the subject has mutant IDH1 gene. In some embodiments, for a Method of the Disclosure, the subject has mutant IDH2 gene. In some embodiments, a subject has wildtype IDH (e.g., IDH1, IDH2) gene. In some embodiments, a subject has wildtype IDH1 gene. In some embodiments, a subject has wildtype IDH2 gene.[000133] In some embodiments, for a Method of the Disclosure, the subject has intactCDKN2A / B genes. In some embodiments, the subject has heterozygous deletion of CDKN2A / B genes. In some embodiments, the subject has no homozygous deletion of CDKN2A / B genes. In some embodiments, the subject has intact CDKN2A gene. In some embodiments, the subject has heterozygous deletion of CDKN2A gene. In some embodiments, the subject has no homozygous deletion of CDKN2A gene. In some embodiments, the subject has intact CDKN2B gene. In some embodiments, the subject has heterozygous deletion of CDKN2B gene. In some embodiments, the subject has no homozygous deletion of CDKN2B gene.[000134] In some embodiments, for a Method of the Disclosure, the subject has mutantIDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2A / B genes. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A gene. In some embodiments, the subject has mutantWSGR Docket No.57339-709601 IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2A gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2B gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2B gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2) and intact CDKN2B gene.[000135] In some embodiments, for a Method of the Disclosure, the subject has wildtypeIDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2A / B genes. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2A gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2) and intact CDKN2A gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2B gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2B gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2) and intact CDKN2B gene.[000136] In some embodiments, a mutant IDH1 gene comprises a mutation at R132X orR100Q codon of the IDH1 gene. In some embodiments, a mutation in the IDH1 gene results in the replacement of arginine residue at site 132 with histidine (H), lysine (K) or cysteine (C). As used herein, a mutation in the IDH1 gene which results in the replacement of arginine residue with another amino acid is referred to as “a mutation at R132.” In some embodiments, a mutant IDH1 gene comprises a base pair exchange of guanine to adenine (G395A), resulting in an arginine to histidine mutation at site 132 (R132H).[000137] In some embodiments, a mutant IDH2 gene comprises a mutation at R140X orR172X of IDH2 gene.[000138] In some embodiments, for a Method of the Disclosure, the evaluation of IDH(e.g., IDH1, IDH2) genetic profiles comprises determining the presence of a mutation in the IDH (e.g., IDH1, IDH2). In some embodiments, the evaluation of IDH (e.g., IDH1, IDH2) genetic profiles comprises determining the presence of a mutation in the IDH (e.g., IDH1, IDH2) gene by examining tumor tissue. In some embodiments, the evaluation of IDH (e.g., IDH1, IDH2) genetic profiles comprises determining the presence of a mutation in the IDH (e.g., IDH1, IDH2) gene by examining stained tumor tissue on a microscope slide usingWSGR Docket No.57339-709601 immunohistochemistry (IHC) technique or gene sequencing, or other methods known in the art. In some embodiments, the evaluation of IDH (e.g., IDH1, IDH2) genetic profiles comprises determining the presence of a mutation in the IDH (e.g., IDH1, IDH2) gene by examining stained tumor tissue on a microscope slide using immunohistochemistry (IHC) technique. In some embodiments, the evaluation of IDH (e.g., IDH1, IDH2) genetic profiles comprises determining the presence of a mutation in the IDH (e.g., IDH1, IDH2) gene by using gene sequencing. In some embodiments, the evaluation of IDH (e.g., IDH1, IDH2) genetic profiles comprises determining the presence of a mutation at R132 in the IDH1 gene by examining stained tumor tissue on a microscope slide using immunohistochemistry (IHC) technique or gene sequencing. In some embodiments, the evaluation of IDH1 genetic profiles comprises determining the presence of a mutation at R132 in the IDH1 gene by examining stained tumor tissue on a microscope slide using immunohistochemistry (IHC) technique. In some embodiments, the evaluation of IDH1 genetic profiles comprises determining the presence of a mutation at R132 in the IDH1 gene by using gene sequencing. In some embodiments, the gene sequencing is PCR.[000139] In some embodiments, for a Method of the Disclosure, the status of CDKN2A / Bis determined by assessing percentage of tumor cells that show intact CDKN2A / B alleles, homozygous deletion of both CDKN2A / B alleles, and heterozygous deletion of CDKN2A / B alleles. In some embodiments, for a Method of the Disclosure, the evaluation of CDKN2A / B genetic profiles comprises determining the percentage of tumor cells that show intact CDKN2A / B alleles, homozygous deletion of both CDKN2A / B alleles, and heterozygous deletion of CDKN2A / B alleles. In some embodiments, the evaluation of CDKN2A / B genetic profiles comprises determining the percentage of tumor cells that show intact CDKN2A / B alleles, homozygous deletion of both CDKN2A / B alleles, and heterozygous deletion of CDKN2A / B alleles, by examining stained tumor tissue on a microscope slide using fluorescence in situ hybridization (FISH) technique. In some embodiments, a subject whose sample shows less than about 25% homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no loss of homozygosity of CDKN2A / B genes. In some embodiments, a subject whose sample shows less than about 24% homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no deletion of homozygosity of CDKN2A / B genes. In some embodiments, a subject whose sample shows less than about 23% homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no deletion of homozygosity of CDKN2A / B genes. In some embodiments, a subject whose sample shows less than about 22% homozygous deletion of CDKN2A / B in a FISH experimentWSGR Docket No.57339-709601 is evaluated as a subject with no deletion of homozygosity of CDKN2A / B genes. In some embodiments, a subject whose sample shows less than about 21% homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no deletion of homozygosity of CDKN2A / B genes. In some embodiments, a subject whose sample shows less than about 20% homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no deletion of homozygosity of CDKN2A / B genes. In some embodiments, a subject whose sample shows less than about 19% homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no deletion of homozygosity of CDKN2A / B genes. In some embodiments, a subject whose sample shows less than about 18% homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no deletion of homozygosity of CDKN2A / B genes. In some embodiments, a subject whose sample shows less than about 17% homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no deletion of homozygosity of CDKN2A / B genes.[000140] In some embodiments, for a Method of the Disclosure, an evaluation of geneticprofile of a subject comprises determining the presence of one or more mutations in one gene. In some embodiments, for a Method of the Disclosure, an evaluation of genetic profile of a subject comprises determining the presence of one or more mutations in more than one gene. In some embodiments, for a Method of the Disclosure, an evaluation of genetic profile of a subject comprises determining status of mutations in IDH (e.g., IDH1, IDH2) gene. In some embodiments, for a Method of the Disclosure, an evaluation of genetic profile of a subject comprises determining status of mutations in CDKN2A / B genes. In some embodiments, for a Method of the Disclosure, an evaluation of genetic profile of a subject comprises determining status of mutations in IDH (e.g., IDH1, IDH2) and CDKN2A / B genes. In some embodiments, for a Method of the Disclosure, an evaluation of genetic profile of a subject comprises determining status of mutations in IDH (e.g., IDH1, IDH2), CDKN2A / B, and ATRX genes. WHO Grade 3 Astrocytoma[000141] Astrocytomas are brain tumors originating from astrocytes. Astrocytes are glialcells located in the brain and spinal cord, although more commonly found in the brain. Astrocytomas are a subset of gliomas, which are tumors arising from glial cells (not limited to the brain or spinal cord). Prior to 2021, astrocytomas were categorized by their malignancy and behavior from grade I to grade IV, wherein grade IV was considered the most aggressive and deadly astrocytoma. This approach employed histological evidence to classify astrocytomas and was primarily based on features observed underneath a microscope. However, thisWSGR Docket No.57339-709601 histological approach was lacking accuracy in guiding treatment and in 2021 the WHO transitioned from solely a histological approach to one that heavily incorporates molecular information, i.e., biomarkers. This paradigm shift in tumor classification – integrating histological features and biomarkers – intends to provide more accurate diagnoses, prognosis, and guide treatment decisions, allowing for more precise patient management. For example, patients having mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B are categorized as grade 2 or grade 3 astrocytoma. Patients having mutant IDH (e.g., IDH1, IDH2) and homozygous deletion of CDKN2A / B are categorized as grade 4 astrocytoma.[000142] The recent re-classification of gliomas by WHO in 2021 highlights the geneticprofile of grade 3 astrocytoma with particular molecular biomarkers, namely IDH (e.g., IDH1, IDH2) mutation in combination with no homozygous deletion of CDKN2A / B. In some embodiments, a grade 3 astrocytoma comprises mutant IDH1 and no homozygous deletion of CDKN2A / B genes. In some embodiments, a grade 3 astrocytoma comprises mutant IDH1 and intact CDKN2A / B genes. In some embodiments, a grade 3 astrocytoma comprises mutant IDH2 and no homozygous deletion of CDKN2A / B genes. In some embodiments, a grade 3 astrocytoma comprises mutant IDH2 and intact CDKN2A / B genes. As used herein, the grade classification of astrocytoma e.g., grade 3 astrocytoma, grade 2 astrocytoma, etc., refers to the WHO 2021 classification unless indicated otherwise. As is well understood by those skill in the art, classification of CNS tumors (e.g., astrocytoma) prior to 2021 did not use the geneticstatus of CDKN2A / B as a parameter. See, e.g., Huang, L.E., Biomedicines 2022, 10, 246. Assuch, grade levels of astrocytoma classified under an old system (e.g., those classified under WHO’s 2016 system) do not equal to grade levels of astrocytoma classified under WHO’s 2021 system.[000143] Cytotoxic chemotherapy is reported to be used in treating astrocytoma. Mostastrocytomas respond to cytotoxic chemotherapy to a variable extent. However, the use of cytotoxic chemotherapy can face significant challenges in the field of brain cancers, e.g., astrocytoma, due to blood-brain-barrier and blood-tumor barrier. As such, many drugs tested over the years have failed to produce meaningful antitumor efficacy, because they were unable to reach invading tumor cells in sufficient dose and for sufficient time.[000144] Additionally, existing treatments such as chemotherapy and radiotherapy, whileoffering some hope for patients with advanced astrocytoma, are often plagued with grave side effects / toxicity issues compared to the moderate benefits it can bring. For example, temozolomide (TMZ) is an alkylating agent that has demonstrated clinical antitumor activity against gliomas, including some astrocytomas. The side effects / toxicity issues regardingWSGR Docket No.57339-709601 temozolomide include, but are not limited to, nausea, thrombocytopenia, leukopenia, neutropenia, and anemia. Furthermore, temozolomide can produce lymphopenia and lymphopenia has been associated with the emergence of Pneumocystis jirovecii pneumonia (PCP). Prophylaxis against PCP is required for all patients receiving concomitant TMZ and radiotherapy. Lomustine is another small-molecule chemotherapeutic agent commonly used for the treatment of brain tumors. The side effects / toxicity issues regarding lomustine include, but are not limited to, myelosuppression, thrombocytopenia, leukopenia, anemia, reversible hepatotoxicity, nephrotoxicity, nausea and vomiting. The outlook for patients whose astrocytoma recurs or relapses after chemotherapy and radiotherapy is even bleaker. As is appreciated by those skilled in the art, there have been no effective treatment strategies for advanced astrocytoma, especially new treatment strategies for patients with astrocytoma that progress / recur after irradiation and adjuvant chemotherapy with a cytotoxic agent such as, but not limited to, temozolomide.[000145] Among other things, the present disclosure encompasses a discovery of methodsfor treating astrocytoma that were previously considered untreatable. In some embodiments, the present disclosure provides a method of treating astrocytoma characterized by certain genetic profiles as described herein. Without wishing to be bound by any particular theory, the present disclosure encompasses a finding that methods of treating astrocytoma as described herein provide improved treatment outcome in subject populations with certain genetic profiles compared to subject populations without such genetic profiles. In some embodiments, an astrocytoma is grade 3 astrocytoma. In some embodiments, for a Method of the Disclosure, the subject has grade 3 astrocytoma. ATRX gene[000146] Alpha Thalassemia / Mental Retardation Syndrome X-linked (ATRX) geneencodes a protein (i.e., Transcriptional regulator ARTX) that is involved in chromatin remodeling, telomere maintenance, and DNA repair. As such, ATRX gene play an important role in maintaining the genomic stability of humans.[000147] Among other things, contrary to existing studies that suggest the loss ofexpression of ATRX leads to more favorable prognosis in cancer subjects, e.g., Leeper et al. Oncotarget.2015 Oct 6;6(30):30295-305, the present disclosure encompasses an unexpected finding that subject populations with intact ATRX gene demonstrate improved treatment outcome in a method of treating cancer as described herein.[000148] In some embodiments, for a Method of the Disclosure, the subject has no lossof ATRX gene expression. In some embodiments, the subject has intact ATRX gene. In someWSGR Docket No.57339-709601 embodiments, the subject has mutant ATRX gene. In some embodiments, the subject has wildtype ATRX gene.[000149] In some embodiments, for a Method of the Disclosure, the subject has mutantIDH (e.g., IDH1, IDH2) gene. In some embodiments, a subject has wildtype IDH (e.g., IDH1, IDH2) gene. In some embodiments, for a Method of the Disclosure, the subject has intact CDKN2A / B genes. In some embodiments, the subject has heterozygous deletion of CDKN2A / B genes and intact ATRX. In some embodiments, the subject has no homozygous deletion of CDKN2A / B genes and intact ATRX. In some embodiments, the subject has intact CDKN2A gene and intact ATRX. In some embodiments, the subject has heterozygous deletion of CDKN2A gene and intact ATRX. In some embodiments, the subject has no homozygous deletion of CDKN2A gene and intact ATRX. In some embodiments, the subject has intact CDKN2B gene and intact ATRX. In some embodiments, the subject has heterozygous deletion of CDKN2B gene and intact ATRX. In some embodiments, the subject has no homozygous deletion of CDKN2B gene and intact ATRX.[000150] In some embodiments, for a Method of the Disclosure, the subject has mutantIDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2A / B genes. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2A gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2B gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2B gene. In some embodiments, the subject has mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2B gene.[000151] In some embodiments, for a Method of the Disclosure, the subject has wildtypeIDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2), intact ATRX and heterozygous deletion of CDKN2A / B genes. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletionWSGR Docket No.57339-709601 of CDKN2A gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2A gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2B gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2B gene. In some embodiments, the subject has wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2B gene.[000152] In some embodiments, the present disclosure provides a method of treatingcancer in a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor. In some embodiments, a provided method further comprises administering a second therapeutic agent or treatment including a chemotherapeutic agent, an immunotherapy agent, or radiation therapy, or a combination thereof. In some embodiments, the second therapeutic agent is a chemotherapeutic agent. In some embodiments, chemotherapeutic agent is selected from an alkylating agent. In some embodiments, alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, mechlorethamine, melphalan, nimustine, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, streptozocin or uramustine, or a salt thereof where applicable. In some embodiments, alkylating agent is lomustine, carmustine, or semustine. In some embodiments, alkylating agent is altretamine. In some embodiments, alkylating agent is bendamustine. In some embodiments, alkylating agent is busulfan. In some embodiments, alkylating agent is carboplatin. In some embodiments, alkylating agent is carmustine. In some embodiments, alkylating agent is chlorambucil. In some embodiments, alkylating agent is cisplatin. In some embodiments, alkylating agent is cyclophosphamide. In some embodiments, alkylating agent is dacarbazine. In some embodiments, alkylating agent is fotemustine. In some embodiments, alkylating agent is ifosfamide. In some embodiments, alkylating agent is lomustine. In some embodiments, alkylating agent is mechlorethamine. In some embodiments, alkylating agent is melphalan. In some embodiments, alkylating agent is nimustine. In some embodiments, alkylating agent is oxaliplatin. In some embodiments, alkylating agent is procarbazine. In some embodiments, alkylating agent is temozolomide. In some embodiments, alkylating agent is thiotepa. In some embodiments, alkylating agent is trabectedin. In some embodiments, alkylating agent is streptozocin. In some embodiments, alkylating agent is uramustine. InWSGR Docket No.57339-709601 some embodiments, the second therapeutic agent is immunotherapy agent. In some embodiments, a provided method further comprises radiation therapy.[000153] In some embodiments, the present disclosure provides a method of treatingcancer in a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, the method of treating a cancer characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes, comprises administering to a subject eflornithine or a salt thereof and lomustine.[000154] In some embodiments, the present disclosure provides a method of treatingcancer in a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor. In some embodiments, a provided method further comprises administering a second therapeutic agent or treatment including a chemotherapeutic agent, an immunotherapy agent, or radiation therapy, or a combination thereof. In some embodiments, the second therapeutic agent is a chemotherapeutic agent. In some embodiments, chemotherapeutic agent is selected from an alkylating agent. In some embodiments, alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, mechlorethamine, melphalan, nimustine, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, streptozocin or uramustine, or a salt thereof where applicable. In some embodiments, alkylating agent is lomustine, carmustine, or semustine. In some embodiments, alkylating agent is altretamine. In some embodiments, alkylating agent is bendamustine. In some embodiments, alkylating agent is busulfan. In some embodiments, alkylating agent is carboplatin. In some embodiments, alkylating agent is carmustine. In some embodiments, alkylating agent is chlorambucil. In some embodiments, alkylating agent is cisplatin. In some embodiments, alkylating agent is cyclophosphamide. In some embodiments, alkylating agent is dacarbazine. In some embodiments, alkylating agent is fotemustine. In some embodiments, alkylating agent is ifosfamide. In some embodiments, alkylating agent is lomustine. In some embodiments, alkylating agent is mechlorethamine. In some embodiments, alkylating agent is melphalan. In some embodiments, alkylating agent is nimustine. In some embodiments, alkylating agent is oxaliplatin. In some embodiments, alkylating agent is procarbazine. In some embodiments, alkylating agent is temozolomide. In some embodiments, alkylating agent is thiotepa. In some embodiments, alkylating agent is trabectedin. In some embodiments, alkylating agent is streptozocin. In some embodiments,WSGR Docket No.57339-709601 alkylating agent is uramustine. In some embodiments, the second therapeutic agent is immunotherapy agent. In some embodiments, a provided method further comprises radiation therapy.[000155] In some embodiments, the present disclosure provides a method of treatingcancer in a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, a method of treating cancer in a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes, comprises administering to the subject eflornithine or a salt thereof and lomustine.[000156] In some embodiments, the present disclosure provides a method of treatingcancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes, and administering to said subject to the subject an ornithine decarboxylase inhibitor. In some embodiments, a provided method further comprises administering a second therapeutic agent or treatment including a chemotherapeutic agent, an immunotherapy agent, or radiation therapy, or a combination thereof. In some embodiments, the second therapeutic agent is a chemotherapeutic agent. In some embodiments, chemotherapeutic agent is selected from an alkylating agent. In some embodiments, alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, mechlorethamine, melphalan, nimustine, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, streptozocin or uramustine, or a salt thereof where applicable. In some embodiments, alkylating agent is lomustine, carmustine, or semustine. In some embodiments, alkylating agent is altretamine. In some embodiments, alkylating agent is bendamustine. In some embodiments, alkylating agent is busulfan. In some embodiments, alkylating agent is carboplatin. In some embodiments, alkylating agent is carmustine. In some embodiments, alkylating agent is chlorambucil. In some embodiments, alkylating agent is cisplatin. In some embodiments, alkylating agent is cyclophosphamide. In some embodiments, alkylating agent is dacarbazine. In some embodiments, alkylating agent is fotemustine. In some embodiments, alkylating agent is ifosfamide. In some embodiments, alkylating agent is lomustine. In some embodiments, alkylating agent is mechlorethamine. In some embodiments, alkylating agent is melphalan. In some embodiments, alkylating agent is nimustine. In some embodiments, alkylating agent is oxaliplatin. In some embodiments, alkylating agent is procarbazine. In some embodiments, alkylating agent is temozolomide. In some embodiments, alkylating agent is thiotepa. In some embodiments, alkylating agent is trabectedin. In some embodiments,WSGR Docket No.57339-709601 alkylating agent is streptozocin. In some embodiments, alkylating agent is uramustine. In some embodiments, the second therapeutic agent is immunotherapy agent. In some embodiments, a provided method further comprises radiation therapy.[000157] In some embodiments, the present disclosure provides a method of treatingcancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, the method of treating cancer, comprises selecting a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine.[000158] In some embodiments, the present disclosure provides a method of treatingcancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes, and administering to said subject to the subject an ornithine decarboxylase inhibitor. In certain embodiments, the subject’s tumor is biopsied and sequenced to determine the IDH (e.g., IDH1, IDH2), ATRX, and CDKN2A / B status. In some embodiments, a provided method further comprises administering a second therapeutic agent or treatment including a chemotherapeutic agent, an immunotherapy agent, or radiation therapy, or a combination thereof. In some embodiments, the second therapeutic agent is a chemotherapeutic agent. In some embodiments, chemotherapeutic agent is selected from an alkylating agent. In some embodiments, alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, fotemustine, ifosfamide, lomustine, mechlorethamine, melphalan, nimustine, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, streptozocin or uramustine, or a salt thereof where applicable. In some embodiments, alkylating agent is lomustine, carmustine, or semustine. In some embodiments, alkylating agent is altretamine. In some embodiments, alkylating agent is bendamustine. In some embodiments, alkylating agent is busulfan. In some embodiments, alkylating agent is carboplatin. In some embodiments, alkylating agent is carmustine. In some embodiments, alkylating agent is chlorambucil. In some embodiments, alkylating agent is cisplatin. In some embodiments, alkylating agent is cyclophosphamide. In some embodiments, alkylating agent is dacarbazine. In some embodiments, alkylating agent is fotemustine. In some embodiments, alkylating agent is ifosfamide. In some embodiments, alkylating agent is lomustine. In some embodiments, alkylating agent is mechlorethamine. In some embodiments, alkylating agent is melphalan. In some embodiments, alkylating agent is nimustine. In some embodiments, alkylating agent is oxaliplatin. In some embodiments,WSGR Docket No.57339-709601 alkylating agent is procarbazine. In some embodiments, alkylating agent is temozolomide. In some embodiments, alkylating agent is thiotepa. In some embodiments, alkylating agent is trabectedin. In some embodiments, alkylating agent is streptozocin. In some embodiments, alkylating agent is uramustine. In some embodiments, the second therapeutic agent is immunotherapy agent. In some embodiments, a provided method further comprises radiation therapy.[000159] In some embodiments, the present disclosure provides a method of treatingcancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, the method of treating cancer, comprises selecting a subject with mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and lomustine.[000160] In some embodiments, the present disclosure provides a method of treatingcancer, comprising: (1) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating ARTX genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who has intact ATRX and no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, the method of treating cancer, comprises: (1) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating ARTX genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who has intact ATRX and no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject eflornithine or a salt thereof and lomustine.[000161] In some embodiments, the present disclosure provides a method of treatingcancer, comprising: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating ARTX genetic profiles of a plurality of subjects suffering from cancer; (3) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (4) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant, has intact ATRX, and has no homozygous deletion of CDKN2A / B genes; and (5) administering to said subject an ornithine decarboxylase inhibitor. In some embodiments, the present disclosure provides a method of treating cancer, comprising: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating ARTX genetic profiles of a plurality of subjects suffering from cancer; (3) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (4) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant, has intact ATRX, and has no homozygous deletion of CDKN2A / B genes;WSGR Docket No.57339-709601 and (5) administering to said subject an ornithine decarboxylase inhibitor and a chemotherapeutic agent. In some embodiments, the present disclosure provides a method of treating cancer, comprising: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating ARTX genetic profiles of a plurality of subjects suffering from cancer; (3) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (4) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant, has intact ATRX, and has no homozygous deletion of CDKN2A / B genes; and (5) administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, the method of treating cancer, comprises: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating ARTX genetic profiles of a plurality of subjects suffering from cancer; (3) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (4) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant and has no homozygous deletion of CDKN2A / B genes; and (5) administering to said subject eflornithine or a salt thereof and lomustine.[000162] In some embodiments, the present disclosure provides a method of treatingcancer, comprising: (1) preparing an oral solution of eflornithine or a salt thereof comprising: adding the contents of a pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate,, wherein the pouch comprises: an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate,; and (2) administering to a subject with the cancer characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes the oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate, and a chemotherapeutic agent, e.g., lomustine. Recurrent / Refractory Cancer[000163] Recurrent cancer is any form of cancer that returns after a period of remissionor after a treatment was thought to have eliminated all detectable cancer cells. Depending on the location of recurrent cancer relative to the original location, the recurrent cancer can beWSGR Docket No.57339-709601 termed local recurrence (i.e., same location as the original tumor), regional recurrence (i.e., in nearby tissues or lymph nodes), or distant / metastatic recurrence (i.e., distant parts of the body). Refractory cancer generally refers to cancer that does not respond to a specific treatment or stops responding to a specific treatment after an initial period of improvement. Although recurrent cancers can be refractory cancers and vice versa, often refractory cancers are considered a subset of recurrent cancers, which are particularly challenging to treat. Some cancers are more prone to being recurrent / refractory, especially brain cancers including, but not limited to, astrocytomas. Furthermore, recurrent / refractory cancers can be classified as a chemotherapy recurrent / refractory cancer, a radiotherapy recurrent / refractory cancer, or a combination thereof. A specific chemotherapy recurrent / refractory cancer is temozolomide recurrent / refractory cancer.[000164] Among other things, the present disclosure provides a discovery of treatmentmethods for recurrent and or refractory cancer, which would normally be considered untreatable.[000165] In some embodiments, for a Method of the Disclosure, the recurrent and orrefractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) gene. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2) gene.[000166] In some embodiments, for a Method of the Disclosure, the recurrent and orrefractory cancer is characterized by intact CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by heterozygous deletion of CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by no homozygous deletion of CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by intact CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by heterozygous deletion of CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by no homozygous deletion of CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by intact CDKN2B gene. In some embodiments, the recurrent and or refractory cancer is characterized by heterozygous deletion of CDKN2B gene. In some embodiments, the recurrent and or refractory cancer is characterized by no homozygous deletion of CDKN2B gene.[000167] In some embodiments, for a Method of the Disclosure, the recurrent and orrefractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer isWSGR Docket No.57339-709601 characterized by mutant IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2B gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) and heterozygous deletion of CDKN2B gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2) and intact CDKN2B gene.[000168] In some embodiments, for a Method of the Disclosure, the recurrent and orrefractory cancer is characterized by intact CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by heterozygous deletion of CDKN2A / B genes and intact ATRX. In some embodiments, the recurrent and or refractory cancer is characterized by no homozygous deletion of CDKN2A / B genes and intact ATRX. In some embodiments, the recurrent and or refractory cancer is characterized by intact CDKN2A gene and intact ATRX. In some embodiments, the recurrent and or refractory cancer is characterized by heterozygous deletion of CDKN2A gene and intact ATRX. In some embodiments, the recurrent and or refractory cancer is characterized by no homozygous deletion of CDKN2A gene and intact ATRX. In some embodiments, the recurrent and or refractory cancer is characterized by intact CDKN2B gene and intact ATRX. In some embodiments, the recurrent and or refractory cancer is characterized by heterozygous deletion of CDKN2B gene and intact ATRX. In some embodiments, the recurrent and or refractory cancer is characterized by no homozygous deletion of CDKN2B gene and intact ATRX.[000169] In some embodiments, for a Method of the Disclosure, the recurrent and orrefractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer isWSGR Docket No.57339-709601 characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2B gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2B gene. In some embodiments, the recurrent and or refractory cancer is characterized by mutant IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2B gene.[000170] In some embodiments, for a Method of the Disclosure, the recurrent and orrefractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX and heterozygous deletion of CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A / B genes. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2A gene. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and no homozygous deletion of CDKN2B gene. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and heterozygous deletion of CDKN2B gene. In some embodiments, the recurrent and or refractory cancer is characterized by wildtype IDH (e.g., IDH1, IDH2), intact ATRX, and intact CDKN2B gene.[000171] In some embodiments, for a Method of the Disclosure, the cancer isradiotherapy recurrent / refractory cancer. In some embodiments, the radiotherapy recurrent / refractory cancer is radiotherapy recurrent / refractory glioma. In some embodiments, the radiotherapy recurrent / refractory cancer is radiotherapy recurrent / refractory grade 2 astrocytoma or radiotherapy recurrent / refractory grade 3 astrocytoma. In some embodiments,WSGR Docket No.57339-709601 the radiotherapy recurrent / refractory cancer is radiotherapy recurrent / refractory grade 2 astrocytoma. In some embodiments, the radiotherapy recurrent / refractory cancer is radiotherapy recurrent / refractory grade 3 astrocytoma. In some embodiments, the subject is a subject who experiences relapse after radiotherapy. In some embodiments, the subject is a glioma subject who experiences relapse after radiotherapy. In some embodiments, the subject is a grade 2 astrocytoma subject who experiences relapse after radiotherapy. In some embodiments, the subject is a grade 3 astrocytoma subject who experiences relapse after radiotherapy.[000172] In some embodiments, for a Method of the Disclosure, the cancer ischemotherapy recurrent / refractory cancer. In some embodiments, the chemotherapy recurrent / refractory cancer is chemotherapy recurrent / refractory glioma. In some embodiments, the chemotherapy recurrent / refractory cancer is chemotherapy recurrent / refractory grade 2 astrocytoma or chemotherapy recurrent / refractory grade 3 astrocytoma. In some embodiments, the chemotherapy recurrent / refractory cancer is chemotherapy recurrent / refractory grade 2 astrocytoma. In some embodiments, the chemotherapy recurrent / refractory cancer is radiotherapy recurrent / refractory grade 3 astrocytoma. In some embodiments, the subject is a subject who experiences relapse after chemotherapy. In some embodiments, the subject is a glioma subject who experiences relapse after chemotherapy. In some embodiments, the subject is a grade 2 astrocytoma subject who experiences relapse after chemotherapy. In some embodiments, the subject is a grade 3 astrocytoma subject who experiences relapse after chemotherapy.[000173] In some embodiments, for a Method of the Disclosure, the cancer istemozolomide recurrent / refractory cancer. In some embodiments, the temozolomide recurrent / refractory cancer is temozolomide recurrent / refractory glioma. In some embodiments, the temozolomide recurrent / refractory cancer is temozolomide recurrent / refractory grade 2 astrocytoma or temozolomide recurrent / refractory grade 3 astrocytoma. In some embodiments, the temozolomide recurrent / refractory cancer is temozolomide recurrent / refractory grade 2 astrocytoma. In some embodiments, the temozolomide recurrent / refractory cancer is temozolomide recurrent / refractory grade 3 astrocytoma. In some embodiments, the subject is a subject who experiences relapse after temozolomide treatment. In some embodiments, the subject is a glioma subject who experiences relapse after temozolomide treatment. In some embodiments, the subject is a grade 2 astrocytoma subject who experiences relapse after temozolomide treatment. In some embodiments, the subject is a grade 3 astrocytoma subject who experiences relapse after temozolomide treatment.WSGR Docket No.57339-709601[000174] In some embodiments, for a Method of the Disclosure, the cancer is selectedfrom radiotherapy recurrent / refractory cancer, chemotherapy recurrent / refractory cancer, temozolomide recurrent / refractory cancer, glioma, grade 2 astrocytoma, grade 3 astrocytoma, and any combination thereof. In some embodiments, radiotherapy recurrent / refractory glioma, chemotherapy recurrent / refractory glioma, temozolomide recurrent / refractory glioma, radiotherapy recurrent / refractory grade 2 astrocytoma, chemotherapy recurrent / refractory grade 2 astrocytoma, temozolomide recurrent / refractory grade 2 astrocytoma, radiotherapy recurrent / refractory grade 3 astrocytoma, chemotherapy recurrent / refractory grade 3 astrocytoma, temozolomide recurrent / refractory grade 3 astrocytoma, and any combination thereof. In some embodiments, the cancer is glioma. In some embodiments, the cancer is grade 2 astrocytoma or grade 3 astrocytoma. In some embodiments, the cancer is grade 3 astrocytoma. Ornithine Decarboxylase Inhibitors[000175] The enzyme ornithine decarboxylase (ODC) is the first and rate limiting enzymein the biosynthesis of polyamines Among other things, the present disclosure recognizes that polyamines play critical roles in differentiation and proliferation of mammalian cells and are essential for neoplastic transformation, making inhibition of ornithine decarboxylase (ODC) activity an attractive target for a chemotherapeutic agent. Various ornithine decarboxylase inhibitors can be used in accordance with the present disclosure. In some embodiments, ornithine decarboxylase inhibitor is eflornithine, caffeic acid, caffeic acid phenethyl ester, caffeic acid methyl ester, (2S)-(+)-Amino-6-iodoacetamidohexanoic acid, or POB-Calbiochem (N-(4ʹ-Pyridoxyl)-Ornithine(BOC)-OMe), or a salt thereof where applicable. In some embodiments, ornithine decarboxylase inhibitor is eflornithine or a salt thereof. In some embodiments, ornithine decarboxylase inhibitor is eflornithine HCl salt. In some embodiments, ornithine decarboxylase inhibitor is eflornithine monohydrochloride hydrate (eflornithine HCl·H2O). In some embodiments, ornithine decarboxylase inhibitor is caffeic acid. In some embodiments, ornithine decarboxylase inhibitor is caffeic acid phenethyl ester. In some embodiments, ornithine decarboxylase inhibitor is caffeic acid methyl ester. In some embodiments, ornithine decarboxylase inhibitor is (2S)-(+)-Amino-6-iodoacetamidohexanoic acid. In some embodiments, ornithine decarboxylase inhibitor is POB-Calbiochem (N-(4ʹ- Pyridoxyl)-Ornithine(BOC)-OMe). Eflornithine and LomustineWSGR Docket No.57339-709601[000176] As used herein, eflornithine refers to difluoromethylornithine (DFMO). In someembodiments, an active ingredient used according to the present disclosure is eflornithine in its free base form. In some embodiments, an active ingredient used according to the present disclosure is a salt of eflornithine. In some embodiments, the salt of eflornithine is a pharmaceutically acceptable salt of eflornithine. In some embodiments, the pharmaceutically acceptable salt of eflornithine further comprises a pharmaceutically acceptable carrier. In some embodiments, an active ingredient used according to the present disclosure is a hydrate of eflornithine. In some embodiments, an active ingredient used according to the present disclosure is eflornithine monohydrochloride hydrate (eflornithine HCl·H2O). Eflornithine is a potent, enzyme-activated, irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), the first and rate limiting enzyme in the biosynthesis of polyamines. Furthermore, eflornithine inhibition of ODC leads to inhibition of tumor cell migration and invasion.[000177] Unless otherwise stated, structures depicted herein (e.g., eflornithine or a saltthereof) are meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13C- or 14C -enriched carbon are within the scope of the disclosure.[000178] Certain compounds described herein may exist as enantiomers and all suchstereochemical forms of the compounds being within the scope of the disclosure. Unless otherwise stated, structures depicted herein (e.g., eflornithine or a salt thereof) are also meant to include all stereochemical forms of the structure, e.g., the R and S configurations for each asymmetric center, otherwise referred to as L and D configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric mixtures of the present compounds are within the scope of the disclosure. In certain embodiments, the present compound is provided in a stereoisomerically enriched form, e.g., one enantiomer is present in a greater amount than another enantiomer. In certain embodiments, the present compound is provided in a racemic form, wherein two enantiomers of such compound are present in about equal amounts.[000179] As used herein, lomustine refers to 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (also referred to as, e.g., CCNU, CeeNU®, and Gleostine®).[000180] Among other things, the present disclosure provides an insight that the treatmentoutcome of a cancer treatment, e.g., overall survival (OS), improves significantly when eflornithine or a salt thereof is administered in combination with lomustine compared to when lomustine is administered alone.WSGR Docket No.57339-709601[000181] In some embodiments, the present disclosure provides an insight that thetreatment outcome of a cancer treatment, e.g., overall survival (OS), improves significantly when eflornithine or a salt thereof is administered in combination with lomustine compared to when lomustine is administered alone in a subject with cancer that progress / recur after irradiation and adjuvant temozolomide chemotherapy.[000182] In some embodiments, the present disclosure provides an insight that thetreatment outcome of a cancer treatment, e.g., progression free survival (PFS), improves significantly when eflornithine or a salt thereof is administered in combination with lomustine compared to when lomustine is administered alone.[000183] In some embodiments, the present disclosure provides an insight that thetreatment outcome e.g., progression free survival (PFS), improves significantly when eflornithine or a salt thereof is administered in combination with lomustine compared to when lomustine is administered alone in a subject with cancer that progress / recur after irradiation and adjuvant temozolomide chemotherapy.[000184] In some embodiments, the present disclosure provides an insight that theimprovement in the treatment outcome of combination of eflornithine or a salt thereof and lomustine compared to lomustine alone is more significant in subject population with certain genetic profiles as described herein. In some embodiments, the certain genetic profiles are charactered by WHO 2021 classification. In some embodiments, certain genetic profiles comprise mutant IDH (e.g., IDH1, IDH2), homozygous deletion of CDKN2A / B genes, no homozygous deletion of CDKN2A / B, heterozygous deletion of CDKN2A / B genes, no heterozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the certain genetic profiles comprise mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, no heterozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the certain genetic profiles comprise mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the certain genetic profiles comprise mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the certain genetic profiles comprise mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, or any combinations thereof. In some embodiments, the certain genetic profiles comprise mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, loss of ATRX gene, or any combinations thereof.WSGR Docket No.57339-709601[000185] In some embodiments, the present disclosure provides a method of treatingcancer characterized by a genetic profile as described herein, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), homozygous deletion of CDKN2A / B genes, no homozygous deletion of CDKN2A / B, heterozygous deletion of CDKN2A / B genes, no heterozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, no heterozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, loss of ATRX gene, or any combinations thereof.[000186] In some embodiments, the present disclosure provides a method of treatingcancer characterized by a genetic profile as described herein, comprising administering to a subject eflornithine or a salt thereof and lomustine. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), homozygous deletion of CDKN2A / B genes, no homozygous deletion of CDKN2A / B, heterozygous deletion of CDKN2A / B genes, no heterozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, no heterozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, mutant ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, loss of ATRX gene, or any combinations thereof. In some embodiments, the genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, intact ATRX gene, or any combinations thereof. In some embodiments, theWSGR Docket No.57339-709601 genetic profile comprises mutant IDH (e.g., IDH1, IDH2), no homozygous deletion of CDKN2A / B, loss of ATRX gene, or any combinations thereof.[000187] In some embodiments, the present disclosure provides a method of treatingcancer in a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.[000188] In some embodiments, the present disclosure provides a method of treating acancer characterized by mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, comprising administering to a subject eflornithine or a salt thereof and lomustine.[000189] In some embodiments, the present disclosure provides a method of treatingcancer in a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.[000190] In some embodiments, the present disclosure provides a method of treatingcancer, comprising selecting a subject with a genetic profile as described herein, and administering to said subject eflornithine or a salt thereof and lomustine.[000191] In some embodiments, the present disclosure provides a method of treatingcancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.[000192] In some embodiments, the present disclosure provides a method of treatingcancer, comprising selecting a subject with mutant IDH (e.g., IDH1, IDH2) and intact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.[000193] In some embodiments, the present disclosure provides a method of treatingcancer, comprising: (1) evaluating the genetic profiles of a plurality of subjects suffering from cancer; (2) selecting a subject who has a genetic profile as described herein; and (3) administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.[000194] In some embodiments, the present disclosure provides a method of treatingcancer, comprising:WSGR Docket No.57339-709601 (1) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (2) selecting a subject who has no homozygous deletion of CDKN2A / B genes; and (3) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof.[000195] In some embodiments, the present disclosure provides a method of treatingcancer, comprising: (1) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (2) selecting a subject who has no homozygous deletion of CDKN2A / B genes; and (3) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and a chemotherapeutic agent, e.g., lomustine.[000196] In some embodiments, the present disclosure provides a method of treatingcancer, comprising: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant and has no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof.[000197] In some embodiments, the present disclosure provides a method of treatingcancer, comprising: (1) evaluating IDH (e.g., IDH1, IDH2) genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH (e.g., IDH1, IDH2) mutant and has no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and a chemotherapeutic agent, e.g., lomustine.[000198] In certain embodiments, the present disclosure provides a kit comprising apouch of a solid eflornithine, e.g., eflornithine hydrochloride hydrate, that is suitable forWSGR Docket No.57339-709601 making an oral solution. In some embodiments, a pouch as described herein comprises an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate.[000199] In some embodiments, the present disclosure provides a method of treatingcancer, comprising: (1) preparing an oral solution of eflornithine or a salt thereof comprising: adding the contents of a pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of solid eflornithine, e.g., eflornithine hydrochloride hydrate,, wherein the pouch comprises: an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate,; and (2) administering to a subject with the cancer characterized by mutant IDH (e.g., IDH1, IDH2) and no homozygous deletion of CDKN2A / B genes the oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate, and a chemotherapeutic agent, e.g., lomustine.[000200] In some embodiments, the present disclosure provides a method of treatinggrade 3 astrocytoma, comprising administering to a subject eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, the method comprises administering to a subject eflornithine or a salt thereof and lomustine.[000201] In some embodiments, for a Method of the Disclosure, the chemotherapeuticagent is selected from bendamustine, carmustine, lomustine, procarbazine, vincristine, temozolomide, bevacizumab, regorafenib, vorasidenib, tovorafenib, carboplatin, cisplatin, irinotecan, fotemustine, 5-fluorouracil, doxorubicin, daunorubicin, paclitaxel, etoposide, and floxuridine. In some embodiments, the chemotherapeutic agent is selected from bendamustine, carmustine, lomustine, procarbazine, vincristine, temozolomide, bevacizumab, regorafenib, vorasidenib, tovorafenib, carboplatin, cisplatin, irinotecan, fotemustine, 5-fluorouracil, doxorubicin, and daunorubicin. In some embodiments, the chemotherapeutic agent is selected from bendamustine, carmustine, lomustine, procarbazine, vincristine, temozolomide, bevacizumab, regorafenib, vorasidenib, tovorafenib, carboplatin, cisplatin, and irinotecan. InWSGR Docket No.57339-709601 some embodiments, the chemotherapeutic agent is selected from bendamustine, carmustine, lomustine, procarbazine, vincristine, temozolomide, bevacizumab, regorafenib, vorasidenib, and tovorafenib. In some embodiments, the chemotherapeutic agent is selected from lomustine, procarbazine, vincristine, temozolomide, bevacizumab, regorafenib, vorasidenib, and tovorafenib. In some embodiments, the chemotherapeutic agent is selected from lomustine, temozolomide, bevacizumab, regorafenib, vorasidenib, and tovorafenib.In some embodiments, the chemotherapeutic agent is selected from lomustine, regorafenib, vorasidenib, and tovorafenib. In some embodiments, the chemotherapeutic agent is bendamustine. In some embodiments, the chemotherapeutic agent is carmustine.In some embodiments, the chemotherapeutic agent is procarbazine. In some embodiments, the chemotherapeutic agent is vincristine. In some embodiments, the chemotherapeutic agent is temozolomide. In some embodiments, the chemotherapeutic agent is bevacizumab. In some embodiments, the chemotherapeutic agent is regorafenib. In some embodiments, the chemotherapeutic agent is vorasidenib. In some embodiments, the chemotherapeutic agent is tovorafenib. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the chemotherapeutic agent is irinotecan. In some embodiments, the chemotherapeutic agent is fotemustine. In some embodiments, the chemotherapeutic agent is 5-fluorouracil. In some embodiments, the chemotherapeutic agent is doxorubicin. In some embodiments, the chemotherapeutic agent is daunorubicin. In some embodiments, the chemotherapeutic agent is paclitaxel. In some embodiments, the chemotherapeutic agent is etoposide. In some embodiments, the chemotherapeutic agent is floxuridine. In some embodiments, the chemotherapeutic agent is lomustine. In some embodiments, the chemotherapeutic agent is carmustine.[000202] In some embodiments, for a Method of the Disclosure, the subject isadministered eflornithine hydrochloride hydrate or eflornithine (free base). In some embodiments, the subject is administered eflornithine hydrochloride hydrate. In some embodiments, the subject is administered eflornithine (free base).[000203] In some embodiments, for a Method of the Disclosure, the method comprisesadministering a therapeutically effective amount of eflornithine or a salt thereof and a chemotherapeutic agent. In some embodiments, the method comprises administering a therapeutically effective amount of eflornithine or a salt thereof and lomustine. In some embodiments, the method comprises administering a therapeutically effective amount of eflornithine or a salt thereof and a therapeutically effective amount of lomustine.WSGR Docket No.57339-709601[000204] Described herein are doses of eflornithine or a salt thereof, e.g., eflornithinemonohydrochloride hydrate, for administration to subjects in need thereof. Unless otherwise indicated, the doses described herein are calculated based upon the anhydrous and free base weight of the active ingredient of eflornithine or salt thereof. For example, a 2.8 g / m2dose of eflornithine monohydrochloride hydrate as discussed herein is based on the mass of the eflornithine and does not include the mass of the HCl or water molecule.[000205] In some embodiments, for a Method of the Disclosure, eflornithine isadministered at a dose from about 0.5 g / m2to about 15 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose from about 1 g / m2to about 10 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose from about 1 g / m2to about 8 g / m2three- times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose from about 1 g / m2to about 6 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose from about 1 g / m2to about 3 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose from about 1.2 g / m2to about 4 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose from about 1.4 g / m2to about 3.5 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose from about 1.4 g / m2to about 3.0 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose from about 1.4 g / m2to about 2.5 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.4 g / m2, 2.1 mg / m2, 2.3 g / m2or 2.8 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.4 g / m2, 2.1 mg / m2, or 2.3 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.8 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.1 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.4 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 0.5 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 0.6 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 0.7 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at aWSGR Docket No.57339-709601 dose of about 0.8 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 0.9 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.1 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.2 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.3 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.5 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.6 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.7 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.8 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 1.9 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.0 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.2 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.4 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.5 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.6 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.7 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 2.9 g / m2three-times daily (every 8 hours) free base equivalent. In some embodiments, eflornithine is administered at a dose of about 3.0 g / m2three-times daily (every 8 hours) free base equivalent.[000206] In some embodiments, for a Method of the Disclosure, eflornithine or a saltthereof is administered on a schedule. In some embodiments, eflornithine or a salt thereof is administered daily on a two-week-on followed by a one-week-off schedule. In some embodiments, eflornithine or a salt thereof is administered in one or more cycles of treatment period and each cycle comprises about 6 weeks. In some embodiments, eflornithine or a salt thereof is administered in one or more cycles of treatment period and each cycle comprises about 8 weeks. In some embodiments, eflornithine or a salt thereof is administered for at leastWSGR Docket No.57339-709601 1 cycle. In some embodiments, eflornithine or a salt thereof is administered for about 1 cycle to about 24 cycles. In some embodiments, eflornithine or a salt thereof is administered for about 2 cycles to about 24 cycles. In some embodiments, eflornithine or a salt thereof is administered for about 1 cycle to about 8 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 3 cycles to about 24 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 6 cycles to about 24 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 6 cycles to about 21 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 6 cycles to about 18 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 6 cycles to about 15 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 6 cycles to about 12 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 6 cycles to about 9 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 6 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 9 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 12 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 15 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 18 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 21 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 24 cycles. In some embodiments, eflornithine or a salt thereof is administered for at least about 12 months to about 72 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 12 months to about 60 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 12 months to about 48 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 12 months to about 36 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 12 months to about 24 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 12 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 24 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 36 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 48 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 60 months. In some embodiments, eflornithine or a salt thereof is administered for at least about 72 months.[000207] In some embodiments, for a Method of the Disclosure, the chemotherapeuticagent is lomustine. In some embodiments, lomustine is administered at a dose from about 30WSGR Docket No.57339-709601 mg / m2to about 110 mg / m2. In some embodiments, lomustine is administered at a dose from about 30 mg / m2to about 110 mg / m2every 6 weeks. In some embodiment, lomustine is administered at a dose from about 50 mg / m2to about 110 mg / m2. In some embodiment, lomustine is administered at a dose from about 50 mg / m2to about 110 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose from about 30 mg / m2to about 90 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose from about 30 mg / m2to about 60 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose from about 60 mg / m2to about 90 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose from about 30 mg / m2to about 90 mg / m2. In some embodiments, lomustine is administered at a dose from about 30 mg / m2to about 60 mg / m2. In some embodiments, lomustine is administered at a dose from about 60 mg / m2to about 90 mg / m2. In some embodiments, lomustine is administered at a dose of from about 50 mg / m2to about 90 mg / m2. In some embodiments, lomustine is administered at a dose of from about 50 mg / m2to about 90 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 110 mg / m2. In some embodiments, lomustine is administered at a dose of about 100 mg / m2. In some embodiments, lomustine is administered at a dose of about 90 mg / m2. In some embodiments, lomustine is administered at a dose of about 80 mg / m2. In some embodiments, lomustine is administered at a dose of about 70 mg / m2. In some embodiments, lomustine is administered at a dose of about 60 mg / m2. In some embodiments, lomustine is administered at a dose of about 50 mg / m2. In some embodiments, lomustine is administered at a dose of about 40 mg / m2. In some embodiments, lomustine is administered at a dose of about 30 mg / m2. In some embodiments, lomustine is administered at a dose of about 110 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 100 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 90 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 80 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 70 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 60 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 50 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 40 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 30 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of no more than about 110 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of no more than about 100 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of no more than about 90 mg / m2every 6 weeks. In some embodiments,WSGR Docket No.57339-709601 lomustine is administered at a dose of about 90 mg / m2to about 110 mg / m2every 6 weeks. In some embodiments, lomustine is administered at a dose of about 90 mg / m2to about 100 mg / m2every 6 weeks.[000208] In some embodiments, for a Method of the Disclosure, the chemotherapeuticagent is lomustine. In some embodiments, lomustine is administered in one or more cycles of treatment period and each cycle comprises about 6 weeks. In some embodiments, lomustine is administered in one or more cycles of treatment period and each cycle comprises about 8 weeks. In some embodiments, lomustine is administered for at least 1 cycle. In some embodiments, lomustine is administered for about 1 cycle to about 24 cycles. In some embodiments, lomustine is administered for about 2 cycles to about 24 cycles. In some embodiments, lomustine is administered for about 1 cycle to about 8 cycles. In some embodiments, lomustine is administered for no more than 24 cycles. In some embodiments, lomustine is administered for no more than 21 cycles. In some embodiments, lomustine is administered for no more than 18 cycles. In some embodiments, lomustine is administered for no more than 15 cycles. In some embodiments, lomustine is administered for no more than 12 cycles. In some embodiments, lomustine is administered for no more than 9 cycles. In some embodiments, lomustine is administered for no more than 6 cycles. In some embodiments, lomustine is administered for no more than 3 cycles.[000209] In some embodiments, for a Method of the Disclosure, the chemotherapeuticagent is lomustine. In some embodiments, lomustine is administered for no more than 72 months. In some embodiments, lomustine is administered for no more than 60 months. In some embodiments, lomustine is administered for no more than 48 months. In some embodiments, lomustine is administered for no more than 36 months. In some embodiments, lomustine is administered for no more than 24 months. In some embodiments, lomustine is administered for no more than 12 months. In some embodiments, lomustine is administered for no more than 6 months. In some embodiments, lomustine is administered for no more than 3 months. In some embodiments, lomustine is administered for no more than 2 months. In some embodiments, lomustine is administered for no more than 1 month.[000210] In some embodiments, for a Method of the Disclosure, lomustine isadministered on a day wherein eflornithine or a salt thereof is not administered. In some embodiments, lomustine is administered on a day in the off-week of the treatment period of eflornithine or a salt thereof. In some embodiments, eflornithine or a salt thereof is administered daily on Days 1–14 (Weeks 1 and 2) and Days 22–35 (Weeks 4 and 5), and lomustine is administered on Day 15 (+2 days) (Week 3). In some embodiments, dose ofWSGR Docket No.57339-709601 lomustine is discontinued after 6 cycles or 12 months, whichever comes first, and eflornithine or a salt thereof is administered for an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months after discontinuation of the dose of lomustine. In some embodiments, dose of lomustine is discontinued after 6 cycles or 12 months, whichever comes first, and eflornithine or a salt thereof is administered for an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 months after discontinuation of the dose of lomustine. In some embodiments, dose of lomustine is discontinued after 6 cycles or 12 months, whichever comes first, and eflornithine or a salt thereof is administered for an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, or 16 months after discontinuation of the dose of lomustine. In some embodiments, dose of lomustine is discontinued after 6 cycles or 12 months, whichever comes first, and eflornithine or a salt thereof is administered for an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, or 12 months after discontinuation of the dose of lomustine. In some embodiments, dose of lomustine is discontinued after 6 cycles or 12 months, whichever comes first, and eflornithine or a salt thereof is administered for an additional 1, 2, 3, 4, 5, 6, 7, or 8 months after discontinuation of the dose of lomustine. In some embodiments, dose of lomustine is discontinued after 6 cycles or 12 months, whichever comes first, and eflornithine or a salt thereof is administered for an additional 1, 2, 3, or 4 months after discontinuation of the dose of lomustine. In some embodiments, dose of lomustine is discontinued after 6 cycles or 12 months, whichever comes first.[000211] In some embodiments, for a Method of the Disclosure, the method furthercomprises adjusting or delaying the dose of eflornithine based on observed toxicity according to CTCAE toxicity grade scale. In some embodiments, the subject develops an adverse event of hearing impairment, tinnitus, diarrhea, nausea, or vomiting, or any combination thereof. In some embodiments, the dose of eflornithine is maintained at original dose if hearing impairment grade is 1 or normal under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 75% of original eflornithine dose if hearing impairment grade is 2 or 3 under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 50% of original eflornithine dose if hearing impairment grade is 4 under CTCAE toxicity grade scale. In some embodiments, the dose of eflornithine is maintained at 2.8 g / m2if hearing impairment grade is 1 or normal under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 2.1 g / m2if hearing impairment grade is 2 or 3 under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 1.4 g / m2if hearing impairment grade is 4 under CTCAE toxicity grade scale.WSGR Docket No.57339-709601[000212] In some embodiments, for a Method of the Disclosure, the method furthercomprises adjusting or delaying the dose of eflornithine based on observed toxicity according to CTCAE toxicity grade scale. In some embodiments, the subject develops an adverse event of hearing impairment, tinnitus, diarrhea, nausea, or vomiting, or any combination thereof. In some embodiments, the dose of eflornithine is maintained at original dose if tinnitus grade is 1 or 2 or normal under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 75% of original eflornithine dose if tinnitus grade is 3 under CTCAE toxicity grade scale. In some embodiments, the dose of eflornithine is maintained at 2.8 g / m2if tinnitus grade is 1 or 2 or normal under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 2.1 g / m2if tinnitus grade is 3 under CTCAE toxicity grade scale.[000213] In some embodiments, for a Method of the Disclosure, the method furthercomprises adjusting or delaying the dose of eflornithine based on observed toxicity according to CTCAE toxicity grade scale. In some embodiments, the subject develops an adverse event of hearing impairment, tinnitus, diarrhea, nausea, or vomiting, or any combination thereof. In some embodiments, the dose of eflornithine is maintained at original dose if diarrhea, nausea, or vomiting grade is 1 or 2 or normal under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 75% of original eflornithine dose if diarrhea, nausea, or vomiting grade is 3 under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 50% of original eflornithine dose if diarrhea or vomiting grade is 4 under CTCAE toxicity grade scale. In some embodiments, the dose of eflornithine is maintained at 2.8 g / m2if diarrhea, nausea, or vomiting grade is 1 or 2 or normal under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 2.1 g / m2if diarrhea, nausea, or vomiting grade is 3 under CTCAE toxicity grade scale, and the dose of eflornithine is reduced to 1.4 g / m2if diarrhea or vomiting grade is 4 under CTCAE toxicity grade scale.[000214] Among other things, the present disclosure encompasses an insight that adverseevents that commonly come with administration of lomustine due to its toxicity can be mitigated by modifying the dose of lomustine. In some embodiments, the present disclosure discovered that reducing the dose of lomustine to a level lower than the dose of standard of care (e.g., 130 mg / m2, 110 mg / 2) mitigates adverse events associated with lomustine without affecting the efficiency of the treatment. In some embodiments, for a Method of the Disclosure, the method further comprises adjusting or delaying the dose of lomustine based on observed toxicity according to CTCAE toxicity grade scale. In some embodiments, the dose of lomustine is maintained at original dose if grade is 1 or normal under CTCAE toxicity grade scale, and the dose of lomustine is reduced to 75% of original lomustine dose if grade is 2 under CTCAEWSGR Docket No.57339-709601 toxicity grade scale, and the dose of lomustine is reduced to 50% of original lomustine dose if grade is 3 or 4 under CTCAE toxicity grade scale.[000215] In some embodiments, for a Method of the Disclosure, the method furthercomprises adjusting or delaying the dose of lomustine for subjects who experienced thrombocytopenia after treatment.[000216] In some embodiments, for a Method of the Disclosure, the method furthercomprises adjusting the dose of lomustine to 110 mg / m2for subjects who experienced thrombocytopenia after receiving treatment. In some embodiments, the method further comprises adjusting the dose of lomustine to 90 mg / m2for subjects who experienced thrombocytopenia after receiving treatment. In some embodiments, the method further comprises adjusting the dose of lomustine to 60 mg / m2for subjects who experienced thrombocytopenia after receiving treatment. In some embodiments, the method further comprises adjusting the dose of lomustine to 30 mg / m2for subjects who experienced thrombocytopenia after receiving treatment.[000217] In some embodiments, for a Method of the Disclosure, the subject isadministered a pharmaceutical composition comprising eflornithine or a salt thereof. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof is formulated as a solution. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof is formulated for oral administration. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof is formulated as a solution for oral administration. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof comprises from about 13.2% to about 22.8% of eflornithine hydrochloride hydrate, water, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof comprises from about 14.2% to about 21.8% of eflornithine hydrochloride hydrate, water, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof comprises from about 15.2% to about 20.8% of eflornithine hydrochloride hydrate, water, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof comprises from about 16.2% to about 19.8% of eflornithine hydrochloride hydrate, water, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof comprises from about 17.2% to about 18.8% of eflornithine hydrochloride hydrate, water, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition of eflornithine or salt thereof comprises about 18% ofWSGR Docket No.57339-709601 eflornithine hydrochloride hydrate (13.9% eflornithine free base equivalent), glycerin, propylene glycol, saccharin sodium, sodium benzoate, and water. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, corn starch, potato starch, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, powdered tragacanth, malt, gelatin, talc, cocoa butter, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, propylene glycol, glycerin, sorbitol, polyethylene glycol ethyl oleate, ethyl laurate, agar, magnesium hydroxide, magnesium stearate, aluminum hydroxide, alginic acid, water, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffer solutions, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, corn starch, potato starch, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, gelatin, talc, cocoa butter, propylene glycol, glycerin, sorbitol, polyethylene glycol ethyl oleate, ethyl laurate, agar, magnesium hydroxide, magnesium stearate, aluminum hydroxide, alginic acid, water, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffer solutions, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, corn starch, potato starch, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, gelatin, talc, propylene glycol, glycerin, sorbitol, polyethylene glycol ethyl oleate, ethyl laurate, alginic acid, water, and ethyl alcohol, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, propylene glycol, glycerin, sorbitol, polyethylene glycol ethyl oleate, ethyl laurate, alginic acid, water, and ethyl alcohol, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, saccharin sodium, sodium benzoate, propylene glycol, glycerin, sorbitol, polyethylene glycol ethyl oleate, ethyl laurate, alginic acid, water, and ethyl alcohol, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, saccharin sodium, sodium benzoate, propylene glycol, glycerin, and water, or any combination thereof. In some embodiments, one or more pharmaceutically acceptable excipients is selected from saccharin sodium, sodium benzoate, propylene glycol, glycerin, and water, or any combination thereof.WSGR Docket No.57339-709601[000218] In some embodiments, for a Method of the Disclosure, the subject isadministered a pharmaceutical composition comprising lomustine. In some embodiments, the subject is administered a pharmaceutical composition comprising lomustine and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition of lomustine is formulated as a capsule. In some embodiments, the pharmaceutical composition of lomustine is formulated for oral administration. In some embodiments, the pharmaceutical composition of lomustine is formulated as a capsule for oral administration. In some embodiments, the pharmaceutical composition of lomustine comprises lomustine and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition of lomustine comprises lomustine, magnesium stearate, and mannitol. In some embodiments, the pharmaceutical composition of lomustine comprises lomustine, magnesium stearate, and mannitol and is formulated as a capsule. In some embodiments, the pharmaceutical composition of lomustine comprises lomustine, magnesium stearate, and mannitol and is formulated as a capsule for oral administration. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, corn starch, potato starch, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, powdered tragacanth, malt, gelatin, talc, cocoa butter, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, propylene glycol, glycerin, sorbitol, mannitol, polyethylene glycol ethyl oleate, ethyl laurate, agar, magnesium hydroxide, magnesium stearate, aluminum hydroxide, alginic acid, water, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffer solutions, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, corn starch, potato starch, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, talc, cocoa butter, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, propylene glycol, glycerin, sorbitol, polyethylene glycol ethyl oleate, ethyl laurate, agar, magnesium hydroxide, magnesium stearate, aluminum hydroxide, alginic acid, and water, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, corn starch, potato starch, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, talc, propylene glycol, glycerin, sorbitol, polyethylene glycol ethyl oleate, ethyl laurate, magnesium hydroxide, magnesium stearate, aluminum hydroxide, alginic acid, and water, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptableWSGR Docket No.57339-709601 excipients is selected from lactose, glucose, sucrose, mannitol, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, talc, propylene glycol, glycerin, sorbitol, magnesium hydroxide, magnesium stearate, aluminum hydroxide, alginic acid, and water, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, saccharin sodium, sodium benzoate, cellulose, sodium carboxymethyl, propylene glycol, glycerin, sorbitol, magnesium hydroxide, magnesium stearate, aluminum hydroxide, alginic acid, and water, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, saccharin sodium, sodium benzoate, sorbitol, magnesium hydroxide, magnesium stearate, aluminum hydroxide, and water, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from lactose, glucose, sucrose, mannitol, sorbitol, magnesium hydroxide, magnesium stearate, aluminum hydroxide, and water, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from glucose, sucrose, mannitol, sorbitol, magnesium hydroxide, and magnesium stearate, or any combination thereof. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from mannitol, and magnesium stearate, or any combination thereof. Pharmaceutical Composition[000219] When the pharmacologically active compound in a pharmaceutical compositionaccording to the present invention possesses a sufficiently acidic, a sufficiently basic, or both a sufficiently acidic and a sufficiently basic functional group, these group or groups can accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the pharmacologically active compound with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, hydroxybutyrates,WSGR Docket No.57339-709601 glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. If the pharmacologically active compound has one or more basic functional groups, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha- hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p- toluenesulfonic acid or ethanesulfonic acid, or the like. If the pharmacologically active compound has one or more acidic functional groups, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.[000220] A pharmaceutical composition as described herein may be manufactured usingtechniques generally known for preparing pharmaceutical compositions, e.g., by conventional techniques such as mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations, which can be used pharmaceutically.[000221] Proper formulation is dependent upon the route of administration chosen. Forinjection, the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.[000222] For oral administration, the compounds can be formulated readily by combiningthe active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules,WSGR Docket No.57339-709601 liquids, gels, syrups, slurries, solutions, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.[000223] Dragee cores are provided with suitable coatings. For this purpose, concentratedsugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.[000224] Pharmaceutical preparations which can be used orally include push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.[000225] Pharmaceutical formulations for parenteral administration can include aqueoussolutions or suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or modulators which increase the solubility or dispersibility of the composition to allow for the preparation of highly concentrated solutions, or can contain suspending or dispersing agents. Pharmaceutical preparations for oral use can be obtained by combining the pharmacologically active agent with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, ifWSGR Docket No.57339-709601 desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating modulators may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.[000226] Other ingredients such as stabilizers, for example, antioxidants such as sodiumcitrate, ascorbyl palmitate, propyl gallate, reducing agents, ascorbic acid, vitamin E, sodium bisulfite, butylated hydroxytoluene, BHA, acetylcysteine, monothioglycerol, phenyl-2- naphthylamine, or lecithin can be used. Also, chelators such as EDTA can be used. Other ingredients that are conventional in the area of pharmaceutical compositions and formulations, such as lubricants in tablets or pills, coloring agents, or flavoring agents, can be used. Also, conventional pharmaceutical excipients or carriers can be used. The pharmaceutical excipients can include, but are not necessarily limited to, calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. Other pharmaceutical excipients are well known in the art. Exemplary pharmaceutically acceptable carriers include, but are not limited to, any and / or all of solvents, including aqueous and non-aqueous solvents, dispersion media, coatings, antibacterial and / or antifungal agents, isotonic and / or absorption delaying agents, and / or the like. The use of such media and / or agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional medium, carrier, or agent is incompatible with the active ingredient or ingredients, its use in a composition according to the present invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions, particularly as described above. For administration of any of the compounds used in the present invention, preparations should meet sterility, pyrogenicity, general safety, and purity standards as required by the FDA Office of Biologics Standards or by other regulatory organizations regulating drugs. For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for useWSGR Docket No.57339-709601 in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.[000227] A pharmaceutical composition can be administered by a variety of methodsknown in the art. The routes and / or modes of administration vary depending upon the desired results. Depending on the route of administration, the pharmacologically active agent may be coated in a material to protect the therapeutic agent or agents from the action of acids and other compounds that may inactivate the agent. Conventional pharmaceutical practice can be employed to provide suitable formulations or compositions for the administration of such pharmaceutical compositions to subjects. Any appropriate route of administration can be employed, for example, but not limited to, intravenous, parenteral, intraperitoneal, intravenous, transcutaneous, subcutaneous, intramuscular, or oral administration. Depending on the severity of the malignancy or other disease, disorder, or condition to be treated, as well as other conditions affecting the subject to be treated, either systemic or localized delivery of the pharmaceutical composition can be used in the course of treatment. The pharmaceutical composition as described above can be administered together with additional therapeutic agents intended to treat a particular disease or condition, which may be the same disease or condition that the pharmaceutical composition is intended to treat, which may be a related disease or condition, or which even may be an unrelated disease or condition. EXAMPLES[000228] The invention now being generally described, it will be more readily understoodby reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:WSGR Docket No.57339-709601 Anaplastic astrocytoma Fluid attenuated inversion Adverse event recovery Anaplastic gliomaGlioblastoma multiformeAlanine aminotransferaseGood Clinical Practice Absolute neutrophil counts (Guidelines) Anaplastic oligodendroglioma Gadolinium Anaplastic oligoastrocytoma High-density polyethylene American Society of Clinical Hazard ratio OncologyInvestigator’s brochureAspartate aminotransferase International Conference on Area under the concentration Harmonisation curve Isocitrate dehydrogenase 1 / 2 Carmustine gene Body surface area Independent Data Monitoring Committee Blood urea nitrogenIndependent Ethics Body weightCommittee Complete blood count Investigational New Drug Clinical benefit response (Application) Lomustine (gleostine) Institutional review board Observed maximum Intention-to-treat concentration Intrauterine device Observed minimum Intrauterine hormone- concentration releasing Central nervous system system Complete response Intravenous Case report form(s)Karnofsky Performance Status Contract (or clinical) researchLactate dehydrogenaseorganization Lower limit of the normal Clinical study report range Common Terminology The University of Texas M.D. Criteria for Adverse Events Anderson Cancer Center Closed testing procedureMedical Dictionary forCoefficient of variation Regulatory Activities α-Difluoromethylornithine, Malignant glioma eflornithine Methylglyoxal bis Duration of objective response (guanylhydrazone) External beam radiation O6-Methylguanine DNA therapy methyltransferase Electrocardiogram MinuteElectronic case report form(s) Millimeters mercury Electronic data capture Magnetic resonance imaging European Organisation forMaximum tolerated doseResearch and Treatment of NanoMolar Cancer National Cancer Institute European UnionNew York Heart Association Full analysis setO’Brien Fleming (United States) Food and Ornithine decarboxylaseDrug Administration Objective response rateOverall survivalWSGR Docket No.57339-709601 OS-18 Overall survival at 18 months PCV Procarbazine, lomustine, and vincristine PD Progressive disease PFS Progression free survival PK Pharmacokinetic PR Partial response QID Four times daily QTc Corrected QT interval RT Radiation therapy SADR Serious Adverse Drug Reaction SAE Serious adverse event SAMDC S-adenosyl-methionine decarboxylase SD Stable disease SDS Safety Data SheetsStD Standard deviationSUSAR Suspected Unexpected Serious Adverse Reaction TEAE Treatment emergent adverse event ULN Upper limit of the normal rangeUK United KingdomUS United States WHO World Health OrganizationWSGR Docket No.57339-709601 Example 1 – Dose Determination and Clinical Pharmacokinetics – Eflornithine & Lomustine[000229] Eflornithine is a cytostatic drug that may interfere with mitosis and malignantprogression. As eflornithine has a short half-life , it has to be administered every 6 to 8 hours.[000230] The human pharmacokinetic (PK) data following oral administration ofeflornithine to a small number of cancer patients (n=6; doses 2.3 and 2.8 g / m2) was evaluated (FIG.1A and FIG.1B). Time to peak Concentrations (Tmax) was similar between doses and days with median values ranging between 2.6 and 3.5 hours. The half-life (T1 / 2) was similar between doses and days with mean values ranging from 2.6 to 3.8 hours.[000231] It has been reported that the recommended dose for treating naïve patients withlomustine was 130 mg / m2. The phase 3 study of the present disclosure (Example 2) started with a reduced dose of 110 mg / m2because the patients had a higher tendency to have compromised bone marrow function due to administration of cytotoxic agent, e.g., temozolomide. After the completion of the second preplanned safety analysis with 42 patients who had completed 28 days of therapy, dose of lomustine was reduced further 90 mg / m2for patients. The present Example and Example 2 demonstrate that even after implementing such a significant reduction of the dose of lomustine from the standard of care dose, e.g., 130 mg / m2or 110 mg / m2, the treatment in the combination arm was well tolerated. Example 2 – Human Clinical Trials – Phase 3 Overview[000232] The present Example demonstrates a Phase 3, randomized, open-label,multicenter, active-controlled study to evaluate the safety and efficacy of eflornithine with lomustine compared to lomustine alone in patients with astrocytoma that progress / recur after irradiation and adjuvant temozolomide chemotherapy. Eflornithine[000233] Eflornithine oral solution, 150 mg / ml, was a clear liquid containing 13.9%eflornithine free base equivalent (18% eflornithine monohydrochloride hydrate). The oral solution was aqueous-based and contained the following inactive ingredients: glycerin, propylene glycol, saccharin sodium dihydrate and sodium benzoate. The dose of eflornithine was based on body surface area. Administration of eflornithine was orally 2.8 g / m2three-times daily (every 8 hours) on a 2 week on, 1 week off schedule using the dosing cup provided. ThisWSGR Docket No.57339-709601 administration permitted combination with lomustine. Dosage modifications were recommended for patients with eflornithine-related side effects.[000234] Eflornithine oral solution was packaged in white 16 oz. HDPE bottles. Eachbottle contained 463 ml of the solution. The bottles were induction sealed and closed with child resistant HDPE cap. Dosing cups were provided for accurate administration. Eflornithine was stored at room temperature of 25°C (77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F). It was protected from cold and light. Lomustine[000235] Lomustine (CeeNU® and Gleostine®) was obtained from a commercial sourcein 10 mg, 40 mg, and 100 mg capsules for oral administration. Inactive ingredients in lomustine capsules were magnesium stearate and mannitol. The dose of lomustine was based on body surface area. Administration of lomustine was orally 90 mg / m2every 6 weeks with or without food. lomustine was not to be taken on the same day as an eflornithine dose.[000236] Lomustine capsules were packaged in individual bottles of 20 capsules each.Lomustine was stored at room temperature of 25°C (77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F). The capsules were protected from cold and light. Study Design[000237] Eligible patients had biopsy-proven astrocytoma prior to randomization or priorto EBRT and adjuvant temozolomide chemotherapy. In the latter case, there was MRI evidence for tumor progression that reflected progression of astrocytoma and not transformation to glioblastoma or radiation therapy (RT) necrosis, which was based on MRI criteria for these two conditions at the time of the present example. Approximately 340 patients met the eligibility criteria and were enrolled. Of the approximately 340 patients in total: 170 patients were randomly assigned to Treatment Arm A and 170 patients were randomly assigned to Treatment Arm B. The implemented study design is presented in Scheme I and described in the text that follows. Scheme I – Study DesignWSGR Docket No.57339-709601Duration of Study / Treatment[000238] The duration of the study was up to approximately 62 months in total, orconcluded with patient death: •Screening Period – Had a maximum duration of 4 weeks.• Treatment Period:• Treatment Arm A: Patients received eflornithine for up to a total of 24 months.Patients received lomustine for up to 6 cycles or 12 months, whichever came first. •Treatment Arm B: Patients received lomustine for up to 6 cycles or 12 months,whichever came first. •End of Treatment Visit – Had a minimum duration of 4 weeks post last treatment forboth arms. •Follow-Up Period – Was up to approximately 36 months, or concluded with patientdeath.[000239] Treatment Arm A (Eflornithine was administered on a 2 week on, 1 week offschedule + Lomustine was administered every 6 weeks (n=170)): •Eflornithine 2.8 g / m2 was administered orally every 8 hours on a 2 week on, 1 week offschedule, without regard to food. Any missed doses of study drug(s) were skipped, and the patient took the next dose at the assigned time.WSGR Docket No.57339-709601 •Lomustine 90 mg / m2 was administered orally once on Day 15 (+2 days) and once every6 weeks thereafter, without regard to food. Lomustine was administered during the eflornithine off-week and was not taken on the same day as an eflornithine dose. •All patients initially received both eflornithine and lomustine. Patients receivedlomustine for up to 6 cycles or 12 months, if AEs allowed, or until tumor progression by MRI, or death, whichever came first. Patients whose astrocytoma tumors did not progress or recured continued to receive single agent eflornithine for up to a total of 2 years. •Lomustine dose was delayed for a maximum of 6 weeks due to toxicities. If dose delaydue to lomustine was longer than 6 weeks beyond the next scheduled dose, then lomustine was permanently discontinued and patient continued single agent eflornithine for a total treatment of up to 2 years. •If dose delay was due to an eflornithine-related toxicity, lomustine dosing may havecontinued while eflornithine was held. Patients may have continued single agent lomustine until eflornithine-related toxicities had resolved, after which eflornithine was restarted.[000240] Treatment Arm B (Lomustine was administered every 6 weeks (n=170)):• Lomustine 110 mg / m2 was administered orally once on Day 15 (+2 days) and onceevery 6 weeks thereafter, without regard to food. •Patients received lomustine for up to 6 cycles or 12 months, if AEs allowed, or untiltumor progression by MRI, or death, whichever came first. •Lomustine dose was delayed for a maximum of 6 weeks due to toxicities. If dose delaywas longer than 6 weeks beyond the next scheduled dose, then lomustine was permanently discontinued.[000241] Doses for both study drugs were based on body surface area (BSA) which werecalculated based on institutional guidelines (i.e., Mosteller or Dubois).[000242] Randomization was stratified by age ≤ 45 years or > 45 years, region (US vsEx-US), IDH-1 status (wild type vs mutant), and number of prior surgeries (biopsy only vs 1 or 2 surgical resections (e.g., surgical resection at primary diagnosis and secondary surgical resection after first progression / recurrence)). Objectives and EndpointsWSGR Docket No.57339-709601[000243] The primary objective of the present Example was to demonstrate superiority inoverall survival (OS) and comparable safety when eflornithine was added to lomustine compared to lomustine alone in patients with astrocytoma that progressed / recurred after irradiation and adjuvant temozolomide chemotherapy.[000244] The primary endpoint was the duration OS as measured from the date ofrandomization to the date of death due to any cause.[000245] The following secondary objectives of the present Example that weredetermined: •Progression-free survival (PFS);• The objective response rate (ORR);• OS for IDH-1 mutant patients; and• OS for IDH-1 wild type patients.[000246] The secondary endpoints included:• Efficacy: PFS; ORR; OS for IDH-1 mutant patients; and OS for IDH-1 wild typepatients. •Safety: Incidence of treatment emergent adverse events; Incidence of serious adverseevents; and Changes and shifts from baseline in hematology and serum chemistry values, ECGs, and vital signs.[000247] The exploratory objectives of this study that were determined:• Clinical benefit response (CBR) based on magnetic resonance imaging (MRI) criteria;• OS rate at 18 months (OS-18);• Relevance of OS, PFS, ORR, and CBR to commonly used molecular / geneticbiomarkers obtained from most recent pre-study tumor samples (i.e., p53 mutation, deletion of chromosomes 1p and 19q, IDH1 mutations, ATRX mutation, Mib-1 labeling index, MGMT promoter methylation); and •Steady-state plasma pharmacokinetics (PK) for eflornithine in patients within 2 weeksof initial dosing. Inclusion Criteria[000248] Patients who met all of the following inclusion criteria were enrolled in thisstudy:WSGR Docket No.57339-7096011. The ability to understand and sign a written informed consent form, which must beobtained prior to initiation of study procedures.2. Age ≥ 18 years.3. Surgical or biopsy-proven diagnosis of WHO grade 3 astrocytoma.4. Received EBRT and temozolomide chemotherapy prior to first tumor progression orrecurrence of WHO grade 3 astrocytoma.5. First astrocytoma tumor progression or recurrence ≤ 6 months prior to randomizationbased on MRI using T2 hyperintensity, Gd-contrast enhancement, or both.6. To avoid enrollment of patients with glioblastoma, patients with Gd-contrast enhancingtumors were eligible if there is no necrosis seen on MRI and any one of the following criteria was true: a. Gd-contrast lesion margins were clearly defined,b. Gd-contrast lesions were only measurable in one dimension,c. Gd-contrast lesion had two perpendicular diameters less than 10mm ,d. Gd-contrast lesion had two perpendicular diameters greater than 10 mmbut less than 20 mm and lesion did not demonstrate central necrosis, or e. Recent histopathological confirmed WHO grade 3 astrocytoma.7. Completion of EBRT ≥ 6 months prior to randomization.8. Stained, unstained slides or tumor tissue block(s) were available from their most recenttumor surgery and were available for central histological confirmation.9. A patient whose astrocytoma tumor had progressed or recurred and had another surgicalresection prior to randomization was eligible if a) pathology review confirmed astrocytoma, and b) post-surgical MRI demonstrated measurable tumor on T2 FLAIR.10. If taking corticosteroids, then was on a stable or decreasing dose for at least 5 days priorto the screening MRI.11. Karnofsky Performance Status (KPS) score of ≥ 70.12. Off anticancer therapy for at least 4 weeks and recovered from any significanttreatment-related toxicities to grade ≤ 1 prior to randomization.13. Adequate recovery from any major surgery was required; at least 4 weeks elapsed fromthe time of any major surgery and recovered from all surgery-related toxicities to grade ≤ 1 prior to randomization.14. Adequate hematologic function (ANC ≥ 1,500 / µL, platelet count ≥ 100,000 / µL, andhemoglobin ≥ 10.5 gm / dL) within 14 days prior to randomization.WSGR Docket No.57339-709601 15. Total bilirubin ≤ 1.5x upper limit of normal (ULN) within 14 days prior torandomization. 16. Hepatic transaminases (AST and ALT) ≤ 2x ULN within 14 days prior to randomization.17. Adequate renal function (serum creatinine ≤ 1.5x ULN) within 14 days prior torandomization. 18. Life expectancy ≥ 6 months.19. Female patients of childbearing potential agreed to utilize acceptable contraceptivemethods from screening throughout the duration of the study period, and for 30 days following the last dose of study drug. Abstinence was an acceptable method of contraception. Otherwise, consistent and current use of 1 of the following methods of birth control was accepted: oral contraceptive, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), tubal sterilization, Essure micro-insert system, or vasectomy in the male partner. Female patients refrained from egg donation and in vitro fertilization during treatment and until at least 30 days after the last dose of study drug. 20. Male patients agreed to abstain from sexual intercourse or used an acceptablecontraceptive method (e.g. condoms) from screening throughout the duration of the study period, and for 90 days following the last dose of study drug. Male patients refrained from sperm donation during treatment and until at least 90 days after the last dose of study drug. Exclusion Criteria[000249] Patients who met any of the following exclusion criteria were excluded fromparticipation: 1. MRI defining progression that was consistent with a diagnosis of glioblastoma orradiation necrosis. 2. Patients who were considered to be refractory to EBRT and temozolomide but who hadnot progressed. 3. Prior systemic therapy for recurrence of astrocytoma.4. Presence of extracranial or leptomeningeal disease.5. Prior lomustine use.6. History of other invasive malignancy, unless adequately treated with curative intent andwith no known active disease present within 2 years prior to the first dose of study drug. Patients with non-melanoma skin cancer, carcinoma in situ (including superficialWSGR Docket No.57339-709601 bladder cancer), cervical intraepithelial neoplasia and organ-confined prostate cancer deemed by the Investigator to be at low risk of recurrence were not excluded. 7. Active infection or serious intercurrent medical illness.8. Known to be HIV positive or had an AIDS-related illness, active Hepatitis B Virus(HBV), or active Hepatitis C Virus (HCV). 9. Poorly controlled seizures.10. Unable to undergo an MRI with contrast.11. Uncontrolled or severe cardiovascular disease, including myocardial infarction orunstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class III or IV congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis. 12. Malabsorption syndrome, history of resection of the stomach or small bowel, activeulcerative colitis or Crohn’s disease, or partial or complete bowel obstruction or other conditions that was expected to alter the absorption or PK of study drugs. 13. Receipt of any other anticancer therapy.14. Concurrent use of any other investigational agent during the study or within 30 daysprior to randomization. 15. Any other clinical condition or prior therapy that, in the opinion of the Investigator,made the patient unsuitable for the study. 16. Pregnant or breastfeeding.Dose Modification and Toxicity Toxicity[000250] Toxicity descriptions and grading scales found in the revised National CancerInstitute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was utilized for AE reporting. Examples of hematologic toxicity grades from the CTCAE is shown in Table 1 below. Table 1: Relationship of Hematologic Toxicity to CTCAE GradesWSGR Docket No.57339-709601LLN = lower limit of normal Note: Lymphopenia was excluded from the table as it is considered an independent hematologic variable in glioma patients being treated with alkylating drugs; it is typically treated with either trimethoprim / sulfamethoxazole or dapsone for prophylaxis against pneumocystis carinii pneumonia.[000251] Study drug treatment were continued as long as there was no tumor recurrenceor progression, or until the duration of therapies was reached. Subsequent drug dosing was determined by the patient’s recovery from any treatment-related adverse events (AEs) associated with the prior dose of study drug(s). If study drug dosing was delayed due to any toxicity, dosing was resumed at the earliest possible opportunity after a patient had recovered from such toxicity. Subsequent Lomustine Drug Dosing[000252] The next lomustine dose was not administered unless the patient had recoveredfrom lomustine-related toxicities. For lomustine, recovery was defined as occurred when both of the following conditions were met: •All lomustine-related hematologic toxicities shown in Table 1 had subsided to agrade 1 level or had returned to baseline; this excluded lymphopenia. •All lomustine-related non-hematologic toxicities had subsided to a grade 1 level orhad returned to baseline; this excluded alopecia and nausea / vomiting.[000253] A lomustine dose was delayed for a maximum of 6 weeks due to toxicities. If adose delay lasted more than 6 weeks beyond the next scheduled dose, then lomustine was permanently discontinued. If the patient had received both eflornithine and lomustine (Treatment Arm A), the patient continued single agent eflornithine for a total treatment of up to 2 years. Subsequent eflornithine drug dosing[000254] The next eflornithine dose was not administered unless the patient hadrecovered from toxicity due to eflornithine treatment-related AEs / toxicities. For eflornithine, recovery was defined as occurred when both of the following conditions were met: •Eflornithine-related diarrhea, nausea, or vomiting had recovered to grade 1 level orhad returned to baseline (see Dose Modification and Table 1).WSGR Docket No.57339-709601 •Grade 4 eflornithine-related hearing impairment or tinnitus had recovered to grade 2or baseline (see Dose Modification and Table 1).[000255] If a dose delay was due to an eflornithine-related toxicity, lomustine dosing wascontinued while eflornithine was held. Patients continued on single agent lomustine until eflornithine-related toxicities had resolved, after which eflornithine was restarted. Dose Modification[000256] Patients received the same dose or a reduced dose for the next treatment,depending upon the toxicities observed.[000257] If multiple toxicities were seen, the subsequent dose to be administered in asubsequent treatment was based on the most severe toxicity observed.[000258] For a hematologic toxicity, the nadir (lowest) count that was measured duringthe prior treatment was used to determine severity. In the case of multiple hematologic toxicities, the toxicity with the highest grade was used to determine dose modifications or delays. For a non hematologic toxicity, the most severe episode during the prior treatment was used to determine severity. Dose Modification – Treatment Arm A[000259] For a patient who received both eflornithine and lomustine, the subsequentdoses of eflornithine and lomustine were determined from Table 2 and Table 3, based on the worst toxicity grade observed. Table 2: Lomustine Doses for Subsequent Treatment Based on CTCAE Toxicity Grade[000260] Patients who developed a specific AE of hearing impairment, tinnitus, diarrhea,nausea, or vomiting that was considered related to eflornithine was dose adjusted according to Table 3 based on the worst toxicity grade observed.[000261] Patients with dose delays due to lomustine-related toxicity continued to receiveeflornithine once the toxicity had subsided to grade 2 or returned to baseline. In cases where the causative agent for the prolonged toxicity was unclear (i.e., lomustine vs eflornithine) andWSGR Docket No.57339-709601 the Investigator wished to continue therapy when more than a 6-week dose delay had occurred, the study medical monitor was informed. Table 3: Eflornithine Doses for Subsequent Treatment Based on CTCAE Toxicity Grade[000262] For hearing impairment:• Equal to CTCAE grade 2 or grade 3 and was considered related to study treatment,eflornithine dose was immediately reduced according to Table 3. •Equal to CTCAE grade 4, eflornithine was delayed until recovery to at least grade 2or baseline. Upon resumption of eflornithine, subsequent eflornithine doses was reduced according to Table 3. •In the absence of audiometry analysis, patients that presented clinically relevanthearing impairment were considered to have grade 2 or grade 3 toxicity and had their dose of eflornithine immediately reduced according to Table 3. Audiometry was obtained as necessary per Investigators’ judgement.[000263] For tinnitus:• Equal to CTCAE grade 3 and was considered related to study treatment, eflornithinedose was immediately reduced according to Table 3.[000264] For diarrhea, nausea, or vomiting:WSGR Docket No.57339-709601 •Investigator judgment prevailed with respect to whether the patient was a candidate toresume eflornithine after a grade 4 episode. •Patients who experienced grade 1 or less after an initial eflornithine dose reductionhad their dose increased to the next highest dose level (i.e., from 1.4 to 2.1 g / m2every 8 hours or from 2.1 to 2.8 g / m2every 8 hours) at the discretion of the treating Investigator. In no case was a patient’s eflornithine dose escalated to higher than the initial starting dose of 2.8 g / m2every 8 hours. Dose Modification – Treatment Arm B[000265] For a patient who received lomustine, the subsequent doses was determinedfrom Table 2 based on the worst toxicity grade observed. Study Procedures[000266] The study procedures conducted for each patient enrolled in the study arepresented in tabular form in Table 4.1, Table 4.2 and described in the text that follows. Screening Visit[000267] Patients were screened up to 4 weeks prior to randomization to determineeligibility for participation in the study.[000268] The following was performed and documented within 4 weeks prior torandomization, unless otherwise specified: •Written informed consent;• Medical history, including history of astrocytoma disease-related events, and surgery;• Obtained documentation of evaluable disease (within 14 days prior to randomization);• Obtained histopathology report that confirmed a diagnosis of astrocytoma (WHOgrade 3) and slides or tissue block(s) were sent to the Referee Neuro-pathologist(s); •Obtained the two most recent brain MRI scans, which included the MRI that definedtumor progression, with the latest MRI being obtained within 14 days of last tumor biopsy if biopsy occured. These scans were submitted to Orbus and included in the clinical data repository; •Completed physical examination including vital signs, body weight and height;• KPS;WSGR Docket No.57339-709601 •Urinalysis;• Steroid and anticonvulsant medication documentation;• Blood sample collection for the following laboratory analyses: (standard of carelaboratory analyses [(e.g., chemistry)] performed prior to the written informed consent, was accepted if within 14 days prior to randomization): •Serum pregnancy test (females of childbearing potential only, within 14 daysprior to randomization), •Chemistry (including liver function tests),• Hematology: completed blood count (CBC) with differential white cell count,and platelet count; and •Recorded any serious adverse events (SAEs) and all AEs related to protocol-mandated procedures occurring after the consent form was signed; and •Obtained concomitant medications taken within 30 days of the screening visit.[000269] From the time of obtaining informed consent through the first administration ofinvestigational medicinal product, recorded all SAEs, as well as any adverse events related to protocol-mandated procedures on the adverse events case report form (eCRF). All other untoward medical occurrences observed during the screening period, including exacerbation or changes in medical history were captured on the medical history eCRF. Randomization (Week 1)[000270] Once eligibility was confirmed, the patient was randomized to either TreatmentArm A or Treatment Arm B using the Electronic Data Capture (EDC) system. The EDC also assigned a unique patient number to the patient. Once a patient number was assigned, it was not reassigned to any other patient.[000271] The following were completed at the Randomization Visit (unless otherwisespecified): •Randomization (was performed up to 2 days prior to the in-clinic randomizationvisit); •Patient number assignment (was performed up to 2 days prior to the in-clinicrandomization visit); •Targeted physical examination;WSGR Docket No.57339-709601 •Vital sign measurement (blood pressure, pulse, respiration rate, and temperature);• Weight;• KPS;• Brain MRI (was obtained within 14 days prior to randomization). This scan wassubmitted to Orbus and included in the clinical data repository; •12-lead ECG (was obtained within 14 days prior to randomization);• Audiometry (was obtained within 14 days prior to randomization);• Pulmonary function test via forced vital capacity (was obtained within 14 days priorto randomization); •Blood sample collection for the following laboratory analyses: (screening laboratoryprocedures was used as baseline if performed within 1 week prior to the randomization visit): •Chemistry (including liver function tests),• Hematology: completed blood count (CBC) with differential white cell count,and platelet count, and •PK (Treatment Arm A sub-study patients only);• Dispense study drug, as appropriate;• Review of changes in concomitant medications; and• Review of AEs.Treatment Assessments[000272] Week 2 (for a subset of Treatment Arm A patients only: n = approximately 20).PK and 12-lead ECG was performed on the same day (between Days 7 and 14). •PK was drawn approximately 3–5 hours post dose and 6–8 hours post dose of the visitday. •12-lead ECG was performed at approximately 3–5 hours post dose of the visit day.[000273] Week 3 (for a subset of Treatment Arm B patients only: n = approximately 20).• 12-lead ECG was performed within one day of initial lomustine dosing.[000274] Year 1 and Year 2. The following assessments were completed at Week 8 (+2weeks), and then every 6 weeks (+2 weeks) thereafter through Month 6. Beginning Month 7,WSGR Docket No.57339-709601 these assessments were completed every 10 weeks (+2 weeks) through Month 12. Year 2 visits had occurred every 3 months (+2 weeks) (Note: Audiometry, urinalysis, and pulmonary function test was performed every 3 months at the closest scheduled study visit.): •Targeted physical examination;• Vital signs measurement (blood pressure, pulse, respiration rate, and temperature);• Weight;• KPS;• Brain MRI (performed per institutional standard of care). MRI scans that showedevidence of progression or response were submitted to Orbus and included in the clinical data repository; •Audiometry (performed every 3 months post randomization);• Urinalysis (performed every 3 months post randomization);• Pulmonary function test via forced vital capacity (performed every 3 months postrandomization and only during lomustine treatment); •Blood sample collection for the following laboratory analyses:• Chemistry (including liver function tests),• Hematology: CBC with differential white cell count, and platelet count, and• Lab draws to assess hematological toxicities for lomustine was performedweekly after the first dose of lomustine per the prescribing information and was continued during lomustine treatment only; •Dispense study drug, as appropriate;• Review changes in concomitant medications; and• Review of AEs.Evaluation of Pharmacokinetics[000275] Blood samples were collected at randomization and within 2 weeks of initialdosing in a subset of Treatment Arm A patients to evaluate steady-state plasma PK of eflornithine. Evaluation of ECGWSGR Docket No.57339-709601[000276] Descriptive statistics were performed on a subset of patients. A 12-lead ECGwas obtained at baseline, Week 2 or 3 (depending on Treatment Arm assignment), and End of Treatment. The ECG parameters assessed included heart rate and PR, QRS, and QTc intervals. Evaluation of Biomarkers[000277] Tissue slides or tumor block were collected to determine relevance of OS, PFS,ORR, and CBR to commonly used molecular / genetic biomarkers (e.g., CDKN2A / B mutations, p53 mutation, deletion of chromosomes 1p and 19q, IDH1 mutations, IDH2 mutations, ATRX mutation, Mib-1 labeling index, MGMT promoter methylation, TERT promoter mutations, EGFR mutations, chromosome 7 / 10 mutations). End of Treatment Assessment[000278] An End of Treatment Visit was performed upon termination of all studytreatments (eflornithine plus lomustine and lomustine alone). The following assessments were performed a minimum of 4 weeks after the last dose of study drug(s): •Complete physical examination including vital signs and body weight;• KPS;• 12-lead ECG;• Blood sample collection for the following laboratory analyses:• Chemistry (including liver function tests), and• Hematology: CBC with differential white cell count, and platelet count;• Review of changes in concomitant medications; and• Review of AEs.Follow-Up Period[000279] For patients who experienced disease progression, information regarding futuretreatment(s) was collected and recorded on the eCRF. The following assessment was performed approximately every 2 months: •Confirmed survival status via phone. Survival status was recorded on the eCRFimmediately after confirmation. Discontinuation of Study TreatmentWSGR Docket No.57339-709601[000280] Patients were withdrawn or removed from study treatment at any time for thefollowing reason: •Unacceptable toxicity, or toxicity that, in the judgment of the Investigator,compromised the ability to continue study-specific procedures or it was considered to not be in the patient’s best interest to continue study treatment; •Disease progression;• Patient requested to discontinue study drug;• Patient was noncompliant; or• Pregnancy during the study.Table 4.1: Study Procedures – Screening to Month 6WSGR Docket No.57339-709601 Table 4.1: Study Procedures – Screening to Month 6WSGR Docket No.57339-709601 Table 4.1: Study Procedures – Months 7-12 to Follow-UpWSGR Docket No.57339-709601 Table 4.1: Study Procedures – Months 7-12 to Follow-UpStatistical Considerations[000281] The primary efficacy analysis was performed in accordance with the intention-to-treat (ITT) principle. All randomized patients were included in the primary efficacy analysis according to their randomly assigned study treatment, irrespective of the actual receipt of such treatment. The primary variable of OS was summarized descriptively using the Kaplan-Meier method. For both endpoints, the primary inferential comparison between treatment arms was performed using the log-rank test stratified by the randomization stratification factors for age, region, IDH-1 status, and number of prior surgeries. Estimation of the hazard ratio (HR) for treatment arm was determined using a stratified Cox proportional hazards model, without any other covariate. Duration of OS in subgroups of IDH-1 mutant and wild type was analyzed similarly to the primary efficacy variable. PFS was summarized similarly to OS. ORR was estimated based on the proportion of patients in each treatment arm whose best overall response during the course of study treatment is CR or PR. Approximate 95% confidence intervals were calculated by treatment arm for the true ORR. The inferential comparison of the observed ORRs was made using the Cochran-Mantel-Haenszel chi-square test, stratified by age, region, IDH-1 status, and number of prior surgeries. Multiplicity AdjustmentWSGR Docket No.57339-709601[000282] The overall type I error rate for the study was set at 0.05 (two-sided). Ifsuperiority of OS was demonstrated at either the interim or primary analysis, formal inferential comparisons between treatment arms was planned for the secondary endpoints PFS and ORR. The tests were performed in a sequential hierarchical manner based on a closed testing procedure (CTP). The CTP was employed to maintain control of the overall type I error rate to account for hypothesis testing of multiple secondary endpoints. Sample Size[000283] The sample size was calculated by assuming true median OS of 12 months forthe treatment arm receiving lomustine monotherapy (control arm). It was hypothesized that true median OS would be 18 months or longer for the treatment arm receiving eflornithine plus lomustine (investigational arm). Under the assumption that OS followed an exponential probability distribution for each treatment arm, such an improvement represents a true hazard ratio of 0.667 (investigational arm / control arm). Inferential comparisons of OS was performed using a stratified log-rank test, stratifying on the randomization stratification factors for age, region, IDH-1 status, and number of prior surgeries. Total accrual of approximately 340 patients (170 per treatment arm) and total information of 261 deaths was estimated to provide 90% power to detect a 33% reduction in the OS failure hazard rate, based on a two- sided overall type I error of 5% with adjustment for one interim analysis for superiority at 75% of total deaths, using O’Brien-Fleming stopping boundary (SEQDESIGN procedure, SAS version 9.4). Results[000284] Based on previous studies (Levin et al., Clinical importance of eflornithine (α-difluoromethylornithine) for the treatment of malignant gliomas, CNS Oncol. (2018) 7(2), CNS16), it was expected that cytostatic action of eflornithine would be relevant to inhibition of the tumor growth in patients with glioma irrespective of its genetic profile. Contrary to this expectation, the results of the current study revealed that when viewed in aggregate (all patients intended to treat), the overall survival and progression free survival of the patients treated during the study were not significantly affected by the addition of eflornithine to the lomustine- only standard of care therapy (FIG.2 and Table 5; and FIG.3 and Table 6). Table 5: Overall Survival (OS) Results for Patients Summary StatisticsWSGR Docket No.57339-709601Table 6: Progression Free Survival (PFS) Results for Patients – Summary Statistics[000285] The improvement in treatment outcome (a combination of eflornithine andlomustine compared to lomustine alone) as measured by OS and PFS was significantly more pronounced when analyzing patient groups with particular genetic profiles. The overall survival (OS) (primary endpoint) rates are summarized in Table 7. The results demonstrate that, among other things, when eflornithine was added to lomustine in patients with astrocytoma that progressed / recured after irradiation and adjuvant temozolomide chemotherapy, patient groups with certain genetic profiles demonstrate superiority in overall survival (OS) and comparable safety compared to those taking lomustine alone. For example,WSGR Docket No.57339-709601 there was statistically significant improvement of OS in grade 3 Astrocytoma patients when adding eflornithine to lomustine when compared to lomustine alone.[000286] The progression free survival (PFS) (secondary endpoint) rates are summarizedin Table 8. The results demonstrate that, among other things, when eflornithine was added to lomustine in patients with astrocytoma that progressed / recured after irradiation and adjuvant temozolomide chemotherapy, patient groups with certain genetic profiles demonstrate superiority in progression free survival (PFS) and comparable safety compared to those taking lomustine alone. For example, there was statistically significant improvement of PFS in grade 3 Astrocytoma patients when adding eflornithine to lomustine when compared to lomustine alone. Table 7: Results – Primary Endpoint: Overall Survival (OS)Table 8: Results – Secondary Endpoint: Progression Free Survival (PFS)[000287] The data described herein (e.g., in Tables 5-12) presents an update to an earlierversion of the data included in the priority document due to further analysis. For example, upon further molecular analysis of patient tumor tissue samples, certain patients that were originally classified as grade 4 glioblastoma were re-classified as grade 3&4 astrocytoma.WSGR Docket No.57339-709601[000288] As described herein, the grade classification is used in accordance with WHO2021 classification. For example, grade 4 glioblastoma refers glioma with wildtype IDH (e.g., IDH1, IDH2). Grade 3 astrocytoma refers to glioma with mutant IDH (either IDH1 or IDH2) and no homozygous deletion of CDKN2A / B. Grade 4 astrocytoma refers to glioma with mutant IDH (either IDH1 or IDH2) and homozygous deletion of CDKN2A / B. Example 3 – Human Clinical Trials – Phase 3 – Subset Analysis[000289] The present Example demonstrates the impact of genetic profiles (e.g., status ofCDKN2A / B, status of ATRX, etc.) on the treatment outcome of eflornithine and lomustine compared to lomustine alone. Subset analysis was performed for the patients with astrocytoma characterized by IDH (IDH1 or IDH2) mutation and no homozygous deletion of CDKN2A / B genes. The analysis illustrated that addition of eflornithine to the standard of care significantly improved OS and PFS in such patient groups (FIG.4 and Table 9; and FIG.5 and Table 10). Table 9: Overall Survival (OS) Results for Patients with IDH (IDH1 or IDH2) Mutant and CDKN2A / B intact – Summary StatisticsTable 10: Progression Free Survival (PFS) Results for Patients with (IDH1 or IDH2) Mutant and CDKN2A / B intact – Summary StatisticsWSGR Docket No.57339-709601[000290] Subset analysis was performed for the patients with astrocytoma characterizedby IDH (IDH1 or IDH2) mutation and no homozygous deletion of CDKN2A / B genes, in addition to intact ATRX. The analysis illustrated that addition of eflornithine to the standard of care significantly improved OS and PFS in such patient groups (FIG.6 and Table 11; and FIG.7 and Table 12). Table 11: Overall Survival (OS) Results for Patients with IDH (IDH1 or IDH2) Mutant, CDKN2A / B and ATRX intact – Summary StatisticsTable 12: Progression Free Survival (PFS) Results for Patients with IDH (IDH1 or IDH2) Mutant, CDKN2A / B and ATRX intact – Summary StatisticsWSGR Docket No.57339-709601[000291] The comparison of the two subgroups of patients (Table 13) showed that whilethe subset of patients without regard to their ATRX mutation status have showed improved OS and PFS when treated with eflornithine and lomustine compared to lomustine alone, such improvement increased by about 10-fold in patients who have IDH (IDH1 or IDH2) mutation, intact CDK2A / B and intact ATRX. Table 13: Effect of Eflornithine on OS and PFS in Patient Populations with IDH (IDH1 or IDH2) MutationExample 4 – IDH Mutation Detection – IDH1 / 2 PCR Assay[000292] As appreciated by those skilled in the art, various methods, e.g.,immunohistochemistry, Western blot, immunocytochemistry, etc. are known in the art to detect mutations in IDH genes. The present Example demonstrates a method of detecting mutations in IDH genes. Detection of mutations at IDH1 codons R132X and R100Q and at IDH2 codons R140X and R172X was performed using real-time PCR conducted by NeoGenomics (i.e.:WSGR Docket No.57339-709601 https: / / neogenomics.com / test-menu / idh1idh2-mutation-analysis-pcr). The real-time PCR- based assay detected somatic mutations in exon 4 of the IDH1 and IDH2 genes. The real-time PCR assay used allele-specific primers to identify the presence of IDH1 and IDH2 mutations in 5 separate reaction mixes per sample. The assay was designed to preferentially amplify mutant DNA, even in samples that contain mostly wild-type DNA. The amplification product was detected by hydrolysis probes. Probes complimentary to the IDH1 and IDH2 genes are labeled with the FAM (5’6-FAM is a fluorescein probe for oligonucleotides) fluorophore, while the probe complimentary to the endogenous control gene was tagged with the VIC (an asymmetric xanthene dye with fluorescence in the yellow-green part of the spectrum) fluorophore. Signal from the VIC tagged probe indicated that there was sufficient amplifiable DNA template in the reaction, while a signal from the FAM fluorophore indicated the presence of a mutation. The sample required for the assays included: 5 mL in EDTA tube for peripheral blood, 2 mL in EDTA tube for bone marrow, or a paraffin block (alternatively 1 H&E slide plus 5-10 unstained slides cut at 5 or more microns with positively-charged slides and 10% NBF fixative) for FFPE solid tumor tissue. Example 5 – CDKN2A / B FISH Assay[000293] The fluorescence in situ hybridization (FISH) is a cytogenetic technique whichis used for detecting and locating the presence or absence of specific DNA sequences in chromosomes. FISH uses fluorescence probes which only bind to some parts of the chromosome with which they show a high degree of sequence similarity. In the present Example, the DNA probe was labeled with a fluorescent molecule or a hapten, in the form of fluor-dUTP, digoxigenin-dUTP, biotin-dUTP or hapten-dUTP which was incorporated in the DNA using enzymatic reactions, such as nick translation or PCR. The sample containing the genetic material (the chromosomes) was placed on glass slides and was denatured by a formamide treatment. The labeled probe was then hybridized with the sample containing the genetic material under suitable conditions. After the hybridization, the sample was viewed either directly (in the case of a probe labeled with fluorine) or indirectly (using fluorescently labeled antibodies to detect the hapten).[000294] Detection of homozygous deletions of CDKN2A / B (also called p16) wasperformed by CDKN2A / B FISH assay conducted by NeoGenomics (i.e.: https: / / neogenomics.com / test-menu / cdkn2ab-p16-deletion-mesothelioma-or-glioma). NeoGenomics FISH assay procedure was similar to Agilent DAKO Histology FISH Kit (Code K5799; see: https: / / www.agilent.com / en / product / molecular-pathology / ish-ancillaries-WSGR Docket No.57339-709601 accessories / ish-ancillaries-accessories-%28manual%29 / histology-fish-accessory-kit-76860 pdf manual), but used Agilent probes CDKN2A and CEP9. While morphologic, immunocytochemical, and immunohistochemical analyses determine the mesothelial origin of such neoplasms, CDKN2A / B FISH enabled differentiation of benign from malignant proliferations with high specificity and positive predictive value, particularly when combined with BAP-1 IHC. The CDKN2A / B FISH determined the presence of CDKN2A homozygous deletion, CDKN2A heterozygous deletion, or chromosome 9 monosomy. The sample required the assays included: a paraffin block or H&E slide (plus 4 unstained slides cut at 4-5 microns).[000295] The examples and embodiments described herein are for illustrative purposesonly and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WSGR Docket No.57339-709601 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject with no homozygous deletion of CDKN2A / Bgenes, comprising administering to the subject an ornithine decarboxylase inhibitor.

2. A method of treating cancer in a subject with intact CDKN2A / B genes, comprisingadministering to the subject an ornithine decarboxylase inhibitor.

3. A method of treating cancer in a subject with mutant IDH and no homozygousdeletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

4. A method of treating cancer in a subject with mutant IDH1 and no homozygousdeletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

5. A method of treating cancer in a subject with mutant IDH2 and no homozygousdeletion of CDKN2A / B genes, comprising administering to the subject an ornithine decarboxylase inhibitor.

6. A method of treating cancer in a subject with mutant IDH and intact CDKN2A / Bgenes, comprising administering to the subject an ornithine decarboxylase inhibitor.

7. A method of treating cancer in a subject with mutant IDH1 and intact CDKN2A / Bgenes, comprising administering to the subject an ornithine decarboxylase inhibitor.

8. A method of treating cancer in a subject with mutant IDH2 and intact CDKN2A / Bgenes, comprising administering to the subject an ornithine decarboxylase inhibitor.

9. The method of any one of claims 1-8, wherein the method further comprisesadministering a second therapeutic agent or treatment including a chemotherapeutic agent, an immunotherapy agent, or radiation therapy, or a combination thereof.

10. The method of claim 8, wherein the second therapeutic agent is a chemotherapeuticagent.

11. The method of claim 10, wherein the chemotherapeutic agent is an alkylating agent.

12. The method of claim 11, wherein the alkylating agent is lomustine, carmustine, orsemustine.

13. The method of claim 12, wherein the chemotherapeutic agent is lomustine.

14. The method of any one of claims 1-13, wherein the ornithine decarboxylase inhibitoris eflornithine or a salt thereof.WSGR Docket No.57339-70960115. A method of treating cancer in a subject with mutant IDH and no homozygousdeletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

16. A method of treating cancer in a subject with mutant IDH1 and no homozygousdeletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

17. A method of treating cancer in a subject with mutant IDH2 and no homozygousdeletion of CDKN2A / B genes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

18. A method of treating cancer in a subject with mutant IDH and intact CDKN2A / Bgenes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

19. A method of treating cancer in a subject with mutant IDH1 and intact CDKN2A / Bgenes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

20. A method of treating cancer in a subject with mutant IDH2 and intact CDKN2A / Bgenes, comprising administering to the subject eflornithine or a salt thereof and a chemotherapeutic agent.

21. A method of treating cancer, comprising selecting a subject with no homozygousdeletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

22. A method of treating cancer, comprising selecting a subject with intact CDKN2A / Bgenes, and administering to said subject an ornithine decarboxylase inhibitor.

23. A method of treating cancer, comprising selecting a subject with mutant IDH and nohomozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

24. A method of treating cancer, comprising selecting a subject with mutant IDH1 and nohomozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

25. A method of treating cancer, comprising selecting a subject with mutant IDH2 and nohomozygous deletion of CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.WSGR Docket No.57339-70960126. A method of treating cancer, comprising selecting a subject with mutant IDH andintact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

27. A method of treating cancer, comprising selecting a subject with mutant IDH1 andintact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

28. A method of treating cancer, comprising selecting a subject with mutant IDH2 andintact CDKN2A / B genes, and administering to said subject an ornithine decarboxylase inhibitor.

29. The method of any one of claims 21-28, wherein the method further comprisesadministering a second therapeutic agent or treatment including a chemotherapeutic agent, an immunotherapy agent, or radiation therapy, or a combination thereof.

30. The method of claim 28, wherein the second therapeutic agent is a chemotherapeuticagent.

31. The method of claim 30, wherein the chemotherapeutic agent is an alkylating agent.

32. The method of claim 31, wherein the alkylating agent is lomustine, carmustine, orsemustine.

33. The method of claim 32, wherein the chemotherapeutic agent is lomustine.

34. The method of any one of claims 21-33, wherein the ornithine decarboxylase inhibitoris eflornithine or a salt thereof.

35. A method of treating cancer, comprising selecting a subject with mutant IDH and nohomozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

36. A method of treating cancer, comprising selecting a subject with mutant IDH1 and nohomozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

37. A method of treating cancer, comprising selecting a subject with mutant IDH2 and nohomozygous deletion of CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

38. A method of treating cancer, comprising selecting a subject with mutant IDH andintact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.WSGR Docket No.57339-70960139. A method of treating cancer, comprising selecting a subject with mutant IDH1 andintact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

40. A method of treating cancer, comprising selecting a subject with mutant IDH2 andintact CDKN2A / B genes, and administering to said subject eflornithine or a salt thereof and a chemotherapeutic agent.

41. A method of treating cancer, comprising:(1) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (2) selecting a subject who has no homozygous deletion of CDKN2A / B genes; and (3) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and optionally a chemotherapeutic agent, e.g., lomustine.

42. A method of treating cancer, comprising:(1) evaluating IDH genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH mutant and has no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and optionally a chemotherapeutic agent, e.g., lomustine.

43. A method of treating cancer, comprising:(1) evaluating IDH1 genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH1 mutant and has no homozygous deletion of CDKN2A / B genes; and (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and optionally a chemotherapeutic agent, e.g., lomustine.

44. A method of treating cancer, comprising:(1) evaluating IDH2 genetic profiles of a plurality of subjects suffering from cancer; (2) evaluating CDKN2A / B genetic profiles of a plurality of subjects suffering from cancer; (3) selecting a subject who is IDH2 mutant and has no homozygous deletion of CDKN2A / B genes; andWSGR Docket No.57339-709601 (4) administering to said subject an ornithine decarboxylase inhibitor, e.g., eflornithine or a salt thereof and optionally a chemotherapeutic agent, e.g., lomustine.

45. The method of any one of claims 4, 7, 9-14, 16, 19, 24, 27, 29-34, 36, 39, and 43,wherein the mutant IDH1 gene comprises a mutation at R132X or R100Q codon.

46. The method of any one of claims 4, 7, 9-14, 16, 19, 24, 27, 29-34, 36, 39, and 43,wherein the mutant IDH1 gene comprises a base pair exchange of guanine to adenine (G395A), resulting in replacement of arginine by histidine at site R132 (R132H).

47. The method of any one of claims 5, 8-14, 17, 20, 25, 28-34, 37, 40, and 44, whereinthe mutant IDH2 gene comprises a mutation at R140X or R172X codon.

48. The method of any one of claims 3, 9-15, 18, 23, 26, 29-35, 38, and 42, the mutantIDH gene is determined by examining tumor tissue.

49. The method of any one of claims 4, 7, 9-14, 16, 19, 24, 27, 29-34, 36, 39, 43, 45, and46, the mutant IDH1 gene is determined by examining tumor tissue.

50. The method of any one of claims 5, 8-14, 17, 20, 25, 28-34, 37, 40, 44, and 47, themutant IDH2 gene is determined by examining tumor tissue.

51. The method of any one of claims 3, 9-15, 18, 23, 26, 29-35, 38, and 42, the mutantIDH gene is determined by examining stained tumor tissue on a microscope slide using immunohistochemistry (IHC) technique or gene sequencing.

52. The method of any one of claims 4, 7, 9-14, 16, 19, 24, 27, 29-34, 36, 39, 43, 45, and46, the mutant IDH1 gene is determined by examining stained tumor tissue on a microscope slide using immunohistochemistry (IHC) technique or gene sequencing.

53. The method of any one of claims 5, 8-14, 17, 20, 25, 28-34, 37, 40, 44, and 47, themutant IDH2 gene is determined by examining stained tumor tissue on a microscope slide using immunohistochemistry (IHC) technique or gene sequencing.

54. The method of any one of claims 1-53, wherein the status of CDKN2A / B isdetermined by assessing percentage of tumor cells that show intact CDKN2A / B alleles, homozygous deletion of both CDKN2A / B alleles, and heterozygous deletion of CDKN2A / B alleles, by examining stained tumor tissue on a microscope slide using fluorescence in situ hybridization (FISH) technique.

55. The method of claim 54, wherein a subject whose sample shows less than about 20%homozygous deletion of CDKN2A / B in a FISH experiment is evaluated as a subject with no homozygous deletion of CDKN2A / B genes.

56. The method of any one of claims 1-55, wherein the subject has intact ATRX gene.WSGR Docket No.57339-70960157. The method of any one of claims 1-56, wherein the cancer is radiotherapyrecurrent / refractory cancer.

58. The method of any one of claims 1-57, wherein the cancer is chemotherapyrecurrent / refractory cancer.

59. The method of any one of claims 1-58, wherein the cancer is temozolomiderecurrent / refractory cancer.

60. The method of any one of claims 1-59, wherein the subject is a subject whoexperiences relapse after radiotherapy.

61. The method of any one of claims 1-59, wherein the subject is a subject whoexperiences relapse after chemotherapy.

62. The method of any one of claims 1-59, wherein the subject is a subject whoexperiences relapse after temozolomide treatment.

63. The method of any one of claims 1-62, wherein the cancer is glioma.

64. The method of any one of claims 1-62, wherein the cancer is grade 2 astrocytoma orgrade 3 astrocytoma.

65. The method of any one of claims 1-64, wherein the cancer is grade 3 astrocytoma.

66. The method of any one of claims 1-65, wherein the method comprises administering atherapeutically effective amount of eflornithine or a salt thereof and a chemotherapeutic agent.

67. The method of any one of claims 1-66, wherein eflornithine or a salt thereof isadministered at a dose from about 1 g / m2to about 10 g / m2three-times daily (every 8 hours) free base equivalent.

68. The method of any one of claims 1-67, wherein eflornithine or a salt thereof isadministered at a dose from about 1.4 g / m2to about 3.5 g / m2three-times daily (every 8 hours) free base equivalent.

69. The method of any one of claims 1-68, wherein eflornithine or a salt thereof isadministered at a dose of about 2.8 g / m2three-times daily (every 8 hours) free base equivalent.

70. The method of any one of claims 1-69, wherein eflornithine or a salt thereof isadministered at a dose of about 1.4 g / m2, 2.1 mg / m2, or 2.3 g / m2three-times daily (every 8 hours) free base equivalent.

71. The method of any one of claims 1-70, wherein eflornithine or a salt thereof isadministered daily on a two-week-on followed by a one-week-off schedule.WSGR Docket No.57339-70960172. The method of any one of claims 1-71, wherein eflornithine or a salt thereof isadministered in one or more cycles of treatment period and each cycle comprises about 6 weeks.

73. The method of claim 72, wherein eflornithine or a salt thereof is administered for atleast about 6 cycles.

74. The method of claim 72, wherein eflornithine or a salt thereof is administered for atleast about 12 months.

75. The method of claim 72, wherein eflornithine or a salt thereof is administered for atleast about 24 months.

76. The method of any one of claims 1-75, wherein the subject is administeredeflornithine hydrochloride hydrate.

77. The method of any one of claims 1-75, wherein the subject is administeredeflornithine.

78. The method of any one of claims 1-77, wherein the chemotherapeutic agent islomustine.

79. The method of any one of claims 78, wherein lomustine is administered at a dosefrom about 50 mg / m2to about 110 mg / m2every 6 weeks.

80. The method of any one of claims 78-79, wherein lomustine is administered at a doseof from about 50 mg / m2to about 90 mg / m2every 6 weeks.

81. The method of any one of claims 78-80, wherein lomustine is administered at a doseof about 90 mg / m2every 6 weeks.

82. The method of any one of claims 78-81, wherein lomustine is administered in one ormore cycles of treatment period and each cycle comprises about 6 weeks.

83. The method of claim 82, wherein lomustine is administered for no more than 6 cycles.

84. The method of claim 82, wherein lomustine is administered for no more than 12months.

85. The method of any one of claims 1-84, wherein lomustine is administered on a daywherein eflornithine or a salt thereof is not administered.

86. The method of any one of claims 1-84, wherein lomustine is administered on a day inthe off-week of the treatment period of eflornithine or a salt thereof.

87. The method of any one of claims 1-86, wherein eflornithine or a salt thereof isadministered daily on Days 1–14 (Weeks 1 and 2) and Days 22–35 (Weeks 4 and 5), and lomustine is administered on Day 15 (+2 days) (Week 3).WSGR Docket No.57339-70960188. The method of any one of claims 82-87, wherein dose of lomustine is discontinuedafter 6 cycles or 12 months, whichever comes first, and eflornithine or a salt thereof is administered for an additional 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months after discontinuation of the dose of lomustine.

89. The method of any one of claims 1-88, wherein the method further comprisesadjusting or delaying the dose of eflornithine or a salt thereof based on observed toxicity according to CTCAE toxicity grade scale.

90. The method of claim 89, wherein the subject develops an adverse event of hearingimpairment, tinnitus, diarrhea, nausea, or vomiting, or any combination thereof.

91. The method of claim 90, wherein the dose of eflornithine or a salt thereof ismaintained at original dose if hearing impairment grade is 1 or normal under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 75% of original eflornithine or a salt thereof dose if hearing impairment grade is 2 or 3 under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 50% of original eflornithine or a salt thereof dose if hearing impairment grade is 4 under CTCAE toxicity grade scale.

92. The method of claim 90, wherein the dose of eflornithine or a salt thereof ismaintained at 2.8 g / m2if hearing impairment grade is 1 or normal under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 2.1 g / m2if hearing impairment grade is 2 or 3 under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 1.4 g / m2if hearing impairment grade is 4 under CTCAE toxicity grade scale.

93. The method of claim 90, wherein the dose of eflornithine or a salt thereof ismaintained at original dose if tinnitus grade is 1 or 2 or normal under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 75% of original eflornithine or a salt thereof dose if tinnitus grade is 3 under CTCAE toxicity grade scale.

94. The method of claim 90, wherein the dose of eflornithine or a salt thereof ismaintained at 2.8 g / m2if tinnitus grade is 1 or 2 or normal under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 2.1 g / m2if tinnitus grade is 3 under CTCAE toxicity grade scale.

95. The method of claim 90, wherein the dose of eflornithine or a salt thereof ismaintained at original dose if diarrhea, nausea, or vomiting grade is 1 or 2 or normal under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 75% of original eflornithine or a salt thereof dose if diarrhea, nausea, or vomiting grade is 3 underWSGR Docket No.57339-709601 CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 50% of original eflornithine or a salt thereof dose if diarrhea or vomiting grade is 4 under CTCAE toxicity grade scale.

96. The method of claim 90, wherein the dose of eflornithine or a salt thereof ismaintained at 2.8 g / m2if diarrhea, nausea, or vomiting grade is 1 or 2 or normal under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 2.1 g / m2if diarrhea, nausea, or vomiting grade is 3 under CTCAE toxicity grade scale, and the dose of eflornithine or a salt thereof is reduced to 1.4 g / m2if diarrhea or vomiting grade is 4 under CTCAE toxicity grade scale.

97. The method of any one of claims 1-96, wherein the method further comprisesadjusting or delaying the dose of lomustine based on observed toxicity according to CTCAE toxicity grade scale.

98. The method of claim 97, wherein the dose of lomustine is maintained at original doseif grade is 1 or normal under CTCAE toxicity grade scale, and the dose of lomustine is reduced to 75% of original lomustine dose if grade is 2 under CTCAE toxicity grade scale, and the dose of lomustine is reduced to 50% of original lomustine dose if grade is 3 or 4 under CTCAE toxicity grade scale,99. The method of claim 97, wherein the method further comprises adjusting or delayingthe dose of lomustine for subjects who experienced thrombocytopenia after treatment.

100. The method of claim 97, wherein the method further comprises adjusting the dose oflomustine to 90 mg / m2for subjects who experienced thrombocytopenia after receiving treatment.

101. The method of any one of claims 1-100, wherein the subject is administered apharmaceutical composition comprising eflornithine or a salt thereof.

102. The method of claim 101, wherein the pharmaceutical composition of eflornithine orsalt thereof is formulated for oral administration.

103. The method of any one of claims 101-102, wherein the pharmaceutical compositionof eflornithine or salt thereof is formulated as a solution for oral administration.

104. The method of any one of claims 101-103, wherein the pharmaceutical compositionof eflornithine or salt thereof comprises from about 16.2% to about 19.8% of eflornithine hydrochloride hydrate, water, and one or more pharmaceutically acceptable excipients.

105. The method of any one of claims 101-104, wherein the pharmaceutical compositionof eflornithine or salt thereof comprises from about 18% of eflornithine hydrochlorideWSGR Docket No.57339-709601 hydrate (13.9% eflornithine free base equivalent), glycerin, propylene glycol, saccharin sodium, sodium benzoate, and water.

106. The method of any one of claims 1-105, wherein the subject is administered apharmaceutical composition comprising lomustine.

107. The method of claim 106, wherein the pharmaceutical composition of lomustine or isformulated for oral administration.

108. The method of any one of claims 106-107, wherein the pharmaceutical compositionof lomustine is formulated as a capsule for oral administration.

109. The method of any one of claims 106-108, wherein the pharmaceutical compositionof lomustine comprises lomustine, magnesium stearate, and mannitol.

110. A method of treating cancer, comprising:(1) preparing an oral solution of eflornithine or a salt thereof comprising adding the contents of a pouch of eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of eflornithine, e.g., eflornithine hydrochloride hydrate, wherein the pouch comprises an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate,; and (2) administering to a subject with the cancer characterized by mutant IDH and no homozygous deletion of CDKN2A / B genes the oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate, and a chemotherapeutic agent, e.g., lomustine.

111. A method of treating cancer, comprising:(1) preparing an oral solution of eflornithine or a salt thereof comprising adding the contents of a pouch of eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of eflornithine, e.g., eflornithine hydrochloride hydrate, wherein the pouch comprises an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate; and (2) administering to a subject with the cancer characterized by mutant IDH1 and no homozygous deletion of CDKN2A / B genes the oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate, and a chemotherapeutic agent, e.g., lomustine.WSGR Docket No.57339-709601112. A method of treating cancer, comprising:(1) preparing an oral solution of eflornithine or a salt thereof comprising adding the contents of a pouch of eflornithine, e.g., eflornithine hydrochloride hydrate, to water according to instructions of a kit to make the oral solution, wherein the kit comprises: the pouch of eflornithine, e.g., eflornithine hydrochloride hydrate, wherein the pouch comprises an individual dosage of eflornithine, e.g., eflornithine hydrochloride hydrate, and a pharmaceutically acceptable excipient; and the instructions to prepare an oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate; and (2) administering to a subject with the cancer characterized by mutant IDH2 and no homozygous deletion of CDKN2A / B genes the oral solution of eflornithine, e.g., eflornithine hydrochloride hydrate, and a chemotherapeutic agent, e.g., lomustine.

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