WO2024173768A1

WO2024173768A1 - Compositions and methods of using eflornithine

Info

Publication number: WO2024173768A1
Application number: PCT/US2024/016110
Authority: WO
Inventors: Victor Levin; Jason Levin; Noymi Yam
Original assignee: Orbus Therapeutics Inc
Current assignee: Orbus Therapeutics Inc
Priority date: 2023-02-17
Filing date: 2024-02-16
Publication date: 2024-08-22
Anticipated expiration: 2025-08-17
Also published as: AU2024223940A1; KR20250172562A; IL322689A; MX2025009584A; EP4665325A1

Abstract

Disclosed herein are compositions, methods, regimens, and kits useful in the treatment of gliomas. As disclosed herein, a composition, method, regimen, or kit, can comprise eflornithine (difluoromethylornithine; DFMO) or a salt thereof and temozolomide or the administration thereof to a subject having a glioma.

Description

COMPOSITIONS AND METHODS OF USING EFLORNITHINE

CROSS REFERENCE

[0001] This application claims priority to U.S. Provisional Patent Application No. 63/446,495, filed on February 17, 2023, which is entirely incorporated herein by reference.

BACKGROUND OF THE DISCLOSURE

[0002] Gliomas, which include astrocytomas and glioblastomas, are exceedingly difficult to treat, and patients have extremely low survival rates with very short life expectancies. 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 as provided some improvement in survival outcomes following surgery but is infrequently curative. Combination chemotherapies have likewise shown 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 or Grade 4 gliomas) beyond the modest benefits of treatments developed decades ago. New treatment strategies are needed.

SUMMARY OF THE DISCLOSURE

[0003] Provided herein are compositions, methods, and kits comprising eflomithine or a salt thereof, which can be useful in the treatment of a subject in need thereof. For instance, compositions, methods, and kits disclosed herein can be useful in the treatment of a glioma of a subject (e.g., a subject having a mutation in a gene, such as IDH1). In some cases, a composition or method disclosed herein can be included in a regimen for treating a subject (e.g., a subject having a glioma). In some cases, use of eflomithine or a salt thereof can prolong survival (e.g., progression-free survival) of a subject (e.g., a subject having a glioma). As disclosed herein, a composition, method, regimen, or kit disclosed herein can comprise temozolomide and eflomithine or a salt thereof. In some cases, use of temozolomide in a method, regimen, kit, or composition comprising eflomithine or a salt thereof can be advantageous to the treatment of a subject (e.g., a subject having a glioma), for example, as compared to a method, regimen, kit, or composition that does not comprise temozolomide. [0004] In various aspects, a regimen for treating a subject with glioma comprises: administering efl ornithine or a salt thereof and temozolomide to the subject for a treatment period, wherein the eflornithine or salt thereof is administered for 14 days or more of the treatment period in a daily amount of 6.9 g/m² (grams per square meter) to 9.0 g/m² free base equivalent and the temozolomide is administered for 5 days or more of the treatment period in a daily amount of 150 to 200 mg/m². In some cases, the eflornithine or salt thereof is administered to the subject twice per day. In some cases, the eflornithine or salt thereof is administered to the subject three times per day. In some cases, the eflornithine or salt thereof is administered to the subject in three separate doses in an amount of from 2.3 g/m² to 4.0 g/m² free base equivalent per dose. In some cases, the temozolomide is administered one time per day. In some cases, the temozolomide is administered to the subject in a single dose per day of 150 mg/m² per dose.

[0005] In various aspects, a regimen for treating a subject with glioma comprises: administering eflornithine or a salt thereof and temozolomide to the subject for a treatment period, wherein the eflornithine or salt thereof is administered for 14 days or more of the treatment period in a daily amount of at least 4.5 g/m² and less than 6.9 g/m² free base equivalent and the temozolomide is administered for 5 days or more of the treatment period in a daily amount of 150 to 200 mg/m². In some cases, the eflornithine or salt thereof is administered to the subject twice per day. In some cases, the eflornithine or salt thereof is administered to the subject three times per day. In some cases, the eflornithine or salt thereof is administered to the subject in three separate doses in an amount of at least 1.5 grams per square meter (g/m²) free base equivalent and less than 2.3 grams per square meter (g/m²) free base equivalent. In some cases, the temozolomide is administered one time per day. In some cases, the temozolomide is administered to the subject in a single dose per day of 150 mg/m². In some cases, the subject was previously administered chemotherapy or radiation therapy. In some cases, the previously administered chemotherapy comprises temozolomide. In some cases, the subject is not concurrently receiving radiation therapy or additional chemotherapy during the treatment period. In some cases, the eflornithine or salt thereof or the temozolomide is administered concurrent with radiation therapy. In some cases, the glioma is not recurrent/refractory. In some cases, the daily administration of eflornithine or a salt thereof does not overlap with the daily administration of temozolomide. In some cases, the daily administration of eflornithine or a salt thereof overlaps by from 1 to 3 days with the daily administration of temozolomide. In some cases, the treatment period is 19 days in duration. In some cases, the treatment period further comprises a treatment holiday. In some cases, the treatment holiday is for 1 week or more. In some cases, the treatment holiday is for 12 days to 18 days. In some cases, the treatment holiday is for two weeks. In some cases, the treatment period is 28 days and wherein the eflornithine or salt thereof is administered to the subject for at least 14 days out of the 28-day treatment period. In some cases, the temozolomide is administered to the subject for at least 5 days out of the 28-day treatment period. In some cases, the eflornithine or salt thereof is administered to the subject on one or more days of the 28-day treatment period on which temozolomide is not administered to the subject. In some cases, the eflornithine or salt thereof is administered to the subject only on days of the 28-day treatment period on which temozolomide is not administered to the subject. In some cases, the eflornithine or salt thereof is administered to the subject on one or more days of the 28-day treatment period on which temozolomide is also administered to the subject. In some cases, the eflornithine or salt thereof is administered to the subject for a period of 14 days prior to administration of temozolomide. In some cases, the eflornithine or salt thereof is administered on days 1 to 14 and temozolomide is administered to the subject on days 15 to 20, and the remaining days of the 28 day treatment period is a drug holiday, wherein neither eflornithine or a salt thereof nor temozolomide are administered to the subject during the drug holiday. In some cases, the temozolomide is administered to the subject for a period of 5 days prior to administration of the eflornithine or salt thereof. In some cases, the regimen is repeated two or more times sequentially. In some cases, the regimen is repeated sequentially for 3 months or more.

[0006] In various aspects, a regimen of treating a subject having a glioma, comprises administering to the subject eflornithine or a salt thereof and temozolomide for a front-line treatment period, wherein the eflornithine or salt thereof is administered at a dose amount of at least 2.3 grams per square meter (g/m²) free-base equivalent and temozolomide at a dose amount of 50 mg/m²to 90 mg/m² during the front-line treatment period. In some cases, the eflornithine or salt thereof is administered for 14 days or more of the front-line treatment period in a daily amount of 6.9 g/m² to 9.0 g/m² free base equivalent. In some cases, the eflornithine or salt thereof is administered to the subject twice per day. In some cases, the eflornithine or salt thereof is administered to the subject three times per day. In some cases, the eflornithine or salt thereof is administered to the subject in three separate doses in an amount of from 2.3 g/m² to 3.0 g/m2 free base equivalent per dose. In some cases, the temozolomide is administered to the subject in a single dose per day of 150 mg/m² per dose. [0007] In various aspects, a regimen of treating a subject having a glioma, comprising administering to the subject eflornithine or a salt thereof and temozolomide for a front-line treatment period, wherein the eflornithine or salt thereof is administered at a dose amount of at least 1.5 grams per square meter (g/m²) free base equivalent and less than 2.8 grams per square meter (g/m²) free-base equivalent and temozolomide at a dose amount of 50 to 90 mg/m² during the front-line treatment period. In some cases, the eflornithine or salt thereof is administered for 14 days or more of the front-line treatment period in a daily amount of at least 4.5 g/m² free base equivalent and less than 6.9 g/m² free base equivalent. In some cases, the eflornithine or salt thereof is administered to the subject twice per day. In some cases, the eflornithine or salt thereof is administered to the subject three times per day. In some cases, the eflornithine or salt thereof is administered to the subject in three equal doses per day. In some cases, the temozolomide is administered to the subject in a single dose per day of 150 mg/m² per dose. In some cases, the subject was not administered chemotherapy prior to the front-line treatment period. In some cases, the subject was not administered radiation therapy prior to the front-line treatment period. In some cases, the subject is not concurrently receiving radiation therapy or additional chemotherapy during the treatment period. In some cases, the eflornithine or salt thereof or the temozolomide is administered concurrent with radiation therapy. In some cases, the regimen further comprises administering to the subject eflornithine or a salt thereof and temozolomide during a subsequent treatment period, wherein the subsequent treatment period occurs after the front-line treatment period. In some cases, the temozolomide is administered to the subject at a higher dose amount during the subsequent treatment period than during the front-line treatment period. In some cases, the temozolomide is administered for 5 days or more of the subsequent treatment period in a daily amount of 150 mg/m² to 200 mg/m². In some cases, the eflornithine or salt thereof is administered at a lower dose amount during the subsequent treatment period than during the front-line treatment period. In some cases, the eflornithine or salt thereof is administered at a higher dose amount during the subsequent treatment period than during the front-line treatment period. In some cases, the eflornithine or salt thereof is administered at the same dose amount during the subsequent treatment period as during the front-line treatment period. In some cases, the daily administration of eflornithine or a salt thereof does not overlap with the daily administration of temozolomide. In some cases, the daily administration of eflornithine or a salt thereof overlaps by from 1 to 3 days with the daily administration of temozolomide. In some cases, the subsequent treatment period further comprises a treatment holiday. In some cases, the treatment holiday is for 1 week or more. In some cases, the treatment holiday is for 12 days to 18 days. In some cases, the treatment holiday is for two weeks. In some cases, the temozolomide is administered one time per day on days that it is administered to the subject. In some cases, the front-line treatment period is 19 days in duration. In some cases, the subsequent treatment period is 28 days and wherein the eflornithine or salt thereof is administered to the subject for at least 14 days out of the 28-day subsequent treatment period. In some cases, the subsequent treatment period is 28 days and wherein the temozolomide is administered to the subject for at least 5 days out of the 28-day subsequent treatment period. In some cases, the eflornithine or salt thereof is administered to the subject on one or more days of the subsequent treatment period on which temozolomide is not administered to the subject. In some cases, the eflornithine or salt thereof is administered to the subject only on days of the subsequent treatment period on which temozolomide is not administered to the subject. In some cases, the eflornithine or salt thereof is administered to the subject on one or more days of the subsequent treatment period on which temozolomide is also administered to the subject. In some cases, the eflornithine or salt thereof is administered to the subject for a period of 14 days prior to administration of temozolomide. In some cases, the eflornithine or salt thereof is administered on days 1 to 14 and temozolomide is administered to the subject on days 15 to 20, and the remaining days of the 28-day subsequent treatment period is a drug holiday, wherein neither eflornithine or a salt thereof nor temozolomide are administered to the subject during the drug holiday. In some cases, the temozolomide is administered to the subject for a period of 5 days prior to administration of the eflornithine or salt thereof. In some cases, the subsequent treatment period is repeated two or more times sequentially. In some cases, the subsequent treatment period is repeated sequentially for 3 months or more. In some cases, the glioma is selected from grade 2 astrocytoma, grade 3 astrocytoma, grade 4 astrocytoma, or grade 4 glioblastoma. In some cases, the glioma is not a recurrent glioma. In some cases, the glioma comprises a mutation in the IDH1 gene. In some cases, the glioma is an IDH1 wild-type glioma.

INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are 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

[0009] The novel features of the invention are set forth with particularity in the appended 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 of which:

DETAILED DESCRIPTION OF THE INVENTION

[0010] Disclosed herein are compositions and methods for the treatment of a subject having or at risk of having a glioma, such as a glioblastoma or an astrocytoma. Compositions and methods disclosed herein can comprise eflornithine (difluoromethylornithine or “DFMO”) or a salt thereof. In some cases, the eflornithine or a salt thereof can be administered to a subject in need thereof (e.g., a subject having a glioma or at risk of having a glioma) concurrently with, as part of a treatment regimen with, prior to, or after treatment with another antineoplastic agent or therapy. For example, eflornithine or a salt thereof can be administered to a subject in a treatment regimen with temozolomide (TMZ). In some cases, the use of eflornithine in the treatment of a subject having a glioma (or at risk of a having a malignant or more severe (e.g., higher grade) glioma) can reduce adverse effects of one or more antineoplastic agents or therapies administered to the subject.

[0011] In some cases, eflornithine (e.g., administered to a subject as a salt and/or along with a pharmaceutically acceptable excipient) can be an ornithine decarboxylase inhibitor and can inhibit polyamine synthase. In some cases, use of eflornithine in a subject that has been treated with or is being treated with (e.g., simultaneously or during the same treatment period as) an additional agent, such as temozolomide, can reduce adverse effects of the agent to the subject. For instance, temozolomide can introduce new mutations into a subject treated therewith, including driver mutations that can cause new tumor or cancer formation or can cause an existing tumor or cancer to progress (e.g., to a more severe or higher grade tumor stage) or recur. In some cases, treatment with temozolomide can cause a new or recurrent tumor or cancer to progress to a more severe (e.g., higher grade) or malignant phenotype (e.g., as a result of the introduction of one or more mutations which can alter the evolutionary path of the tumor or cancer). In some cases, eflornithine can reduce the rate at which mutations are introduced or retained in a tumor or cancer, e.g., by slowing or interrupting cell cycle progression in tumor cells, for instance, through its activity as an ornithine decarboxylase inhibitor. In some cases, eflomithine (e.g., administered as eflomithine or a salt thereof) can reduce the mutation load of a subject (e.g., over time). In some cases, reduction of a mutation load in a subject and/or reducing a rate at which mutations are introduced (e.g., from a treatment or therapy comprising, for instance, temozolomide and/or radiation therapy) or retained in a tumor or cancer can improve the overall survival rate, survival time, tumor progression rate or status, and/or quality of life of a subject (e.g., a subject having a glioma, such as a glioblastoma or astrocytoma having an IDH1 mutation). [0012] Eflomithine or a salt thereof can be administered to a subject having a glioma as part of a regimen for treating the subject. In some cases, the treatment regimen can comprise administering eflomithine or a salt thereof to the subject. In some cases, a treatment regimen can comprise administering the eflomithine or a salt thereof to the subject for a treatment period. A treatment period can comprise one or more days on which eflomithine or a salt thereof can be administered to the subject. In some cases, a treatment period can be 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, or more than 31 days in duration (e.g., length). For instance, a treatment period can be 7 days or more, 14 days or more, 21 days or more, 28 days or more 30 days or more, or 31 days or more. In some cases, a treatment period is 19 days in duration. In some cases, a treatment period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or more than 24 months in length. In some cases, a treatment period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10 years in length. In some cases, a treatment period can recur. For instance, a treatment period can recur 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 times. In some cases, a treatment period can recur consecutively with a previous treatment period. In some cases, a new treatment period can commence one or more days after the end of a previous treatment period. In some cases, the treatment period can comprise one or more days (e.g., during a treatment holiday) in which eflomithine or a salt thereof is not administered to the subject.

[0013] In some cases, the treatment regimen can comprise administering a second therapeutic agent and/or an additional therapy to the subject. For instance, a treatment regimen can comprise administering temozolomide to the subject. In some cases, a treatment regimen can comprise administering the temozolomide to the subject during a treatment period (e.g., a treatment period in which eflomithine is administered to the subject one or more times). A treatment period can comprise one or more days on which temozolomide can be administered to the subject. [0014] A treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can be 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, or more than 31 days in length. A treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can be 7 days or more, 14 days or more, 21 days or more, 28 days or more 30 days or more, or 31 days or more. A treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or more than 24 months in length. A treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10 years in length. Eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can be administered to the subject on 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, or more than 31 days of the treatment period. In some cases, eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can be administered to the subject on 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, or more than 31 consecutive days of the treatment period. In some cases, eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can be administered to the subject on 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, or more than 31 non-consecutive days of the treatment period. In some cases, a treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can recur. For instance, a treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can recur 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 times. In some cases, a treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can recur consecutively with a previous treatment period. In some cases, a new treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can commence one or more days after the end of a previous treatment period.

[0015] In some cases, eflornithine or a salt thereof can be administered to a subject daily. In some cases, eflornithine or a salt thereof can be administered to a subject only once a day (e.g., on days of a treatment period on which the eflornithine or salt thereof is administered to the subject). In some case, eflornithine or a salt thereof can be administered to a subject twice per day (e.g., on days of a treatment period on which the eflornithine or salt thereof is administered to the subject). In some cases, eflornithine or a salt thereof can be administered to a subject three times per day (e.g., on days of a treatment period on which the eflornithine or salt thereof is administered to the subject).

[0016] In some cases, eflornithine or a salt thereof can be administered to the subject in a daily amount of at least 1.5 g/m² to less than 2.3 g/m², from about 2.3 g/m² to about 4.0 g/m², more than 2.3 g/m² to less than 4.5 g/m², at least 4.5 g/m² and less than 6.9 g/m², about 6.9 g/m² to about 9.0 g/m², or more than 9.0 g/m² free base equivalent (e.g., on days of the treatment period on which eflornithine is administered to the subject). For example, eflornithine or a salt thereof can be administered to the subject in a daily amount of about 6.9 g/m² to about 9.0 g/m² (e.g., on days of the treatment period on which eflornithine is administered to the subject). In some cases, eflornithine or a salt thereof can be administered to the subject in an amount of at least 1.5 g/m² to less than 2.3 g/m², from about 2.3 g/m² to about 4.0 g/m², more than 2.3 g/m² to less than 4.5 g/m², at least 4.5 g/m² and less than 6.9 g/m², about 6.9 g/m² to about 9.0 g/m², or more than 9.0 g/m² free base equivalent per dose (e.g., on days of the treatment period on which eflornithine is administered to the subject). In some cases, eflornithine or a salt thereof can be administered in a daily amount of at least 1.5 g/m² to less than 2.3 g/m², from about 2.3 g/m² to about 4.0 g/m², more than 2.3 g/m² to less than 4.5 g/m², at least 4.5 g/m² and less than 6.9 g/m², about 6.9 g/m² to about 9.0 g/m², or more than 9.0 g/m² free base equivalent for 1 to 6 days of a treatment period. In some cases, eflornithine or a salt thereof can be administered in a daily amount of at least 1.5 g/m² to less than 2.3 g/m², from about 2.3 g/m² to about 4.0 g/m², more than 2.3 g/m² to less than 4.5 g/m², at least 4.5 g/m² and less than 6.9 g/m², about 6.9 g/m² to about 9.0 g/m², or more than 9.0 g/m² free base equivalent for 7 to 13 days of a treatment period. In some cases, eflornithine or a salt thereof can be administered in a daily amount of at least 1.5 g/m² to less than 2.3 g/m², from about 2.3 g/m² to about 4.0 g/m², more than 2.3 g/m² to less than 4.5 g/m², at least 4.5 g/m² and less than 6.9 g/m², about 6.9 g/m² to about 9.0 g/m², or more than 9.0 g/m² free base equivalent for 14 or more days of a treatment period.

[0017] In some cases, efl ornithine or a salt thereof can be administered to the subject during a treatment period in a daily amount of about 6.9 g/m² to 9.0 g/m² free base equivalent (e.g., on days that efl ornithine or a salt thereof is administered to the subject) and temozolomide can be administered to the subject during the same treatment period. In some cases, efl ornithine or a salt thereof can be administered to the subject in a daily amount of about 6.9 g/m² to 9.0 g/m² free base equivalent during a treatment period (e.g., on days that eflornithine or a salt thereof is administered to the subject) and temozolomide can be administered to the subject in a daily amount of about 50 mg/m² to about 90 mg/m², about 75 mg/m² to about 100 mg/m², at least 101 mg/m² to less than about 150 mg/m², about 150 mg/m², about 150 mg/m² to about 200 mg/m², or more than 200 mg/m² during the same treatment period (e.g., on days that temozolomide is administered to the subject). In some cases, eflornithine or a salt thereof can be administered to the subject in a daily amount of at least about 4.5 g/m² to less than about 6.9 g/m² free base equivalent during a treatment period (e.g., on days that eflornithine or a salt thereof is administered to the subject) and temozolomide can be administered to the subject in a daily amount of about 50 mg/m² to about 90 mg/m², about 75 mg/m² to about 100 mg/m², more than 100 mg/m² and less than about 150 mg/m², about 150 mg/m², about 150 mg/m² to about 200 mg/m², or more than 200 mg/m² during the same treatment period (e.g., on days that temozolomide is administered to the subject).

[0018] In some cases, eflornithine or a salt thereof can be administered to the subject during a treatment period in a dose amount of at least 2.3 grams per square meter (g/m²) free-base equivalent (e.g., on days that eflornithine or a salt thereof is administered to the subject) and temozolomide can be administered to the subject during the same treatment period. In some cases, eflornithine or a salt thereof can be administered to the subject in a dose amount of at least 2.3 grams per square meter free-base equivalent during a treatment period (e.g., on days that eflornithine or a salt thereof is administered to the subject) and temozolomide can be administered to the subject in a dose amount of about 50 mg/m² to about 90 mg/m², about 75 mg/m² to about 100 mg/m², at least 101 mg/m² to less than about 150 mg/m², about 150 mg/m², about 150 mg/m² to about 200 mg/m², or more than 200 mg/m² during the same treatment period (e.g., on days that temozolomide is administered to the subject). In some cases, eflornithine or a salt thereof can be administered to the subject in a dose amount of at least 2.3 grams per square meter (g/m2) free-base equivalent (e.g., on days that eflornithine or a salt thereof is administered to the subject) and temozolomide can be administered to the subject in a dose amount of about 50 mg/m² to about 90 mg/m², about 75 mg/m² to about 100 mg/m², more than 100 mg/m² and less than about 150 mg/m², about 150 mg/m², about 150 mg/m² to about 200 mg/m², or more than 200 mg/m² during the same treatment period (e.g., on days that temozolomide is administered to the subject).

[0019] In some cases, temozolomide can be administered to a subject daily. In some cases, temozolomide can be administered only once per day (e.g., a single dose administered one time per day on days of a treatment period on which temozolomide is administered to the subject). In some cases, the (e.g., daily) administration of efl ornithine or a salt thereof does not overlap with the (e.g., daily) administration of temozolomide. For example, in some cases, efl ornithine or a salt thereof can be not administered to the subject on a day on which temozolomide is administered. In some cases, (e.g., daily) administration of eflornithine or a salt thereof can overlap by from 1 to 3 days with the (e.g., daily) administration of temozolomide.

[0020] In some cases, a treatment period can be 28 days, e.g., wherein the eflornithine or salt thereof can be administered to the subject for at least 5 days, at least 7 days, at least 14 days, or at least 21 days of the treatment period. In some cases, eflornithine or a salt thereof can be administered to the subject on one or more days of the 28-day treatment period on which temozolomide is not administered to the subject. In some cases, eflornithine can be administered to the subject only on days of the (e.g., 28-day) treatment period on which temozolomide is not administered to the subject. In some cases, eflornithine or a salt thereof can be administered to the subject on one or more days of the (e.g., 28-day) treatment period on which temozolomide is also administered to the subject. In some cases, eflornithine or a salt thereof can be administered to the subject for a period of at least 5 day, at least 7 days, at least 14 days, or at least 21 days prior to the administration of temozolomide to the subject. [0021] In some cases, the treatment period in which eflornithine or a salt thereof and/or temozolomide (and/or one or more additional agent, such as lomustine, or additional therapies, such as radiation therapy) can comprise a treatment holiday. A treatment holiday can comprise one or more days (e.g., of a treatment period of a treatment regimen) in which eflornithine or a salt thereof is not administered to the subject. A treatment holiday can comprise one or more days (e.g., of a treatment period of a treatment regimen) in which temozolomide is not administered to the subject. In some cases, treatment holiday can comprise one or more days (e.g., of a treatment period of a treatment regimen) in which neither eflornithine or a salt thereof nor temozolomide is administered to the subject. In some cases, a treatment holiday can comprise one or more days (e.g., of a treatment period of a treatment regimen) in which no antineoplastic agent (such as eflornithine or a salt thereof nor temozolomide) is administered to the subject. In some cases, a treatment holiday can comprise one or more days (e.g., of a treatment period of a treatment regimen) in which no additional antineoplastic therapy (e.g., radiation therapy, such as external beam radiation) is administered to the subject. In some cases, a treatment holiday can comprise one or more days (e.g., of a treatment period of a treatment regimen) in which no antineoplastic agent (such as eflornithine or a salt thereof nor temozolomide) and no additional antineoplastic therapy (e.g., radiation therapy, such as external beam radiation) is administered to the subject. In some cases, standard care practices or treatment for a separate condition (e.g., non-cancer condition) may be administered to a subject during a treatment holiday.

[0022] In some cases, a treatment holiday can be 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, or more than 28 consecutive or non- consecutive days in length (e.g., during a treatment period of a treatment regimen). In some cases, a treatment holiday can be 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, or more than 4 weeks of a treatment period or treatment regimen. In some cases, a treatment holiday can be 1 to 6 days, 8 to 12 days, 12 to 13 days, 15 to 18 days, 12 to 18 days, 19 to 20 days, or more than 22 days in length.

Compositions

[0023] A composition disclosed herein can comprise one or more therapeutic compounds. In some cases, the one or more therapeutic compounds can include eflornithine (difluoromethylornithine, DFMO) and/or a salt thereof. A composition can comprise an enantiomer of eflornithine or a salt thereof. In some cases, a composition can comprise L- eflornithine (or a salt thereof). In some cases, a composition can comprise D-eflornithine (or a salt thereof). In some cases, a composition can comprise a combination of L-efl ornithine (or a salt thereof) and D-eflomithine (or a salt thereof). In some cases, a composition can comprise a racemic mixture of L-efl ornithine (or a salt thereof) and D-eflomithine (or a salt thereof). In some cases, a composition can comprise both L-eflornithine (or a salt thereof) and D-eflomithine (or a salt thereof) and can comprise more (e.g., a greater weight %) L- eflornithine (or a salt thereof) than D-eflornithine (or a salt thereof). In some cases, a composition can comprise both L-eflomithine (or a salt thereof) and D-eflomithine (or a salt thereof) and can comprise more (e.g., a greater weight %) D-eflornithine (or a salt thereof) than L-eflornithine (or a salt thereof). In some cases, a composition can comprise D- eflornithine (or a salt thereof) and no L-eflomithine (or a salt thereof). In some cases, a composition can comprise L-eflomithine (or a salt thereof) and no D-eflornithine (or a salt thereof).

[0024] A composition disclosed herein can comprise an ornithine decarboxylase inhibitor. In some cases, the ornithine decarboxylase inhibitor can be eflornithine or salt thereof. In some cases, a composition disclosed herein can comprise a polyamine synthesis inhibitor. In some cases, the polyamine synthesis inhibitor can be eflornithine or a salt thereof. In some cases, inclusion of eflornithine or a salt thereof in a composition, method, regimen, or kit disclosed herein can be advantageous, for example, because the eflornithine or a salt thereof can cause cell cycle arrest (e.g., by causing increases in p21 (wafl/cipl) and/or p27kip-l levels, and/or by inhibiting polyamine synthesis). In some cases, causing cell cycle arrest, increasing p21 or p27kip-l levels, or inhibiting polyamine synthesis can be advantageous, e.g., in the treatment of a subject having a glioma (such as a subject having a glioma and a mutation in an oncogene, such as PTEN, p53, CDKN2A/B, and/or EGFR, for instance, when the subject is IDH1 wildtype), for example, in reducing tumor proliferation, inhibiting metastasis or transition to metastasis, and/or reducing a risk of progression to a more severe (higher grade) tumor.

[0025] A composition disclosed herein can comprise one or more anti -neoplastic or chemotherapeutic agents. In some cases, an anti-neoplastic agent can be an alkylating agent, an antimetabolite, an anti-angiogenic agent, an EGFR inhibitor, a platinum-containing agent, or a topoisomerase inhibitor. In some cases, the one or more anti -neoplastic or chemotherapeutic agents can comprise one or more of: temozolomide, lomustine (CCNU), carmustine (BCNU), procarbazine, prednisone, vincristine, PCT (e.g., a combination of lomustine, procarbazine, and vincristine, carboplatin, carboplatin plus thymidine, carmustine plus temozolomide, erlotinib, carboplating plus erlotinib, cloretazine, lomustine plus cloretazine, imatinib, hydroxyurea, hydroxyurea plus imatinib, irinotecan, thalidomide, temozolomide plus thalidomide, rilotumumab, cilengitide, cis-retinoic acid, celecoxib, cisretinoic acid plus celecoxib, enzastaurin, sirolimus, erlotinib plus sirolimus, fenretinide, gefitinib, lapatinib, temsirolimus, tipifarnib, vorinostat, diaziquone, methotrexate, melphalan, a combination of vincristine, prednisone, and procarbazine, thioguanine, TPDCV (thioguanine, procarbazine, dibromodulcitol, lomustine, vincristine), carboplatin plus tenoposide, or a combination of nitrogen mustard, vincristine, and procarbazine, tenoposide. In some cases, In some cases, a composition disclosed herein can comprise one or more alkylating agents. In some cases, the alkylating agent can be temozolomide. In some cases, an alkylating agent can be mutagenic, for example, in a subject to whom the alkylating agent is administered. In some cases, a composition, method, or kit described herein can comprise temozolomide (TMZ). In some cases, a composition, method, or kit described herein can comprise administering efl ornithine (or a salt thereof) and temozolomide to a subject (e.g., having a glioma). In some cases, a composition, method, or kit described herein can comprise administering efl ornithine (or a salt thereof) and lomustine to a subject (e.g., having a glioma). In some cases, a composition, method, or kit described herein can comprise administering efl ornithine (or a salt thereof), temozolomide, and lomustine to a subject (e.g., having a glioma).

[0026] In some cases, a composition or method can comprise eflomithine or a salt thereof at a concentration (e.g., by weight %) of from about 1 % to about 40 %. In some cases, a composition or method can comprise eflomithine or a salt thereof at a concentration (e.g., by weight %) of from about 1 % to about 5 %, about 1 % to about 13.5 %, about 1 % to about 19.8 %, about 1 % to about 19.8 %, about 1 % to about 21 %, about 1 % to about 25 %, about 1 % to about 30 %, about 1 % to about 35 %, about 1 % to about 40 %, about 5 % to about 13.5 %, about 5 % to about 19.8 %, about 5 % to about 19.8 %, about 5 % to about 21 %, about 5 % to about 25 %, about 5 % to about 30 %, about 5 % to about 35 %, about 5 % to about 40 %, about 13.5 % to about 19.8 %, about 13.5 % to about 19.8 %, about 13.5 % to about 21 %, about 13.5 % to about 25 %, about 13.5 % to about 30 %, about 13.5 % to about 35 %, about 13.5 % to about 40 %, about 19.8 % to about 19.8 %, about 19.8 % to about 21 %, about 19.8 % to about 25 %, about 19.8 % to about 30 %, about 19.8 % to about 35 %, about 19.8 % to about 40 %, about 19.8 % to about 21 %, about 19.8 % to about 25 %, about 19.8 % to about 30 %, about 19.8 % to about 35 %, about 19.8 % to about 40 %, about 21 % to about 25 %, about 21 % to about 30 %, about 21 % to about 35 %, about 21 % to about 40 %, about 25 % to about 30 %, about 25 % to about 35 %, about 25 % to about 40 %, about 30 % to about 35 %, about 30 % to about 40 %, or about 35 % to about 40 %. In some cases, a composition or method can comprise eflomithine or a salt thereof at a concentration (e.g., by weight %) of from about 1 %, about 5 %, about 13.5 %, about 19.8 %, about 19.8 %, about 21 %, about 25 %, about 30 %, about 35 %, or about 40 %. In some cases, a composition or method can comprise eflomithine or a salt thereof at a concentration (e.g., by weight %) of from at least about 1 %, about 5 %, about 13.5 %, about 19.8 %, about 19.8 %, about 21 %, about 25 %, about 30 %, about 35 %, or about 40 %. In some cases, a composition or method can comprise eflomithine or a salt thereof at a concentration (e.g., by weight %) of from at most about 1 %, about 5 %, about 13.5 %, about 19.8 %, about 19.8 %, about 21 %, about 25 %, about 30 %, about 35 %, or about 40 %. In some cases, eflomithine can be provided in a solution at 13.9% free base equivalent (18% eflornithine hydrochloride monohydrate), e.g., for oral administration. In some cases, an oral solution (e.g., comprising 13.9% free base equivalent of eflornithine) can comprise one or more additional ingredients (e.g., excipients or additives), such as glycerin, propylene glycol, saccharin sodium dihydrate, and/or sodium benzoate.

[0027] In some cases, a composition, kit, or method can comprise a dose amount eflornithine or a salt thereof of from about 1.5 grams per square meter to about 9 grams per square meter (free base equivalent). In some cases, a composition, kit, or method can comprise a dose amount eflornithine or a salt thereof of from about 1.5 grams per square meter to about 2.3 grams per square meter, about 1.5 grams per square meter to about 4 grams per square meter, about 1.5 grams per square meter to about 4.5 grams per square meter, about 1.5 grams per square meter to about 6.9 grams per square meter, about 1.5 grams per square meter to about 9 grams per square meter, about 2.3 grams per square meter to about 4 grams per square meter, about 2.3 grams per square meter to about 4.5 grams per square meter, about 2.3 grams per square meter to about 6.9 grams per square meter, about 2.3 grams per square meter to about 9 grams per square meter, about 4 grams per square meter to about 4.5 grams per square meter, about 4 grams per square meter to about 6.9 grams per square meter, about 4 grams per square meter to about 9 grams per square meter, about 4.5 grams per square meter to about 6.9 grams per square meter, about 4.5 grams per square meter to about 9 grams per square meter, or about 6.9 grams per square meter to about 9 grams per square meter (free base equivalent). In some cases, a composition, kit, or method can comprise a dose amount eflornithine or a salt thereof of from about 1.5 grams per square meter, about 2.3 grams per square meter, about 4 grams per square meter, about 4.5 grams per square meter, about 6.9 grams per square meter, or about 9 grams per square meter (free base equivalent). In some cases, a composition, kit, or method can comprise a dose amount eflornithine or a salt thereof of from at least about 1.5 grams per square meter, about 2.3 grams per square meter, about 4 grams per square meter, about 4.5 grams per square meter, about 6.9 grams per square meter, or about 9 grams per square meter (free base equivalent). In some cases, a composition, kit, or method can comprise a dose amount eflornithine or a salt thereof of from at most about 1.5 grams per square meter, about 2.3 grams per square meter, about 4 grams per square meter, about 4.5 grams per square meter, about 6.9 grams per square meter, or about 9 grams per square meter (free base equivalent).

[0028] In some cases, a composition, kit, or method can comprise a daily dose of eflornithine or a salt thereof of from about 1.5 grams per square meter to about 9 grams per square meter (free base equivalent). In some cases, a composition, kit, or method can comprise a daily dose of eflornithine or a salt thereof of from about 1.5 grams per square meter to about 2.3 grams per square meter, about 1.5 grams per square meter to about 4 grams per square meter, about 1.5 grams per square meter to about 4.5 grams per square meter, about 1.5 grams per square meter to about 6.9 grams per square meter, about 1.5 grams per square meter to about 9 grams per square meter, about 2.3 grams per square meter to about 4 grams per square meter, about 2.3 grams per square meter to about 4.5 grams per square meter, about 2.3 grams per square meter to about 6.9 grams per square meter, about 2.3 grams per square meter to about 9 grams per square meter, about 4 grams per square meter to about 4.5 grams per square meter, about 4 grams per square meter to about 6.9 grams per square meter, about 4 grams per square meter to about 9 grams per square meter, about 4.5 grams per square meter to about 6.9 grams per square meter, about 4.5 grams per square meter to about 9 grams per square meter, or about 6.9 grams per square meter to about 9 grams per square meter (free base equivalent). In some cases, a composition, kit, or method can comprise a daily dose of eflornithine or a salt thereof of from about 1.5 grams per square meter, about 2.3 grams per square meter, about 4 grams per square meter, about 4.5 grams per square meter, about 6.9 grams per square meter, or about 9 grams per square meter (free base equivalent). In some cases, a composition, kit, or method can comprise a daily dose of eflornithine or a salt thereof of from at least about 1.5 grams per square meter, about 2.3 grams per square meter, about 4 grams per square meter, about 4.5 grams per square meter, about 6.9 grams per square meter, or about 9 grams per square meter (free base equivalent). In some cases, a composition, kit, or method can comprise a daily dose of eflornithine or a salt thereof of from at most about 1.5 grams per square meter, about 2.3 grams per square meter, about 4 grams per square meter, about 4.5 grams per square meter, about 6.9 grams per square meter, or about 9 grams per square meter (free base equivalent).

[0029] In some cases, the eflornithine or a salt thereof can be in the form of a solid. In some cases, the eflornithine or a salt thereof can be in the form of a powder. In some cases, the eflornithine or a salt thereof can be in the form of a liquid solution (e.g., an aqueous solution), for example, at a concentration (e.g., weight % free base equivalent) or dose amount (e.g., free base equivalent grams per square meter) described herein. In some cases, the eflornithine or salt thereof can be formulated for oral administration (e.g., as an oral solution or as an oral solid, such as a pill or tablet). In some cases, the eflornithine or salt thereof can be formulated for intravenous delivery. In some cases, the eflornithine or salt thereof can be formulated for intraperitoneal delivery. In some cases, the eflornithine or salt thereof can be formulated for parenteral delivery. In some cases, the eflornithine or salt thereof can be formulated for transcutaneous delivery. In some cases, the eflornithine or salt thereof can be formulated for subcutaneous delivery. In some cases, the eflornithine or salt thereof can be formulated for intramuscular delivery.

[0030] In some cases, a composition, kit, or method can comprise a dose amount of temozolomide of from about 50 milligrams per square meter to about 200 milligrams per square meter. In some cases, a composition, kit, or method can comprise a dose amount of temozolomide of from about 50 milligrams per square meter to about 75 milligrams per square meter, about 50 milligrams per square meter to about 90 milligrams per square meter, about 50 milligrams per square meter to about 100 milligrams per square meter, about 50 milligrams per square meter to about 101 milligrams per square meter, about 50 milligrams per square meter to about 150 milligrams per square meter, about 50 milligrams per square meter to about 200 milligrams per square meter, about 75 milligrams per square meter to about 90 milligrams per square meter, about 75 milligrams per square meter to about 100 milligrams per square meter, about 75 milligrams per square meter to about 101 milligrams per square meter, about 75 milligrams per square meter to about 150 milligrams per square meter, about 75 milligrams per square meter to about 200 milligrams per square meter, about 90 milligrams per square meter to about 100 milligrams per square meter, about 90 milligrams per square meter to about 101 milligrams per square meter, about 90 milligrams per square meter to about 150 milligrams per square meter, about 90 milligrams per square meter to about 200 milligrams per square meter, about 100 milligrams per square meter to about 101 milligrams per square meter, about 100 milligrams per square meter to about 150 milligrams per square meter, about 100 milligrams per square meter to about 200 milligrams per square meter, about 101 milligrams per square meter to about 150 milligrams per square meter, about 101 milligrams per square meter to about 200 milligrams per square meter, or about 150 milligrams per square meter to about 200 milligrams per square meter. In some cases, a composition, kit, or method can comprise a dose amount of temozolomide of from about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 101 milligrams per square meter, about 150 milligrams per square meter, or about 200 milligrams per square meter. In some cases, a composition, kit, or method can comprise a dose amount of temozolomide of from at least about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 101 milligrams per square meter, about 150 milligrams per square meter, or about 200 milligrams per square meter. In some cases, a composition, kit, or method can comprise a dose amount of temozolomide of from at most about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 101 milligrams per square meter, about 150 milligrams per square meter, or about 200 milligrams per square meter.

[0031] In some cases, a composition, kit, or method can comprise a daily dose of temozolomide of from about 50 milligrams per square meter to about 200 milligrams per square meter. In some cases, a composition, kit, or method can comprise a daily dose of temozolomide of from about 50 milligrams per square meter to about 75 milligrams per square meter, about 50 milligrams per square meter to about 90 milligrams per square meter, about 50 milligrams per square meter to about 100 milligrams per square meter, about 50 milligrams per square meter to about 101 milligrams per square meter, about 50 milligrams per square meter to about 150 milligrams per square meter, about 50 milligrams per square meter to about 200 milligrams per square meter, about 75 milligrams per square meter to about 90 milligrams per square meter, about 75 milligrams per square meter to about 100 milligrams per square meter, about 75 milligrams per square meter to about 101 milligrams per square meter, about 75 milligrams per square meter to about 150 milligrams per square meter, about 75 milligrams per square meter to about 200 milligrams per square meter, about 90 milligrams per square meter to about 100 milligrams per square meter, about 90 milligrams per square meter to about 101 milligrams per square meter, about 90 milligrams per square meter to about 150 milligrams per square meter, about 90 milligrams per square meter to about 200 milligrams per square meter, about 100 milligrams per square meter to about 101 milligrams per square meter, about 100 milligrams per square meter to about 150 milligrams per square meter, about 100 milligrams per square meter to about 200 milligrams per square meter, about 101 milligrams per square meter to about 150 milligrams per square meter, about 101 milligrams per square meter to about 200 milligrams per square meter, or about 150 milligrams per square meter to about 200 milligrams per square meter. In some cases, a composition, kit, or method can comprise a daily dose of temozolomide of from about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 101 milligrams per square meter, about 150 milligrams per square meter, or about 200 milligrams per square meter. In some cases, a composition, kit, or method can comprise a daily dose of temozolomide of from at least about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 101 milligrams per square meter, about 150 milligrams per square meter, or about 200 milligrams per square meter.. In some cases, a composition, kit, or method can comprise a daily dose of temozolomide of from at most about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 101 milligrams per square meter, about 150 milligrams per square meter, or about 200 milligrams per square meter.

[0032] In some cases, the temozolomide can be in the form of a solid. In some cases, the temozolomide can be in the form of a powder. In some cases, the temozolomide can be in the form of a liquid solution (e.g., an aqueous solution), for example, at a concentration (e.g., weight % free base equivalent) or dose amount (e.g., free base equivalent grams per square meter) described herein. In some cases, the temozolomide can be formulated for oral administration (e.g., as an oral solution or as an oral solid, such as a pill or tablet). In some cases, the temozolomide can be formulated for intravenous delivery. In some cases, the temozolomide can be formulated for intraperitoneal delivery. In some cases, the temozolomide can be formulated for parenteral delivery. In some cases, the temozolomide can be formulated for transcutaneous delivery. In some cases, the temozolomide can be formulated for subcutaneous delivery. In some cases, the temozolomide can be formulated for intramuscular delivery.

[0033] In some cases, a composition, kit, or method can comprise a dose amount of lomustine of from about 50 milligrams per square meter to about 150 milligrams per square meter. In some cases, a composition, kit, or method can comprise a dose amount of lomustine of from about 50 milligrams per square meter to about 75 milligrams per square meter, about 50 milligrams per square meter to about 90 milligrams per square meter, about 50 milligrams per square meter to about 100 milligrams per square meter, about 50 milligrams per square meter to about 110 milligrams per square meter, about 50 milligrams per square meter to about 120 milligrams per square meter, about 50 milligrams per square meter to about 150 milligrams per square meter, about 75 milligrams per square meter to about 90 milligrams per square meter, about 75 milligrams per square meter to about 100 milligrams per square meter, about 75 milligrams per square meter to about 110 milligrams per square meter, about 75 milligrams per square meter to about 120 milligrams per square meter, about 75 milligrams per square meter to about 150 milligrams per square meter, about 90 milligrams per square meter to about 100 milligrams per square meter, about 90 milligrams per square meter to about 110 milligrams per square meter, about 90 milligrams per square meter to about 120 milligrams per square meter, about 90 milligrams per square meter to about 150 milligrams per square meter, about 100 milligrams per square meter to about 110 milligrams per square meter, about 100 milligrams per square meter to about 120 milligrams per square meter, about 100 milligrams per square meter to about 150 milligrams per square meter, about 110 milligrams per square meter to about 120 milligrams per square meter, about 110 milligrams per square meter to about 150 milligrams per square meter, or about 120 milligrams per square meter to about 150 milligrams per square meter. In some cases, a composition, kit, or method can comprise a dose amount of lomustine of from about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 110 milligrams per square meter, about 120 milligrams per square meter, or about 150 milligrams per square meter. In some cases, a composition, kit, or method can comprise a dose amount of lomustine of from at least about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 110 milligrams per square meter, about 120 milligrams per square meter, or about 150 milligrams per square meter. In some cases, a composition, kit, or method can comprise a dose amount of lomustine of from at most about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 110 milligrams per square meter, about 120 milligrams per square meter, or about 150 milligrams per square meter.

[0034] In some cases, a composition, kit, or method can comprise a daily dose of lomustine of from about 50 milligrams per square meter to about 150 milligrams per square meter. In some cases, a composition, kit, or method can comprise a daily dose of lomustine of from about 50 milligrams per square meter to about 75 milligrams per square meter, about 50 milligrams per square meter to about 90 milligrams per square meter, about 50 milligrams per square meter to about 100 milligrams per square meter, about 50 milligrams per square meter to about 110 milligrams per square meter, about 50 milligrams per square meter to about 120 milligrams per square meter, about 50 milligrams per square meter to about 150 milligrams per square meter, about 75 milligrams per square meter to about 90 milligrams per square meter, about 75 milligrams per square meter to about 100 milligrams per square meter, about 75 milligrams per square meter to about 110 milligrams per square meter, about 75 milligrams per square meter to about 120 milligrams per square meter, about 75 milligrams per square meter to about 150 milligrams per square meter, about 90 milligrams per square meter to about 100 milligrams per square meter, about 90 milligrams per square meter to about 110 milligrams per square meter, about 90 milligrams per square meter to about 120 milligrams per square meter, about 90 milligrams per square meter to about 150 milligrams per square meter, about 100 milligrams per square meter to about 110 milligrams per square meter, about 100 milligrams per square meter to about 120 milligrams per square meter, about 100 milligrams per square meter to about 150 milligrams per square meter, about 110 milligrams per square meter to about 120 milligrams per square meter, about 110 milligrams per square meter to about 150 milligrams per square meter, or about 120 milligrams per square meter to about 150 milligrams per square meter. In some cases, a composition, kit, or method can comprise a daily dose of lomustine of from about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 110 milligrams per square meter, about 120 milligrams per square meter, or about 150 milligrams per square meter. In some cases, a composition, kit, or method can comprise a daily dose of lomustine of from at least about 50 milligrams per square meter, about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 110 milligrams per square meter, or about 120 milligrams per square meter, or about 150 milligrams per square meter. In some cases, a composition, kit, or method can comprise a daily dose of lomustine of from at most about 75 milligrams per square meter, about 90 milligrams per square meter, about 100 milligrams per square meter, about 110 milligrams per square meter, about 120 milligrams per square meter, or about 150 milligrams per square meter.

[0035] In some cases, the lomustine can be in the form of a solid. In some cases, the lomustine thereof can be in the form of a powder. In some cases, the lomustine can be in the form of a liquid solution (e.g., an aqueous solution), for example, at a concentration (e.g., weight % free base equivalent) or dose amount (e.g., free base equivalent grams per square meter) described herein. In some cases, the lomustine can be formulated for oral administration (e.g., as an oral solution or as an oral solid, such as a pill or tablet).

[0036] In some cases, a composition can comprise one or more pharmaceutically acceptable excipients. In some cases, the one or more pharmaceutically acceptable excipients can be selected from a preservative, a sweetening agent, a thickening agent, a buffer, a liquid carrier, an isotonic agent, a wetting agent, a solubilizing agent, an emulsifying agent, an acidifying agent, an alkalinizing agent, a carrying agent, a chelating agent, a colorant, a complexing agent, a solvent, a suspending agent, a viscosity-increasing agent, a flavor, a perfume, an oil, a penetration enhancer, a polymer, a stiffening agent, a protein, a carbohydrate, a bulking agent, and/or a lubricating agent. In some cases, the one or more excipients can be selected from sodium benzoate, saccharine sodium dihydrate, glycerol, and/or propylene glycol. In some cases, a composition can comprise eflornithine or a salt thereof at a concentration or dose amount described herein, one or more pharmaceutically acceptable excipients, with water to 100%. In some cases, a composition can comprise temozolomide at a concentration or dose amount described herein, one or more pharmaceutically acceptable excipients, with water to 100%. In some cases, a composition can comprise lomustine at a concentration or dose amount described herein, one or more pharmaceutically acceptable excipients, with water to 100%.

[0037] Compositions (e.g., pharmaceutical compositions) disclosed herein (e.g., comprising eflornithine or a salt thereof and/or temozolomide) may be manufactured using techniques for preparing pharmaceutical compositions, which may comprise mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping, and/or lyophilizing. Pharmaceutical compositions may be formulated 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. [0038] Specific embodiments of formulations of pharmaceutical compositions disclosed herein can be informed by the route of administration chosen. In some cases, compositions intended for administration to a subject by injection can be formulated into aqueous solutions, for example, in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. Penetrants appropriate to the barrier to be permeated can be used in the formulation, e.g., for transmucosal administration.

[0039] Compounds can be formulated readily by combining one or more compounds (e.g., agents such as eflornithine or a salt thereof or temozolomide) with one or more pharmaceutically acceptable carriers, e.g., for oral administration. Such carriers can enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, solutions, suspensions and the like, e.g., 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 can 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, hydroxypropylmethylcellulose, 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. [0040] In some embodiments, dragee cores can be provided with suitable coatings. Concentrated sugar solutions can be used for this purpose, e.g., wherein the concentrated sugar solution(s) 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.

[0041] Pharmaceutical preparations which can be used orally can include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. 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. Formulations for oral administration can be prepared and/or utilized in dosages suitable for such administration (e.g., in accordance with instructions of a kit disclosed herein). Compositions may take the form of tablets or lozenges formulated in conventional manner, which can be useful for buccal administration.

[0042] Pharmaceutical formulations for parenteral administration can include aqueous solutions or suspensions. Suitable lipophilic solvents or vehicles can 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, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). 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. [0043] Other ingredients such as stabilizers, for example, antioxidants such as sodium citrate, ascorbyl palmitate, propyl gallate, reducing agents, ascorbic acid, vitamin E, sodium bisulfite, butylated hydroxytoluene, BHA, acetylcysteine, monothioglycerol, phenyl-a-naphthylamine, or lecithin can be used. Also, chelators such as EDTA can be used in compositions (e.g., pharmaceutical compositions) disclosed herein. Other ingredients, such as lubricants in tablets or pills, coloring agents, or flavoring agents, can be used. Pharmaceutical excipients used in compositions disclosed herein 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 can be used as well, in some embodiments. Exemplary pharmaceutically acceptable carriers include, but are not limited to, 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. 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 herein.

Subjects

[0044] In some cases, a subject or population of subjects (e.g., a patient population) can be identified, selected for treatment, and/or treated (e.g., administered one or more compositions or therapies, for example, using one or more steps of a method described herein) based on one or more criteria. In some cases, the one or more criteria can be a clinical condition of the subject. For instance, a subject identified, selected for treatment and/or administered with a treatment or therapy as described herein can have a tumor (e.g., a glioma). In some cases, the tumor can be a benign tumor. In some cases, the tumor can be a malignant tumor (e.g., a cancer). In some cases, the tumor can be a brain tumor. In some cases, the brain tumor can be a glioma. In some cases, the glioma can be a glioblastoma or an astrocytoma. In some cases, the astrocytoma can be a diffuse astrocytoma. In some cases, the astrocytoma can be an anaplastic astrocytoma. In some cases, the tumor can be oligodendroglioma, anaplastic oligodendroglioma, or anaplastic ependymoma.

[0045] In some cases, the subject (e.g., a glioma of the subject) can have a genetic mutation. In some cases, a genetic mutation can affect the severity, treatment resistance, progression rate, and/or progression mechanism or pathway of a tumor or the risk of the same in the subject. In some cases, a mutation (e.g., a driver mutation) in one or more of the IDH1, IDH2, CDKN2A/B, PTEN, ERCC1, MGMT, p53, EGFR, ATRX, SMARCA4 and/or BRAF genes can affect the severity, treatment resistance, progression rate (e.g., to a higher grade tumor classification), and/or progression mechanism or pathway of a tumor or the risk of the same in the subject. In some cases, a composition, method, regimen, or kit described herein can be effective at reducing the progression rate, increasing overall survival, and/or increasing progression free survival in a subject or tumor, wherein the subject or tumor has a mutation in one or more of the IDH1, IDH2, CDKN2A/B, PTEN, ERCC1, MGMT, p53, EGFR, ATRX, SMARCA4 and/or BRAF genes. For instance, a composition, regimen, method, or kit described herein can be effective in treating a glioma of a subject that has a mutation in the IDH1 gene (e.g., and/or one or more of the other genes disclosed herein). In some cases, a subject or glioma can be wild-type for one or more of the IDH1, IDH2, CDKN2A/B, PTEN, ERCC1, MGMT, p53, EGFR, ATRX, SMARCA4 and/or BRAF genes. In some cases, a composition, method, regimen, or kit described herein can be effective at reducing the progression rate, increasing overall survival, and/or increasing progression free survival in a subject or tumor, wherein the subject or tumor is wild type for one or more of the IDH1, IDH2, CDKN2A/B, PTEN, ERCC1, MGMT, p53, EGFR, ATRX, SMARCA4 and/or BRAF genes. For instance, a composition, regimen, method, or kit described herein can be effective in treating a glioma of a subject that wild type for the IDH1 gene (e.g., and/or one or more of the other genes disclosed herein). In some cases, a mutation in IDH1 can increase cell cycle arrest. In some cases, a subject having an IDH1 -wildtype glioma can be at greater risk for tumor progression and/or metastasis than a subject having an IDH1 mutation (e.g., an IDH1- mutant glioma of a subject), for example, in some cases in which the IDH1 mutation increases cell cycle arrest. In some cases, IDH1 -wildtype gliomas can be more difficult to treat with current therapies than IDH1 -mutant gliomas, for example, because a lack of mutation in the IDH1 gene may allow the tumor cells to proliferate and/or migrate at a greater rate and/or to a greater extent in IDHl-wildtype gliomas than in IDHl-mutant gliomas. Compositions, methods, regimens, and/or kits disclosed herein comprising eflomithine or a salt thereof (e.g., in combination with one or more additional agents, such as an anti- neoplastic agent like temozolomide, or therapies such as radiation therapy) can be advantageous in reducing proliferation rates, tumor stage progression, and/or metastasis in IDHl-mutant and IDHl-wildtype gliomas. In some embodiments, use of eflomithine or a salt thereof can be advantageous in treating an IDHl-mutant tumor (e.g., glioma) of a subject, for example, because the eflomithine or a salt thereof can in some cases further inhibit cell cycle progression in tumor (e.g., glioma) cells beyond an effect of the IDH1 mutation on the tumor cells’ cell cycle progression, which may in some cases allow one or more antineoplastic agents of a composition, method, regimen, or kit disclosed herein (e.g., temozolomide and/or lomustine) to adversely affect the viability of the tumor cells (e.g., by increasing the time to progression, decreasing a rate of proliferation, and/or decreasing a rate of migration or metastasis in the subject). In some cases, the advantages of including efl ornithine or a salt thereof (e.g., in combination with one or more additional agents, such as an anti -neoplastic agent like temozolomide, or therapies such as radiation therapy) in a composition, method, regimen, or kit disclosed herein can be especially valuable in the treatment of an IDH1- wildtype tumor (e.g., glioma) of a subject, for example, because the tumor (e.g., glioma) may not be impeded with respect to any inhibitory effects that an IDH1 mutation may otherwise have on the tumor cells’ cell cycle progression. As a result, lack of an IDH1 mutation in a subject or tumor thereof, may allow an IDH1 -wildtype tumor to proliferate, migrate, metastasize and/or progress (e.g., to a higher severity stage) at a greater rate than an IDH1 mutant tumor and may shorten the amount of time an antineoplastic agent has to destroy the tumor cells, e.g., before they proliferate or migrate, in some cases. Inclusion of eflornithine or a salt thereof in a composition, method, regimen, or kit disclosed herein can inhibit cell cycle progression in IDH1 wildtype tumor cells, which can, in some cases, allow more opportunity (e.g., due to slower proliferation, migration, progression, and/or metastasis) for antineoplastic agents or other therapies to destroy the tumor cells before the tumor cells proliferate, migrate, progression to a more severe stage (e.g., higher tumor classification grade), and/or metastasize to a different location. In some cases, a tumor (e.g., glioma) may be identified for treatment using a composition, method, regimen, or kit disclosed herein based (e.g., at least in part) on an epigenetic state of the tumor. For example, a composition, method, regimen, or kit disclosed herein can be advantageous in the treatment of a tumor having O6-methylguanine DNA methyltransferase (MGMT) methylation (e.g., in addition to or in the absence of one or more genetic mutations disclosed herein, such as IDH1 -wildtype status), for instance, as confirmed by historical standard of care testing.

[0046] In some cases, a subject was previously administered an anti -neoplastic therapy. In some cases, a subject was previously administered chemotherapy (e.g., comprising temozolomide, lomustine or another anti -neoplastic agent) or radiation therapy (e.g., external beam radiation therapy). In some cases, the subject can be not concurrently receiving radiation therapy or additional chemotherapy during the treatment period. In some cases, eflornithine or a salt thereof and/or temozolomide can be administered concurrently with radiation therapy.

[0047] In some cases, a tumor (e.g., a glioma, such as an astrocytoma or a glioblastoma) of a subject can be recurrent or refractory (e.g., “recurrent/refractory”). For example, a composition, method, regimen, or kit disclosed herein (e.g., comprising eflornithine or a salt thereof, temozolomide, and/or lomustine) can be administered to a subject having a recurrent or refractory tumor (e.g., glioma, for instance, an astrocytoma or a glioblastoma). A recurrent or refractory (e.g., “recurrent/refractory”) tumor or glioma (such as a recurrent or refractory astrocytoma or a recurrent or refractory glioblastoma) can be one that has recurred in a subject, for example, after an earlier (e.g., an initial) treatment or therapy, for instance, wherein the earlier treatment or therapy comprises radiation therapy (e.g., external beam radiation therapy or treatment with a radioisotope), treatment with an anti -neoplastic agent (e.g., an alkylating agent such as temozolomide and/or lomustine), and/or another anti-cancer or therapeutic composition or therapy (e.g., treatment comprising an antibody or other targetbinding composition, eflornithine or a salt thereof, or a cell-based anti-cancer treatment comprising, e.g., CAR-T cells). In some cases, a composition, method, regimen, or kit disclosed herein (e.g., comprising eflornithine or a salt thereof, temozolomide, and/or lomustine) can reduce a rate of progression, reduce a rate of proliferation, and/or reduce a risk of metastasis in a recurrent or refractory tumor (e.g., a recurrent or refractory glioma, such as a recurrent or refractory astrocytoma and/or a recurrent of refractory glioblastoma). In some cases, a composition, method, regimen, or kit disclosed herein (e.g., comprising eflornithine or a salt thereof, temozolomide, and/or lomustine) can increase a progression- free survival time or an overall survival time in a subject having a recurrent or refractory tumor (e.g., a recurrent or refractory glioma, such as a recurrent or refractory astrocytoma and/or a recurrent of refractory glioblastoma). For instance, a composition, method, regimen, or kit disclosed herein (e.g., comprising eflornithine or a salt thereof, temozolomide, and/or lomustine) can increase a progression-free survival time or an overall survival time in a subject having a recurrent or refractory tumor (e.g., a recurrent or refractory glioma, such as a recurrent or refractory astrocytoma and/or a recurrent of refractory glioblastoma) by 1 day to 28 days, less than one month, by 1 month to 72 months, 1 month to 3 months, 1 month to 6 months, 1 month to 12 months, 1 month to 18 months, 1 month to 24 months, 1 month to 30 months, 1 month to 36 months, 1 month to 48 months, 1 month to 60 months, 1 month to 72 months, 3 months to 6 months, 3 months to 12 months, 3 months to 18 months, 3 months to

24 months, 3 months to 30 months, 3 months to 36 months, 3 months to 48 months, 3 months to 60 months, 3 months to 72 months, 6 months to 12 months, 6 months to 18 months, 6 months to 24 months, 6 months to 30 months, 6 months to 36 months, 6 months to 48 months, 6 months to 60 months, 6 months to 72 months, 12 months to 18 months, 12 months to 24 months, 12 months to 30 months, 12 months to 36 months, 12 months to 48 months, 12 months to 60 months, 12 months to 72 months, 18 months to 24 months, 18 months to 30 months, 18 months to 36 months, 18 months to 48 months, 18 months to 60 months, 18 months to 72 months, 24 months to 30 months, 24 months to 36 months, 24 months to 48 months, 24 months to 60 months, 24 months to 72 months, 30 months to 36 months, 30 months to 48 months, 30 months to 60 months, 30 months to 72 months, 36 months to 48 months, 36 months to 60 months, 36 months to 72 months, 48 months to 60 months, 48 months to 72 months, 60 months to 72 months, 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 60 months, or 72 months, at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 48 months, at least 60 months, at least 72 months, at most 1 month, at most 3 months, at most 6 months, at most 12 months, at most 18 months, at most 24 months, at most 30 months, at most 36 months, at most 48 months, at most 60 months, or at most 72 months. In some cases, a glioma of a subject is not recurrent or refractory during at least a portion of the treatment period.

[0048] In some cases, a glioma of a subject is selected from grade 2 astrocytoma, grade 3 astrocytoma, grade 4 astrocytoma, or grade 4 glioblastoma. In some cases, a glioma can comprise a mutation. In some cases, the glioma can comprise a mutation in the IDH1 gene. In some cases, the glioma can be an IDH1 wild-type glioma. In some cases, a composition, method, regimen, or kit disclosed herein can be used to treat a central nervous system (CNS) tumor (e.g., a glioma), wherein the CNS tumor has a mutation in the IDH1 gene, which may be a grade 3 central nervous system (CNS) tumor in accordance with the World Health Organization (WHO) 2016 CNS tumor classification system. In some cases, a composition, method, regimen, or kit disclosed herein can be used to treat a CNS tumor, wherein the CNS tumor has a mutation in the IDH1 gene and wildtype alleles of the CDKN2A/B gene, which may be a grade 3 astrocytoma, IDH-1 mutant in accordance with the WHO 2021 classification system. In some cases, a composition, method, regimen, or kit disclosed herein can be used to treat CNS tumor, wherein the CNS tumor has a mutation in the IDH1 gene and one or more mutation (e.g., a homozygous deletion) in the CDKN2A/B gene, which may be classified as a grade 4 astrocytoma, IDH-1 -mutant in accordance with the WHO 2021 classification system. In some cases, a composition, method, regimen, or kit disclosed herein can be used to treat a CNS tumor, wherein the CNS tumor is wildtype for the IDH1, which may be classified as a grade 3 anaplastic astrocytoma in accordance with the WHO 2016 classification system or a grade 4 glioblastoma, IDH-1 -wildtype in accordance with the WHO 2021 classification system.

[0049] RANO criteria (e.g., Response Assessment in Neuro-Oncology criteria for Gliomas) can be used for measuring disease progression and response in subjects (e.g., wherein progression can be defined as worsening enhancement and/or unequivocal changes in T2 fluid attenuated inversion recovery (FLAIR)). In some cases, recurrence of high-grade gliomas can be assessed by structural MRI (e.g., contrast-enhanced T1 -weighted MRI, which allows assessment of the integrity of the blood-brain barrier, wherein micro-structural disruption can signal an active tumor) and/or assessment of enhancement or increase in tumor size (e.g., using T2-weighted MRI imaging or T2-weighted fluid attenuated inversion recovery (T2-weighted FLAIR) MRI images).

[0050] Progression free survival can be determined to assess efficacy of compositions, methods, regimen, or kits disclosed herein. In some cases, progression free survival can be evaluated by establishing a subject baseline using RANO criteria prior to treatment. Progression can be determined in one or more of the following ways: recurrence/progression can be determined by increase in either T2 hyperintensity, gadolinium contrast enhancement, or both, e.g., wherein progression by T2 hyperintensity can be determined by an increase in the size (e.g., extension into the brain and/or presence of a new lesion) of T2 hyperintensity on T2-weighted and/or T2-weighted FLAIR images and wherein progression by gadolinium- contrast enhancement can be determined by an increase in the size of one or more gadolinium-contrast lesions seen on T1 -weighted images.

[0051] Objective response rate (ORR) can be determined to assess efficacy of compositions, methods, regimen, or kits disclosed herein. In some cases, RANO criteria can be used for measuring on-study ORR. In some cases, ORR response categories can be based on MRI using RANO criteria for glioblastoma (GBM). In some cases, ORR can be estimated based on the crude proportion of patients whose best overall response during the course of study treatment is complete response (CR) or partial response (PR). In some cases, the clinical benefit rate (CBR) can be determined to assess efficacy of compositions, methods, regimen, or kits disclosed herein. In some cases, CBR can be estimated based on the crude proportion of patients whose best overall response during the course of study treatment with the combination of complete response (CR), partial response (PR), and stable disease (SD). [0052] In some cases, plasma concentration of L-efl ornithine (or a salt thereof) and/or D- eflornithine (or a salt thereof) can be determined to assess efficacy and/or safety of a composition, method, regimen, or kit disclosed herein.

Kits

[0053] Disclosed herein are kits comprising one or more pharmaceutical compositions, for example, together with instructions for use of the one or more pharmaceutical compositions. The instructions of a kit can comprise instructions for use of the one or more pharmaceutical compositions in treating a condition of a subject (for instance, treating a glioma of a subject as described herein). In some cases, the instructions can comprise one or more steps of a method or regimen described herein. In some cases, a kit can comprise a composition comprising eflomithine or a salt thereof together with instructions for use (e.g., administration) thereof. For instance, a kit can comprise a composition comprising eflomithine or a salt thereof together with instructions for use in treating a condition such as a glioma (e.g., according to a method or regimen disclosed herein). In some cases, a kit can comprise a composition comprising temozolomide together with instructions for use (e.g., administration) thereof. For instance, a kit can comprise a composition comprising temozolomide together with instructions for use in treating a condition such as a glioma (e.g., according to a method or regimen disclosed herein). In some cases, a kit can comprise a composition comprising lomustine together with instructions for use (e.g., administration) thereof. For instance, a kit can comprise a composition comprising lomustine together with instructions for use in treating a condition such as a glioma (e.g., according to a method or regimen disclosed herein).

[0054] In some cases, the instructions comprise instructions for the preparation of a composition described herein (e.g., a composition for use in treating a glioma, for example, wherein the composition can comprise an aqueous solution comprising eflomithine or a salt thereof and/or temozolomide). In some cases, instructions for the preparation of a composition described herein can comprise instructions indicating an amount of a solid (e.g., a solid included in the kit) to be added to a solvent (e.g., to produce a composition described herein, such as an aqueous solution) and/or a method of accomplishing the same. In some cases, the solvent is water. In some cases, the solvent is hydrophobic. In some cases, the solvent comprises an alcohol and/or an oil. In some cases, a kit described herein can comprise one or more solvents, for example, a solvent selected from water, an alcohol, or an oil. [0055] In some cases, a kit can comprise one or more dispensing devices and/or one or more pharmaceutical formulations of a liquid and/or a solid (e.g., a powder, a solution, or a suspension) comprising one or more compositions described herein (e.g., comprising eflornithine or a salt thereof or temozolomide). For instance, a kit can comprise one or more cups, one or more bottles, one or more ampoules, one or more syringes, one or more pouches, one or more wafers, one or more pills, one or more tablets, and/or one or more dragees. [0056] In some cases, one or more cups, one or more bottles, one or more ampoules, one or more syringes, one or more pouches, one or more wafers, one or more pills, one or more tablets, and/or one or more dragees of the kit can comprise eflornithine or a salt thereof (e.g., less than 400 ml of eflornithine oral solution formulation, 400 to 450 ml of eflornithine or a salt thereof in oral solution formulation, 450 ml of eflornithine or a salt thereof in oral solution formulation, or more than 500 ml of eflornithine or a salt thereof in an oral solution formulation). In some cases, a cup, a bottle, an ampoule, a syringe, a pouch, a wafer, a pill, a dragee, and/or a tablet of the kit can comprise a dose of eflornithine or a salt thereof (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, a cup, a bottle, an ampoule, a syringe, a pouch, a wafer, a pill, a dragee, and/or a tablet of the kit can comprise exactly one dose of eflornithine or a salt thereof (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, kit can comprise a plurality of cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and/or tablets, wherein each of the cups, bottles, ampoules, syringes, pouches, wafers, pills, and/or tablets comprises a dose of eflornithine or a salt thereof (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, kit can comprise a plurality of cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and/or tablets, wherein each of the cups, bottles, ampoules, syringes, pouches, wafers, pills, and/or tablets comprises exactly one dose of eflornithine or a salt thereof.

[0057] In some cases, one or more cups, one or more bottles, one or more ampoules, one or more syringes, one or more pouches, one or more wafers, one or more pills, one or more tablets, and/or one or more dragees of the kit can comprise temozolomide. In some cases, a cup, a bottle, an ampoule, a syringe, a pouch, a wafer, a pill, a dragee, and/or a tablet of the kit can comprise a dose of temozolomide (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, a cup, a bottle, an ampoule, a syringe, a pouch, a wafer, a pill, a dragee, and/or a tablet of the kit can comprise exactly one dose of temozolomide (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, kit can comprise a plurality of cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and/or tablets, wherein each of the cups, bottles, ampoules, syringes, pouches, wafers, pills, and/or tablets comprises a dose of temozolomide (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, kit can comprise a plurality of cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and/or tablets, wherein each of the cups, bottles, ampoules, syringes, pouches, wafers, pills, and/or tablets comprises exactly one dose of temozolomide. In some cases, temozolomide can be provided in one or more capsules for oral administration, e.g., wherein one or more capsule (e.g., each capsule) contains 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide.

[0058] In some cases, one or more cups, one or more bottles, one or more ampoules, one or more syringes, one or more pouches, one or more wafers, one or more pills, one or more tablets, and/or one or more dragees of the kit can comprise lomustine. In some cases, a cup, a bottle, an ampoule, a syringe, a pouch, a wafer, a pill, a dragee, and/or a tablet of the kit can comprise a dose of lomustine (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, a cup, a bottle, an ampoule, a syringe, a pouch, a wafer, a pill, a dragee, and/or a tablet of the kit can comprise exactly one dose of lomustine (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, kit can comprise a plurality of cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and/or tablets, wherein each of the cups, bottles, ampoules, syringes, pouches, wafers, pills, and/or tablets comprises a dose of lomustine (e.g., a dose amount described herein, for instance a daily dose amount). In some cases, kit can comprise a plurality of cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and/or tablets, wherein each of the cups, bottles, ampoules, syringes, pouches, wafers, pills, and/or tablets comprises exactly one dose of lomustine.

[0059] In some cases, it can be advantageous to provide a kit comprising one or more dispensing devices and/or one or more compositions, each comprising one dose amount of efl ornithine or salt thereof, one dose amount of temozolomide, one dose amount of lomustine, one dose amount of lomustine and efl ornithine or a salt thereof, one dose amount of temozolomide and efl ornithine or a salt thereof, and/or one dose amount of lomustine and temozolomide, for example, because it can reduce the complexity of preparing and/or selfadministering treatment by a subject, which can improve adherence to a method or regimen described herein and can improve the effectiveness of the regimen.

[0060] In some cases, a kit, method, or regimen can comprise a plurality of doses (e.g., wherein a dose comprises eflornithine or a salt thereof, temozolomide, and/or lomustine). In some cases, two or more of the plurality of doses of a kit, method or regimen can have the same dose amount of each component (e.g., eflornithine or a salt thereof, temozolomide, and/or lomustine). In some cases, the dose amount of two or more of the components of a dose of a kit, method, or regimen can be different. In some cases, the dose amount of a given component (e.g., efl ornithine, temozolomide, or lomustine) of a first dose of the kit, method, or regimen can be different than a second dose of the kit, method, or regimen. In some cases, a first dose of a kit, method, or regimen can have a higher dose amount of one or more components of the first dose than a dose amount of the same one or more components of a second dose, for example, wherein the second dose is administered to the subject after the first dose. In some cases, a first dose of a kit, method, or regimen can have a lower dose amount of one or more components of the first dose than a dose amount of the same one or more components of a second dose, for example, wherein the second dose is administered to the subject after the first dose. In some cases, instructions of a kit can comprise instructions as to the order of administration of two or more doses of the kit (e.g., wherein the two or more doses are marked to indicate the identity or order of the doses).

Definitions

[0061] The term “a” and “an” refers to one or more (i.e., at least one) of the grammatical object of the article. By way of example, “a polypeptide” encompasses one or more polypeptides.

[0062] As used herein, the terms “about” and “approximately,” when used to modify an amount specified in a numeric value or range, indicate that the numeric value as well as reasonable deviations from the value known to the skilled person in the art, for example ± 20%, ± 10%, or ± 5%, are within the intended meaning of the recited value.

EXAMPLES

Example 1: Selection of Subjects Comprising Evaluation of IDH1 Genetic Background [0063] This example describes selection of a population of subjects for treatment with eflornithine or a salt thereof and temozolomide.

[0064] A tissue sample, for example collected from a tissue biopsy (e.g., a tumor biopsy) or a fluid sample (e.g., a blood sample), is collected from a potential subject having a glioma, such as an astrocytoma or a glioblastoma, for treatment with eflornithine or a salt thereof and temozolomide according to a composition or method described herein. Mutational analysis is performed on the tissue sample. Subjects having a mutation in the IDH1 gene are treated with eflornithine (or a salt thereof) and temozolomide according to a method or regimen described herein (e.g., as described in one of Examples 2-4) . In some cases, subjects that are wild type for IDH1 are treated with eflomithine (or a salt thereof) and temozolomide in a separate group according to a method or regimen described herein (e.g., as described in one of Examples 2-4). Optionally, a subject may have a glioma that is refractory or recurrent following previous temozolomide treatment (and/or previous radiation therapy).

Example 2: Treatment of Subjects with Eflornithine and Temozolomide Dose Level 1 [0065] This example describes treatment of a population of subjects for treatment with eflornithine or a salt thereof and temozolomide.

[0066] Subjects are treated with eflomithine at a dose amount of 2.3 g/m², administered orally every 8 hours, daily, for 2 weeks of a treatment period, followed by a period of 2 weeks of the treatment period wherein the eflomithine is not administered to the subject. Temozolomide is administered to a subject at 150 mg/m² orally once a day for 5 days within the treatment period. The temozolomide is not administered to the subject on a day wherein the eflomithine is administered to the subject.

Example 3: Treatment of Subjects with Eflornithine and Temozolomide Dose Level 2 [0067] This example describes treatment of a population of subjects for treatment with eflornithine or a salt thereof and temozolomide.

[0068] Subjects are treated with eflomithine at a dose amount of 2.8 g/m², administered orally every 8 hours, daily, for 2 weeks of a treatment period, followed by a period of 2 weeks of the treatment period wherein the eflomithine is not administered to the subject. Temozolomide is administered to a subject at 150 mg/m² orally once a day for 5 days within the treatment period. The temozolomide is not administered to the subject on a day wherein the eflomithine is administered to the subject.

Example 4: Treatment of Subjects with Eflornithine and Temozolomide Dose Level -1 [0069] This example describes treatment of a population of subjects for treatment with eflornithine or a salt thereof and temozolomide.

[0070] Subjects are treated with eflomithine at a dose amount of 1.75 g/m², administered orally every 8 hours, daily, for 2 weeks of a treatment period, followed by a period of 2 weeks of the treatment period wherein the eflomithine is not administered to the subject. Temozolomide is administered to a subject at 150 mg/m² orally once a day for 5 days within the treatment period. The temozolomide is not administered to the subject on a day wherein the eflomithine is administered to the subject. Example 5: Treatment of Subject Cohorts with Eflornithine and Temozolomide [0071] This example describes treatment of a population of subjects for treatment with eflornithine or a salt thereof and temozolomide.

[0072] Subjects having newly diagnosed glioblastoma following radiation therapy are selected for treatment with eflornithine plus temozolomide.

[0073] Doses for both study drugs (eflornithine and temozolomide) are based on body surface area, calculated based on institutional guidelines on Study Day 1. Doses are adjusted for subjects who have a 10% or greater change in weight used to calculate dose during the course of the study. Subject cohort dosing is as follows.

[0074] Cohort -1 : (Dose level -1): eflornithine dosing 14 days out of 28 days (Days 1-14: eflornithine 1.75 g/m² administered orally every 8 hours.

[0075] Cohort 1 (Dose level 1): eflornithine dosing 14 days out of 28 days (Days 1-14: eflornithine 2.3 g/m² administered orally every 8 hours.

[0076] Cohort 2: (Dose level 2): eflornithine dosing 14 days out of 28 days (Days 1-14: eflornithine 2.8 g/m² administered orally every 8 hours.

[0077] All Cohorts: Days 15-19: temozolomide (TMZ) 150 mg/m² administered once daily for 5 days, with the possibility of dose escalation; Days 20-28: no therapy.

[0078] Subjects are treated for one or more 28 day treatment period cycles as described above, up to twelve 28-day treatment period cycles (e.g., up to 48 weeks).

[0079] Dose escalation from Cohort 1 to Cohort 2 (Dose Level 2) can proceed if and when all subjects in Cohort 1 have completed 56 days (e.g., two consecutive cycles) of treatment. [0080] Dose de-escalation from Cohort 1 to Cohort -1 (Dose level -1) can proceed if and when 2 or more subjects experience a dose-limiting toxicity (DLT) event, which may include grade 4 neutropenia, grade 3 or greater febrile neutropenia, grade 4 thrombocytopenia, or grade 4 anemia, during the first 56 days of treatment (e.g., the first two cycles of treatment). [0081] It is to be understood that while the inventions described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0082] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, section headings, the materials, methods, and examples are illustrative and are not necessarily intended to be limiting to the scope of the inventions.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A regimen for treating a subj ect with glioma comprising: administering efl ornithine or a salt thereof and temozolomide to the subject for a treatment period, wherein the eflomithine or salt thereof is administered for 14 days or more of the treatment period in a daily amount of 6.9 g/m² (grams per square meter) to 9.0 g/m² free base equivalent and the temozolomide is administered for 5 days or more of the treatment period in a daily amount of 150 mg/m² (milligrams per square meter) to 200 mg/m².

2. The regimen of claim 1, wherein the eflomithine or salt thereof is administered to the subject twice per day.

3. The regimen of claim 1, wherein the eflomithine or salt thereof is administered to the subject three times per day.

4. The regimen of claim 1 or claim 3, wherein the eflomithine or salt thereof is administered to the subject in three separate doses in an amount of from 2.3 g/m² to 4.0 g/m² free base equivalent per dose.

5. The regimen of any one of the preceding claims, wherein the temozolomide is administered one time per day.

6. The regimen of any one of the preceding claims, wherein the temozolomide is administered to the subject in a single dose per day of 150 mg/m² per dose.

7. A regimen for treating a subject with glioma comprising: administering eflomithine or a salt thereof and temozolomide to the subject for a treatment period, wherein the eflomithine or salt thereof is administered for 14 days or more of the treatment period in a daily amount of at least 4.5 g/m² (grams per square meter) and less than 6.9 g/m² free base equivalent and the temozolomide is administered for 5 days or more of the treatment period in a daily amount of 150 mg/m² (milligrams per square meter) to 200 mg/m².

8. The regimen of claim 7, wherein the eflomithine or salt thereof is administered to the subject twice per day.

9. The regimen of claim 7, wherein the eflomithine or salt thereof is administered to the subject three times per day.

10. The regimen of claim 7 or claim 9, wherein the efl ornithine or salt thereof is administered to the subject in three separate doses in an amount of at least 1.5 grams per square meter (g/m²) free base equivalent and less than 2.3 grams per square meter (g/m²) free base equivalent.

11. The regimen of any one of claims 7-10, wherein the temozolomide is administered one time per day.

12. The regimen of any one of claims 7-11, wherein the temozolomide is administered to the subject in a single dose per day of 150 mg/m².

13. The regimen of any one of claims 1 to 12, wherein the subject was previously administered chemotherapy or radiation therapy.

14. The regimen of claim 13, wherein the previously administered chemotherapy comprises temozolomide.

15. The regimen of any one of claims 1-14, wherein the subject is not concurrently receiving radiation therapy or additional chemotherapy during the treatment period.

16. The regimen of any one of claims 1-14, wherein the eflomithine or salt thereof or the temozolomide is administered concurrent with radiation therapy.

17. The regimen of any one of claims 1-16, wherein the glioma is not recurrent/ refractory .

18. The regimen of any one of claims 1-17, wherein the daily administration of eflomithine or a salt thereof does not overlap with the daily administration of temozolomide.

19. The regimen of any one of claims 1-17, wherein the daily administration of eflomithine or a salt thereof overlaps by from 1 to 3 days with the daily administration of temozolomide.

20. The regimen of any one of claims 1-19, wherein the treatment period is 19 days in duration.

21. The regimen of any one of claims 1-19, wherein the treatment period further comprises a treatment holiday.

22. The regimen of claim 21, wherein the treatment holiday is for 1 week or more.

23. The regimen of claim 22, wherein the treatment holiday is for 12 days to 18 days.

24. The regimen of claim 23, wherein the treatment holiday is for two weeks.

25. The regimen of any one of claims 1-19 or 21-24, wherein the treatment period is 28 days and wherein the efl ornithine or salt thereof is administered to the subject for at least 14 days out of the 28-day treatment period.

26. The regimen of claim 25, wherein the temozolomide is administered to the subject for at least 5 days out of the 28-day treatment period.

27. The regimen of claim 25 or claim 26, wherein the eflornithine or salt thereof is administered to the subject on one or more days of the 28-day treatment period on which temozolomide is not administered to the subject.

28. The regimen of any one of claims 25-27, wherein the eflornithine or salt thereof is administered to the subject only on days of the 28-day treatment period on which temozolomide is not administered to the subject

29. The regimen of any one of claims 25-27, wherein the eflornithine or salt thereof is administered to the subject on one or more days of the 28-day treatment period on which temozolomide is also administered to the subject.

30. The regimen of any one of claims 1-29, wherein the eflornithine or salt thereof is administered to the subject for a period of 14 days prior to administration of temozolomide.

31. The regimen of any one of claims 25-30, wherein the eflornithine or salt thereof is administered on days 1 to 14 and temozolomide is administered to the subject on days 15 to 20, and the remaining days of the 28 day treatment period is a drug holiday, wherein neither eflornithine or a salt thereof nor temozolomide are administered to the subject during the drug holiday.

32. The regimen of any one of claims 1-29, wherein the temozolomide is administered to the subject for a period of 5 days prior to administration of the efl ornithine or salt thereof.

33. The regimen of any one of the preceding claims, wherein the regimen is repeated two or more times sequentially.

34. The regimen of any one of the preceding claims, wherein the regimen is repeated sequentially for 3 months or more.

35. A regimen of treating a subject having a glioma, comprising administering to the subject efl ornithine or a salt thereof and temozolomide for a front-line treatment period, wherein the eflomithine or salt thereof is administered at a dose amount of at least 2.3 grams per square meter (g/m²) free-base equivalent and temozolomide at a dose amount of 50 mg/m² (milligrams per square meter) to 90 mg/m² during the front-line treatment period.

36. The regimen of claim 35, wherein the eflomithine or salt thereof is administered for 14 days or more of the front-line treatment period in a daily amount of 6.9 g/m² to 9.0 g/m² free base equivalent.

37. The regimen of claim 35 or claim 36, wherein the eflomithine or salt thereof is administered to the subject twice per day.

38. The regimen of claim 35 or claim 36, wherein the eflomithine or salt thereof is administered to the subject three times per day.

39. The regimen of claim 38, wherein the eflomithine or salt thereof is administered to the subject in three separate doses in an amount of from 2.3 g/m² to 3.0 g/m² free base equivalent per dose.

40. The regimen of any one of claims 35-39, wherein the temozolomide is administered to the subject in a single dose per day of 150 mg/m² per dose.

41. A regimen of treating a subject having a glioma, comprising administering to the subject eflomithine or a salt thereof and temozolomide for a front-line treatment period, wherein the eflomithine or salt thereof is administered at a dose amount of at least 1.5 grams per square meter (g/m²) free base equivalent and less than 2.3 grams per square meter (g/m²) free-base equivalent and temozolomide at a dose amount of 50 mg/m² (milligrams per square meter) to 90 mg/m² during the front-line treatment period.

42. The regimen of claim 41, wherein the efl ornithine or salt thereof is administered for 14 days or more of the front-line treatment period in a daily amount of at least 4.5 g/m² free base equivalent and less than 6.9 g/m² free base equivalent.

43. The regimen of claim 41 or claim 42, wherein the efl ornithine or salt thereof is administered to the subject twice per day.

44. The regimen of claim 41 or claim 42, wherein the efl ornithine or salt thereof is administered to the subject three times per day.

45. The regimen of claim 44, wherein the efl ornithine or salt thereof is administered to the subject in three equal doses per day.

46. The regimen of any one of claims 41-45, wherein the temozolomide is administered to the subject in a single dose per day of 150 mg/m² per dose.

47. The regimen of any one of claims 41-46, wherein the subject was not administered chemotherapy prior to the front-line treatment period.

48. The regimen of any one of claims 41-47, wherein the subject was not administered radiation therapy prior to the front-line treatment period.

49. The regimen of any one of claims 41-48, wherein the subject is not concurrently receiving radiation therapy or additional chemotherapy during the treatment period.

50. The regimen of any one of claims 41-49, wherein the efl ornithine or salt thereof or the temozolomide is administered concurrent with radiation therapy.

51. The regimen of any one of claims 41-50, further comprising administering to the subject efl ornithine or a salt thereof and temozolomide during a subsequent treatment period , wherein the subsequent treatment period occurs after the front-line treatment period.

52. The regimen of claim 51, wherein the temozolomide is administered to the subject at a higher dose amount during the subsequent treatment period than during the frontline treatment period.

53. The regimen of claim 51, wherein the temozolomide is administered for 5 days or more of the subsequent treatment period in a daily amount of 150 mg/m² to 200 mg/m².

54. The regimen of any one of claims 51-53, wherein the eflomithine or salt thereof is administered at a lower dose amount during the subsequent treatment period than during the front-line treatment period.

55. The regimen of any one of claims 51-53, wherein the eflomithine or salt thereof is administered at a higher dose amount during the subsequent treatment period than during the front-line treatment period.

56. The regimen of any one of claims 51-53, wherein the eflomithine or salt thereof is administered at the same dose amount during the subsequent treatment period as during the front-line treatment period.

57. The regimen of any one of claims 41 to 56, wherein the daily administration of eflomithine or a salt thereof does not overlap with the daily administration of temozolomide.

58. The regimen of any one of claims 41 to 56, wherein the daily administration of eflomithine or a salt thereof overlaps by from 1 to 3 days with the daily administration of temozolomide.

59. The regimen of any one of claims 51 to 57, wherein the subsequent treatment period further comprises a treatment holiday.

60. The regimen of claim 59, wherein the treatment holiday is for 1 week or more.

61. The regimen of claim 60, wherein the treatment holiday is for 12 days to 18 days.

62. The regimen of claim 61, wherein the treatment holiday is for two weeks.

63. The regimen of any one of claims 41-62, herein the temozolomide is administered one time per day on days that it is administered to the subject.

64. The regimen of any one of claims 41-63, wherein the front-line treatment period is 19 days in duration.

65. The regimen of any one of claims 51-64, wherein the subsequent treatment period is 28 days and wherein the efl ornithine or salt thereof is administered to the subject for at least 14 days out of the 28-day subsequent treatment period.

66. The regimen of any one of claims 51-65, wherein the subsequent treatment period is 28 days and wherein the temozolomide is administered to the subject for at least 5 days out of the 28-day subsequent treatment period.

67. The regimen of claim 65 or claim 66, wherein the eflornithine or salt thereof is administered to the subject on one or more days of the subsequent treatment period on which temozolomide is not administered to the subject.

68. The regimen of claim 67, wherein the eflornithine or salt thereof is administered to the subject only on days of the subsequent treatment period on which temozolomide is not administered to the subject

69. The regimen of claim 65 or claim 66, wherein the eflornithine or salt thereof is administered to the subject on one or more days of the subsequent treatment period on which temozolomide is also administered to the subject.

70. The regimen of any one of claims 41-69, wherein the eflornithine or salt thereof is administered to the subject for a period of 14 days prior to administration of temozolomide.

71. The regimen of any one of claims 65-70, wherein the eflornithine or salt thereof is administered on days 1 to 14 and temozolomide is administered to the subject on days 15 to 20, and the remaining days of the 28-day subsequent treatment period is a drug holiday, wherein neither eflornithine or a salt thereof nor temozolomide are administered to the subject during the drug holiday.

72. The regimen of any one of claims 41-69, wherein the temozolomide is administered to the subject for a period of 5 days prior to administration of the efl ornithine or salt thereof.

73. The regimen of any one of claims 51-72, wherein the subsequent treatment period is repeated two or more times sequentially.

74. The regimen of any one of claims 51-73, wherein the subsequent treatment period is repeated sequentially for 3 months or more.

75. The regimen of any one of the preceding claims, wherein the glioma is selected from grade 2 astrocytoma, grade 3 astrocytoma, grade 4 astrocytoma, or grade 4 glioblastoma.

76. The regimen of any one of the preceding claims, wherein the glioma is not a recurrent glioma.

77. The regimen of any one of the preceding claims, wherein the glioma comprises a mutation in the IDH1 gene.

78. The regimen of any one of claims 1-76, wherein the glioma is an IDH1 wildtype glioma.