Compositions and Methods Using Eflornithine

Abstract

Disclosed herein are compositions, methods, regimens and kits that are useful for treating glioma.As disclosed herein, compositions, methods, regimens or kits can include eflornithine (difluoromethylornithine; DFMO) or its salt and temozolomide, or its administration to the subject with glioma.For example, disclosed herein are compositions, methods and kits that can be used for treating glioma in subject (for example, subject with mutation in gene such as IDH1).

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 446,495, filed February 17, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Background of the Disclosure Gliomas, including astrocytomas and glioblastomas, are extremely difficult to treat, with extremely low patient survival rates and very short life expectancies. Because rapid proliferation into surrounding normal brain tissue can complicate surgical access, surgical intervention is rarely a viable interventional strategy on its own, and recurrence is common in cases where tumor removal is incomplete. The addition of radiation therapy has resulted in some improvement in survival outcomes after surgery but is rarely curative. Combination chemotherapy has also shown limited therapeutic efficacy to date. A wide range of chemotherapeutic agents and combinations of chemotherapeutic agents have been used, with or without additional treatments (e.g., surgical intervention), but no treatment regimens or strategies have been successful in extending the lives of subjects with 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 Invention [Means for solving the problem]

[0003] Summary of the Disclosure Provided herein are compositions, methods, and kits comprising eflornithine or its salt, which can be useful for treating subjects in need thereof.For example, the compositions, methods, and kits disclosed herein can be useful for treating glioma in subjects (e.g., subjects with mutations in genes such as IDH1).In some cases, the compositions or methods disclosed herein can be included in a regimen for treating a subject (e.g., a subject with glioma).In some cases, the use of eflornithine or its salt can prolong the survival (e.g., progression-free survival) of a subject (e.g., a subject with glioma).As disclosed herein, the compositions, methods, regimens, or kits disclosed herein can include temozolomide and eflornithine or its salt.In some cases, the use of temozolomide in a method, regimen, kit, or composition comprising eflornithine or its salt can be advantageous for treating a subject (e.g., a subject with glioma), for example, compared with a method, regimen, kit, or composition that does not include temozolomide.

[0004] In various embodiments, 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 at a dose of 6.9 g / m 2 (grams / square meter) ~ 9.0g / m 2 free base equivalent daily dose for 14 days or longer of the treatment period, and temozolomide is administered at a dose of 150-200 mg / m 2 For 5 days or more of the treatment period, eflornithine or a salt thereof is administered to the subject at a daily dose of 2.3 g / m. In some cases, eflornithine or a salt thereof is administered to the subject twice per day. In some cases, eflornithine or a salt thereof is administered to the subject three times per day. In some cases, eflornithine or a salt thereof is administered at a daily dose of 2.3 g / m. 2 ~4.0g / m 2In some cases, temozolomide is administered to a subject in three separate doses at a free base equivalent amount of 150 mg / m per dose. In some cases, temozolomide is administered once per day. In some cases, temozolomide is administered at a dose of 150 mg / m per dose. 2 is administered to the subject in a single dose per day.

[0005] In various embodiments, 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 at a dose of at least 4.5 g / m 2 And 6.9g / m 2 Temozolomide is administered at a daily dose of less than 150-200 mg / m free base equivalent for 14 days or longer of the treatment period. 2 For 5 days or more of the treatment period, eflornithine or a salt thereof is administered to the subject at a daily dose of at least 1.5 grams per square meter (g / m). In some cases, eflornithine or a salt thereof is administered to the subject twice per day. In some cases, eflornithine or a salt thereof is administered to the subject three times per day. In some cases, eflornithine or a salt thereof is administered at a daily dose of at least 1.5 grams per square meter (g / m). 2 ) and a free base equivalent of 2.3 grams per square meter (g / m 2 In some cases, temozolomide is administered to a subject in three separate doses in an amount of less than 150 mg / m free base equivalent. In some cases, temozolomide is administered once per day. In some cases, temozolomide is administered at a dose of 150 mg / m free base equivalent. 2In some cases, the subject is administered a single daily dose of eflornithine or a salt thereof. In some cases, the subject has previously received chemotherapy or radiation therapy. In some cases, the previously administered chemotherapy includes temozolomide. In some cases, the subject is not receiving concurrent radiation therapy or additional chemotherapy during the treatment period. In some cases, eflornithine or a salt thereof or temozolomide is administered concurrently 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 with the daily administration of temozolomide by 1 to 3 days. In some cases, the treatment period is 19 days in duration. In some cases, the treatment period further includes a treatment holiday. In some cases, the treatment holiday is 1 week or longer. In some cases, the treatment holiday is 12 to 18 days. In some cases, the treatment holiday is 2 weeks.In some cases, the treatment period is 28 days, and eflornithine or its salt is administered to the subject for at least 14 days during the 28-day treatment period.In some cases, temozolomide is administered to the subject for at least 5 days during the 28-day treatment period.In some cases, eflornithine or its salt is administered to the subject on one or more days during the 28-day treatment period when temozolomide is not administered to the subject.In some cases, eflornithine or its salt is administered to the subject only on the days during the 28-day treatment period when temozolomide is not administered to the subject.In some cases, eflornithine or its salt is administered to the subject on one or more days during the 28-day treatment period when temozolomide is also administered to the subject.In some cases, eflornithine or its salt is administered to the subject for a period of 14 days before the administration of temozolomide. In some cases, eflornithine or a salt thereof is administered to the subject on days 1 through 14, temozolomide is administered to the subject on days 15 through 20, and the remaining days of the 28-day treatment period are drug holidays, and neither eflornithine or a salt thereof nor temozolomide is administered to the subject during the drug holidays. In some cases, temozolomide is administered to the subject for a period of 5 days prior to the administration of eflornithine or a salt thereof.In some cases, the regimen is repeated two or more times sequentially. In some cases, the regimen is repeated sequentially over a period of three months or longer.

[0006] In various embodiments, a regimen for treating a subject with glioma comprises administering eflornithine or a salt thereof and temozolomide to the subject during a first-line treatment period, wherein during the first-line treatment period, the eflornithine or salt thereof is administered at a dose of at least 2.3 grams per square meter (g / m 2 ) free base equivalent dose amount, and temozolomide is administered at a dose of 50 mg / m 2 ~90mg / m 2 In some cases, eflornithine or a salt thereof is administered at a dose of 6.9 g / m 2 ~9.0g / m 2 The free base equivalent of eflornithine or its salt is administered at a daily dose of 2.3 g / m per dose for 14 days or longer during the first-line treatment period. In some cases, eflornithine or its salt is administered to a subject twice per day. In some cases, eflornithine or its salt is administered to a subject three times per day. In some cases, eflornithine or its salt is administered at a daily dose of 2.3 g / m per dose. 2 In some cases, temozolomide is administered to a subject in three separate doses in an amount of 150 mg / m free base equivalent. 2 is administered to the subject in a single dose per day.

[0007] In various embodiments, a regimen for treating a subject with glioma comprises administering eflornithine or a salt thereof and temozolomide to the subject during a first-line treatment period, wherein the eflornithine or salt thereof is administered at a dose of at least 1.5 grams per square meter (g / m) during the first-line treatment period. 2 ) and a free base equivalent of 2.8 grams per square meter (g / m 2 ) and temozolomide is administered at a dose of 50-90 mg / m 2In some cases, the eflornithine or salt thereof is administered at a dose of at least 4.5 g / m 2 of free base equivalent and 6.9 g / m 2 In some cases, eflornithine or a salt thereof is administered to a subject at a daily dose of less than 150 mg / m free base equivalent for 14 days or longer during the first-line treatment period. In some cases, eflornithine or a salt thereof is administered to a subject twice per day. In some cases, eflornithine or a salt thereof is administered to a subject three times per day. In some cases, eflornithine or a salt thereof is administered to a subject at three equal doses per day. In some cases, temozolomide is administered at a dose of 150 mg / m per dose. 2 In some cases, the subject is administered a single daily dose of eflornithine or a salt thereof or temozolomide. In some cases, the subject has not received chemotherapy before the first-line treatment period. In some cases, the subject has not received radiation therapy before the first-line treatment period. In some cases, the subject is not receiving concurrent radiation therapy or additional chemotherapy during the treatment period. In some cases, eflornithine or a salt thereof or temozolomide is administered concurrently with radiation therapy. In some cases, the regimen further comprises administering eflornithine or a salt thereof and temozolomide to the subject during a subsequent treatment period, wherein the subsequent treatment period occurs after the first-line treatment period. In some cases, temozolomide is administered to the subject during the subsequent treatment period at a higher dose than during the first-line treatment period. In some cases, temozolomide is administered at a dose of 150 mg / m 2 ~200mg / m 2and administered for 5 days or longer during the subsequent treatment period. In some cases, eflornithine or its salt is administered at a lower dose during the subsequent treatment period than during the first-line treatment period. In some cases, eflornithine or its salt is administered at a higher dose during the subsequent treatment period than during the first-line treatment period. In some cases, eflornithine or its salt is administered at the same dose during the subsequent treatment period as during the first-line treatment period. In some cases, the daily administration of eflornithine or its salt does not overlap with the daily administration of temozolomide. In some cases, the daily administration of eflornithine or its salt overlaps with the daily administration of temozolomide for 1 to 3 days. In some cases, the subsequent treatment period further includes a treatment holiday. In some cases, the treatment holiday is 1 week or longer. In some cases, the treatment holiday is 12 to 18 days. In some cases, the treatment holiday is 2 weeks. In some cases, temozolomide is administered to the subject once a day on the day it is administered. In some cases, the first-line treatment period is 19 days in duration. In some cases, the subsequent treatment period is 28 days, and eflornithine or its salt is administered to the subject for at least 14 days during the subsequent 28-day treatment period. In some cases, the subsequent treatment period is 28 days, and temozolomide is administered to the subject for at least 5 days during the subsequent 28-day treatment period. In some cases, eflornithine or its salt is administered to the subject on one or more days during the subsequent treatment period when temozolomide is not administered to the subject. In some cases, eflornithine or its salt is administered to the subject only on the days during the subsequent treatment period when temozolomide is not administered to the subject. In some cases, eflornithine or its salt is administered to the subject on one or more days during the subsequent treatment period when temozolomide is also administered to the subject. In some instances, eflornithine or a salt thereof is administered to the subject for a period of 14 days prior to the administration of temozolomide.In some cases, eflornithine or a salt thereof is administered to the subject on days 1 to 14, and temozolomide is administered to the subject on days 15 to 20, and the remaining days of the subsequent 28-day treatment period are drug holidays, and neither eflornithine or a salt thereof nor temozolomide is administered to the subject during the drug holidays. In some cases, temozolomide is administered to the subject for a period of 5 days prior to the administration of eflornithine or a salt thereof. In some cases, the subsequent treatment periods are repeated sequentially two or more times. In some cases, the subsequent treatment periods are repeated sequentially for three months or longer. 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 contains a mutation in the IDH1 gene. In some cases, the glioma is an IDH1 wild-type glioma.

[0008] Incorporation by Reference 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, and patent application was specifically and individually indicated to be incorporated by reference.

[0009] BRIEF DESCRIPTION OF THE DRAWINGS 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. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of the Invention Disclosed herein are compositions and methods for treating subjects with or at risk of having gliomas, such as glioblastomas or astrocytomas.The compositions and methods disclosed herein can comprise eflornithine (difluoromethylornithine or "DFMO") or its salt.In some cases, eflornithine or its salt can be administered to a subject in need thereof (such as a subject with glioma or at risk of having glioma) in parallel with, before, or after the treatment of another anti-cancer agent or therapy.For example, eflornithine or its salt can be administered to a subject in a treatment regimen with temozolomide (TMZ).In some cases, the use of eflornithine in treating a subject with glioma (or at risk of having malignant or more severe (for example, higher grade) gliomas) can reduce the adverse effects of one or more anti-cancer agents or therapies administered to the subject.

[0011] In some cases, eflornithine (e.g., administered to a subject as a salt and / or with a pharmaceutically acceptable additive) may be an ornithine decarboxylase inhibitor and can inhibit polyamine synthase. In some cases, the use of eflornithine in a subject who has been or is being treated with an additional drug such as temozolomide (e.g., simultaneously or during the same treatment period) can reduce the adverse effects of the drug on the subject. For example, temozolomide may introduce new mutations, including driver mutations, into the treated subject, which may cause the formation of new tumors or cancers, or the progression (e.g., to a more severe or higher-grade tumor stage) or recurrence of existing tumors or cancers. In some cases, treatment with temozolomide may cause new or recurrent tumors or cancers 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 that may change the evolutionary path of tumors or cancers). In some cases, eflornithine can, for example, slow down or prevent cell cycle progression in tumor cells through its ornithine decarboxylase inhibitor activity, thereby reducing the rate at which mutations are introduced or maintained in tumor or cancer.In some cases, eflornithine (for example, administered as eflornithine or its salt) can reduce the mutation load of the subject (for example, over time).In some cases, reducing the mutation load of the subject and / or reducing the rate at which mutations are introduced or maintained in tumor or cancer (for example, from treatment or therapy comprising temozolomide and / or radiotherapy) can improve the overall survival rate, survival time, tumor progression rate or condition, and / or quality of life of the subject (for example, the subject with glioma, such as glioblastoma or astrocytoma, with IDH1 mutation).

[0012] Eflornithine or its salt can be administered to a subject with glioma as part of the regimen for treating the subject.In some cases, the treatment regimen can include administering eflornithine or its salt to the subject.In some cases, the treatment regimen can include administering eflornithine or its salt to the subject during a treatment period.The treatment period can include one or more days that eflornithine or its salt can be administered to the subject.In some cases, the 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 days or more than 31 days in duration (for example, length). For example, the 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, the treatment period is 19 days in duration. In some cases, the 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 months, or more than 24 months. In some cases, the treatment period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years, or more than 10 years. In some cases, the treatment period can be repeated. For example, a treatment period can be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more than 20 times. In some cases, a treatment period can be repeated consecutively with a previous treatment period. In some cases, a new treatment period can start one or more days after the end of a previous treatment period. In some cases, a treatment period can include one or more days (e.g., during a treatment holiday) during which eflornithine or a salt thereof is not administered to the subject.

[0013] In some cases, the treatment regimen can include administering a second therapeutic agent and / or additional therapy to the subject.For example, the treatment regimen can include administering temozolomide to the subject.In some cases, the treatment regimen can include administering temozolomide to the subject during a treatment period (e.g., a treatment period in which eflornithine is administered to the subject one or more times).The treatment period can include one or more days on which temozolomide can be administered to the subject.

[0014] The treatment duration of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., 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 days, or longer than 31 days. The treatment duration of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., 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. The treatment duration of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., 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 months, or more than 24 months. The treatment duration of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., radiation therapy) can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years, or more than 10 years. Eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., radiation therapy) can be administered to a 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 agents, e.g., lomustine, or additional therapies, e.g., radiation therapy) can be administered to a 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 agents, e.g., lomustine, or additional therapies, e.g., radiation therapy) can be administered to a 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, the treatment period of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., radiation therapy) can be repeated. For example, a treatment period of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., radiation therapy) can be repeated 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 of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., radiation therapy) can be repeated consecutively with a previous treatment period. In some cases, a new treatment period of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, e.g., lomustine, or additional therapies, e.g., radiation therapy) can begin one or more days after the end of the previous treatment period.

[0015] In some cases, eflornithine or its salt can be administered to the subject every day.In some cases, eflornithine or its salt can be administered to the subject only once a day (for example, on the day that eflornithine or its salt is administered to the subject during treatment period).In some cases, eflornithine or its salt can be administered to the subject twice a day (for example, on the day that eflornithine or its salt is administered to the subject during treatment period).In some cases, eflornithine or its salt can be administered to the subject three times a day (for example, on the day that eflornithine or its salt is administered to the subject during treatment period).

[0016] In some cases, the eflornithine or salt thereof is administered at a dose of at least 1.5 g / m 2 ~2.3g / m 2 Less than 2.3g / m 2 ~about 4.0g / m 2 , 2.3g / m 2 Super~4.5g / m 2 Less than 4.5g / m 2 And 6.9g / m 2 Less than 6.9g / m 2 ~Approx. 9.0g / m 2 , or 9.0 g / m 2 For example, eflornithine or a salt thereof can be administered to a subject in a daily dose of about 6.9 g / m free base equivalent (e.g., on days during the treatment period when eflornithine is administered to the subject). 2 ~Approx. 9.0g / m 2 In some cases, eflornithine or a salt thereof can be administered to a subject at a daily dose of at least 1.5 g / m per dose (e.g., on days during the treatment period when eflornithine is administered to the subject). 2 ~2.3g / m 2 Less than 2.3g / m 2 ~about 4.0g / m 2 , 2.3g / m 2 Super~4.5g / m 2 Less than 4.5g / m 2 And 6.9g / m 2 Less than 6.9g / m 2 ~Approx. 9.0g / m2 , or 9.0 g / m 2 In some cases, eflornithine or a salt thereof can be administered to a subject in an amount of at least 1.5 g / m free base equivalent (e.g., on days during the treatment period when eflornithine is administered to the subject). 2 ~2.3g / m 2 Less than 2.3g / m 2 ~about 4.0g / m 2 , 2.3g / m 2 Super~4.5g / m 2 Less than 4.5g / m 2 And 6.9g / m 2 Less than 6.9g / m 2 ~Approx. 9.0g / m 2 , or 9.0 g / m 2 In some cases, eflornithine or a salt thereof may be administered at a daily dose of at least 1.5 g / m2 or more of the free base equivalent for 1 to 6 days of the treatment period. 2 ~2.3g / m 2 Less than 2.3g / m 2 ~about 4.0g / m 2 , 2.3g / m 2 Super~4.5g / m 2 Less than 4.5g / m 2 And 6.9g / m 2 Less than 6.9g / m 2 ~Approx. 9.0g / m 2 , or 9.0 g / m 2 In some cases, eflornithine or a salt thereof may be administered at a daily dose of at least 1.5 g / m2 free base equivalent for a period of 7 to 13 days of treatment. 2 ~2.3g / m 2 Less than 2.3g / m 2 ~about 4.0g / m 2 , 2.3g / m 2 Super~4.5g / m 2 Less than 4.5g / m 2 And 6.9g / m 2 Less than 6.9g / m 2 ~Approx. 9.0g / m 2 , or 9.0 g / m 2Daily doses of more than 100 mg of the free base equivalent may be administered for a treatment period of 14 days or longer.

[0017] In some cases, eflornithine or a salt thereof is administered at a dose of about 6.9 g / m during the treatment period. 2 ~9.0g / m 2 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 at a daily dose of about 6.9 g / m during the treatment period (e.g., on the days when eflornithine or a salt thereof is administered to the subject), ... 2 ~9.0g / m 2 and temozolomide can be administered to a subject at a daily dose of about 50 mg / m free base equivalent during the same treatment period (e.g., on the days that temozolomide is administered to the subject). 2 ~about 90mg / m 2 , about 75mg / m 2 ~about 100mg / m 2 , at least 101 mg / m 2 ~about 150mg / m 2 Less than about 150 mg / m 2 , about 150mg / m 2 ~about 200mg / m 2 , or 200 mg / m 2 In some cases, eflornithine or a salt thereof can be administered to a subject at a daily dose of at least about 4.5 g / m during the treatment period (e.g., on the days that eflornithine or a salt thereof is administered to the subject). 2 ~approx. 6.9g / m 2 and temozolomide can be administered to a subject at a daily dose of less than about 50 mg / m free base equivalent during the same treatment period (e.g., on the days that temozolomide is administered to the subject). 2 ~about 90mg / m 2 , about 75mg / m 2 ~about 100mg / m 2 , 100 mg / m 2 Over 150 mg / m 2 Less than about 150 mg / m 2 , about 150mg / m 2~about 200mg / m 2 , or 200 mg / m 2 A daily dose of more than 100 mg / kg can be administered to a subject.

[0018] In some cases, eflornithine or a salt thereof is administered at a dose of at least 2.3 grams per square meter (g / m) during the treatment period. 2 In some cases, eflornithine or a salt thereof can be administered to a subject in an amount of a free base equivalent dose of at least 2.3 grams per square meter during a treatment period (e.g., on the day that eflornithine or a salt thereof is administered to the subject), and temozolomide can be administered to the subject during the same treatment period (e.g., on the day that eflornithine or a salt thereof is administered to the subject), and temozolomide can be administered to the subject during the same treatment period (e.g., on the day that temozolomide is administered to the subject) in an amount of a free base equivalent dose of at least 50 mg / m 2 ~about 90mg / m 2 , about 75mg / m 2 ~about 100mg / m 2 , at least 101 mg / m 2 ~about 150mg / m 2 Less than about 150 mg / m 2 , about 150mg / m 2 ~about 200mg / m 2 , or 200 mg / m 2 In some cases, eflornithine or a salt thereof can be administered to a subject in a dose amount of at least 2.3 grams per square meter (g / m²) of free base equivalent (e.g., on the day that eflornithine or a salt thereof is administered to the subject), and temozolomide can be administered to a subject in a dose amount of at least about 50 mg / m² during the same treatment period (e.g., on the day that temozolomide is administered to the subject). 2 ~about 90mg / m 2 , about 75mg / m 2 ~about 100mg / m 2 , 100 mg / m 2 Over 150 mg / m 2 Less than about 150 mg / m 2 , about 150mg / m 2 ~about 200mg / m 2 , or 200 mg / m2 The subject may be administered a dose of more than

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

[0020] In some cases, the treatment period can be 28 days, for example, where eflornithine or its salt 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 its salt can be administered to the subject on one or more days during the 28-day treatment period when temozolomide is not administered to the subject.In some cases, eflornithine can be administered to the subject only on the days during the (for example, 28-day) treatment period when temozolomide is not administered to the subject.In some cases, eflornithine or its salt can be administered to the subject on one or more days during the (for example, 28-day) treatment period when temozolomide is also administered to the subject.In some cases, eflornithine or its salt can be administered to the subject for at least 5 days, at least 7 days, at least 14 days, or at least 21 days before the administration of temozolomide to the subject.

[0021] In some cases, the treatment period of eflornithine or a salt thereof and / or temozolomide (and / or one or more additional agents, such as lomustine, or additional therapy, such as radiation therapy) can include a treatment holiday.A treatment holiday can include one or more days (e.g., during the treatment period of a treatment regimen) when eflornithine or a salt thereof is not administered to a subject.A treatment holiday can include one or more days (e.g., during the treatment period of a treatment regimen) when temozolomide is not administered to a subject.In some cases, a treatment holiday can include one or more days (e.g., during the treatment period of a treatment regimen) when neither eflornithine or a salt thereof nor temozolomide is administered to a subject.In some cases, a treatment holiday can include one or more days (e.g., during the treatment period of a treatment regimen) when an anti-cancer agent is not administered to a subject (e.g., when neither eflornithine or a salt thereof nor temozolomide is administered). In some cases, a treatment holiday can include one or more days on which the subject is not administered additional anti-cancer therapy (e.g., radiation therapy such as external beam radiation) (e.g., during the treatment period of a treatment regimen).In some cases, a treatment holiday can include one or more days on which the subject is not administered additional anti-cancer therapy (e.g., during the treatment period of a treatment regimen) (e.g., neither eflornithine or its salt nor temozolomide) and additional anti-cancer therapy (e.g., radiation therapy such as external beam radiation).In some cases, the subject may be administered standard care practices or treatments for another condition (e.g., non-cancer condition) during a treatment holiday.

[0022] In some cases, the 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 days in length (e.g., during the treatment period of the treatment regimen), whether consecutive or non-consecutive. In some cases, the 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 during the treatment period of the treatment regimen. In some cases, the treatment holiday can be 1-6 days, 8-12 days, 12-13 days, 15-18 days, 12-18 days, 19-20 days, or more than 22 days in length.

[0023] composition The compositions disclosed herein can include one or more therapeutic compounds. In some cases, the one or more therapeutic compounds can include eflornithine (difluoromethylornithine, DFMO) and / or a salt thereof. The compositions can include an enantiomer of eflornithine or a salt thereof. In some cases, the compositions can include L-eflornithine (or a salt thereof). In some cases, the compositions can include D-eflornithine (or a salt thereof). In some cases, the compositions can include a combination of L-eflornithine (or a salt thereof) and D-eflornithine (or a salt thereof). In some cases, the compositions can include a racemic mixture of L-eflornithine (or a salt thereof) and D-eflornithine (or a salt thereof). In some cases, the compositions can include both L-eflornithine (or a salt thereof) and D-eflornithine (or a salt thereof), and can include more (e.g., a higher weight percentage) L-eflornithine (or a salt thereof) than D-eflornithine (or a salt thereof). In some cases, the composition may contain both L-eflornithine (or a salt thereof) and D-eflornithine (or a salt thereof), and may contain more (e.g., a higher weight percentage) D-eflornithine (or a salt thereof) than L-eflornithine (or a salt thereof). In some cases, the composition may contain D-eflornithine (or a salt thereof) but not L-eflornithine (or a salt thereof). In some cases, the composition may contain L-eflornithine (or a salt thereof) but not D-eflornithine (or a salt thereof).

[0024] The compositions disclosed herein can include an ornithine decarboxylase inhibitor.In some cases, the ornithine decarboxylase inhibitor can be eflornithine or its salt.In some cases, the compositions disclosed herein can include a polyamine synthesis inhibitor.In some cases, the polyamine synthesis inhibitor can be eflornithine or its salt.In some cases, it can be advantageous to include eflornithine or its salt in the compositions, methods, regimens, or kits disclosed herein, for example, because eflornithine or its salt can cause cell cycle arrest (for example, by causing an increase in p21(waf1 / cip1) and / or p27kip-1 level, and / or by inhibiting polyamine synthesis). In some cases, causing cell cycle arrest, increasing p21 or p27kip-1 levels, or inhibiting polyamine synthesis may be advantageous, for example, in treating a subject with a glioma (e.g., a subject with a glioma and a mutation in an oncogene such as PTEN, p53, CDKN2A / B, and / or EGFR, e.g., when the subject is IDH1 wild-type), for example, to reduce tumor growth, inhibit metastasis or transition to metastasis, and / or reduce the risk of progression to a more severe (higher grade) tumor.

[0025] The compositions disclosed herein can include one or more antineoplastic or chemotherapeutic agents. In some cases, the antineoplastic agent can be an alkylating agent, an antimetabolite, an antiangiogenic agent, an EGFR inhibitor, a platinum-containing agent, or a topoisomerase inhibitor. In some cases, the one or more antineoplastic or chemotherapeutic agents can be temozolomide, lomustine (CCNU), carmustine (BCNU), procarbazine, prednisone, vincristine, PCT (e.g., a combination of lomustine, procarbazine, and vincristine), carboplatin, carboplatin and thymidine, carmustine and temozolomide, erlotinib, carboplating and erlotinib, chloretazine, lomustine and chloretazine, imatinib ... nib, hydroxyurea, hydroxyurea and imatinib, irinotecan, thalidomide, temozolomide and thalidomide, rilotumumab, cilengitide, cis-retinoic acid, celecoxib, cis-retinoic acid and celecoxib, enzastaurin, sirolimus, erlotinib and sirolimus, fenretinide, gefitinib, lapatinib, temsirolimus, tipifarnib, vorinostat, diaziquone, methotrexate, melphalan, vincristine, prednisone, and protease inhibitors. The compositions disclosed herein may include one or more of the following: a combination of eflornithine (or a salt thereof) and temozolomide; thioguanine; TPDCV (thioguanine, procarbazine, dibromodulcitol, lomustine, vincristine); carboplatin and tenoposide; or a combination of nitrogen mustard, vincristine, procarbazine, and tenoposide. In some cases, the compositions disclosed herein may include one or more alkylating agents. In some cases, the alkylating agent may be temozolomide. In some cases, the alkylating agent may be mutagenic, for example, in a subject to which the alkylating agent is administered. In some cases, the compositions, methods, or kits described herein may include temozolomide (TMZ). In some cases, the compositions, methods, or kits described herein may include administering eflornithine (or a salt thereof) and temozolomide to a subject (e.g., having a glioma).In some cases, the compositions, methods, or kits described herein can include administering eflornithine (or a salt thereof) and lomustine to a subject (e.g., having a glioma). In some cases, the compositions, methods, or kits described herein can include administering eflornithine (or a salt thereof), temozolomide, and lomustine to a subject (e.g., having a glioma).

[0026] In some cases, the composition or method can include eflornithine or a salt thereof at a concentration (e.g., by weight) of about 1% to about 40%. In some cases, the composition or method can include 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 1 9.8% to approximately 19.8%, approximately 19.8% to approximately 21%, approximately 19.8% to approximately 25%, approximately 19.8% to approximately 30%, approximately 19.8% to approximately 35%, approximately 19.8% to approximately 40%, approximately 19.8% to approximately 21%, approximately 19.8% to approximately 25%, approximately 19.8% to approximately 30%, approximately 19.8% to approximately 35%, approximately 19.8% to approximately 40%, approximately 21% The composition or method can include eflornithine or a salt thereof at a concentration (e.g., by weight) of about 1%, about 5%, about 13.5%, about 19.8%, about 19.8%, about 21%, about 25%, about 30%, about 35%, or about 40% (e.g., by weight) of about 1%, about 5%, about 13.5%, about 19.8%, about 21%, about 25%, about 30%, about 35%, or about 40% (e.g., by weight) of about 1%, about 5%, about 13.5%, about 19.8%, about 19.8%, about 21%, about 25%, about 30%, about 35%, or about 40% (e.g., by weight). In some cases, the composition or method can include eflornithine or a salt thereof at a concentration (e.g., by weight) of 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, the composition or method can include eflornithine or a salt thereof at a concentration (e.g., by weight) of 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, eflornithine can be provided in a solution of 13.9% free base equivalent (18% eflornithine hydrochloride monohydrate), for example, for oral administration. In some cases, an oral solution (e.g., containing 13.9% eflornithine free base equivalent) can include one or more additional components (e.g., additives or additives), such as glycerin, propylene glycol, sodium saccharin dihydrate, and / or sodium benzoate.

[0027] In some cases, the composition, kit, or method can include a dosage amount of eflornithine or a salt thereof from about 1.5 grams / m² to about 9 grams / m² (free base equivalent). In some cases, the composition, kit, or method can include a dosage amount of about 1.5 grams / m² to about 2.3 grams / m², about 1.5 grams / m² to about 4 grams / m², about 1.5 grams / m² to about 4.5 grams / m², about 1.5 grams / m² to about 6.9 grams / m², about 1.5 grams / m² to about 9 grams / m², about 2.3 grams / m² to about 4 grams / m², about 2.3 grams / m² to about 4.5 grams / m², or about 2.3 grams / m² to about 6.9 grams / m². The dosage amount of eflornithine or a salt thereof can be about 1.5 grams / m², about 2.3 grams / m² to about 9 grams / m², about 4 grams / m² to about 4.5 grams / m², about 4 grams / m² to about 6.9 grams / m², about 4 grams / m² to about 9 grams / m², about 4.5 grams / m² to about 6.9 grams / m², about 4.5 grams / m² to about 9 grams / m², or about 6.9 grams / m² to about 9 grams / m² (free base equivalent). In some cases, the composition, kit, or method can include a dosage amount of eflornithine or a salt thereof of about 1.5 grams / m², about 2.3 grams / m², about 4 grams / m², about 4.5 grams / m², about 6.9 grams / m², or about 9 grams / m² (free base equivalent). In some cases, the composition, kit, or method can include a dosage amount of eflornithine or a salt thereof of 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, the composition, kit, or method can include a dosage amount of eflornithine or a salt thereof of 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, the composition, kit, or method can include a daily dose of eflornithine or a salt thereof of about 1.5 grams / m² to about 9 grams / m² (free base equivalent). In some cases, the composition, kit, or method can include a daily dose of about 1.5 grams / m² to about 2.3 grams / m², about 1.5 grams / m² to about 4 grams / m², about 1.5 grams / m² to about 4.5 grams / m², about 1.5 grams / m² to about 6.9 grams / m², about 1.5 grams / m² to about 9 grams / m², about 2.3 grams / m² to about 4 grams / m², about 2.3 grams / m² to about 4.5 grams / m², or about 2.3 grams / m² to about 6.9 grams / m². The daily dose of eflornithine or a salt thereof can be about 1.5 grams / m², about 2.3 grams / m² to about 9 grams / m², about 4 grams / m² to about 4.5 grams / m², about 4 grams / m² to about 6.9 grams / m², about 4 grams / m² to about 9 grams / m², about 4.5 grams / m² to about 6.9 grams / m², about 4.5 grams / m² to about 9 grams / m², or about 6.9 grams / m² to about 9 grams / m² (free base equivalent). In some cases, the composition, kit, or method can include a daily dose of eflornithine or a salt thereof of about 1.5 grams / m², about 2.3 grams / m², about 4 grams / m², about 4.5 grams / m², about 6.9 grams / m², or about 9 grams / m² (free base equivalent). In some cases, the composition, kit, or method can include a daily dose of 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) of eflornithine or a salt thereof.In some cases, the composition, kit, or method can include a daily dose of at most about 1.5 grams / m², about 2.3 grams / m², about 4 grams / m², about 4.5 grams / m², about 6.9 grams / m², or about 9 grams / m² (free base equivalent) of eflornithine or a salt thereof.

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

[0030] In some cases, the composition, kit, or method can include a dosage amount of temozolomide of about 50 milligrams per square meter to about 200 milligrams per square meter. In some cases, the composition, kit, or method provides a stimulant having a stimulant concentration of about 50 milligrams / square meter to about 75 milligrams / square meter, about 50 milligrams / square meter to about 90 milligrams / square meter, about 50 milligrams / square meter to about 100 milligrams / square meter, about 50 milligrams / square meter to about 101 milligrams / square meter, about 50 milligrams / square meter to about 150 milligrams / square meter, about 50 milligrams / square meter to about 200 milligrams / square meter, about 75 milligrams / square meter to about 90 milligrams / square meter, about 75 milligrams / square meter to about 100 milligrams / square meter, about 75 milligrams / square meter to about 101 milligrams / square meter, about 75 milligrams / square meter to about 150 milligrams / square meter, or about 75 milligrams / square meter to about 200 milligrams / square meter. The dosage amount of temozolomide may include about 90 milligrams / square meter, about 90 milligrams / square meter to about 100 milligrams / square meter, about 90 milligrams / square meter to about 101 milligrams / square meter, about 90 milligrams / square meter to about 150 milligrams / square meter, about 90 milligrams / square meter to about 200 milligrams / square meter, about 100 milligrams / square meter to about 101 milligrams / square meter, about 100 milligrams / square meter to about 150 milligrams / square meter, about 100 milligrams / square meter to about 200 milligrams / square meter, about 101 milligrams / square meter to about 150 milligrams / square meter, about 101 milligrams / square meter to about 200 milligrams / square meter, or about 150 milligrams / square meter to about 200 milligrams / square meter. In some cases, the composition, kit, or method can include a dose amount of temozolomide of 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, the composition, kit, or method can include a temozolomide dose amount of 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, the composition, kit, or method can include a temozolomide dose amount of 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, the composition, kit, or method can include a daily dose of temozolomide of about 50 milligrams per square meter to about 200 milligrams per square meter. In some cases, the composition, kit, or method provides a stimulant having a stimulant concentration of about 50 milligrams / square meter to about 75 milligrams / square meter, about 50 milligrams / square meter to about 90 milligrams / square meter, about 50 milligrams / square meter to about 100 milligrams / square meter, about 50 milligrams / square meter to about 101 milligrams / square meter, about 50 milligrams / square meter to about 150 milligrams / square meter, about 50 milligrams / square meter to about 200 milligrams / square meter, about 75 milligrams / square meter to about 90 milligrams / square meter, about 75 milligrams / square meter to about 100 milligrams / square meter, about 75 milligrams / square meter to about 101 milligrams / square meter, about 75 milligrams / square meter to about 150 milligrams / square meter, or about 75 milligrams / square meter to about 200 milligrams / square meter. The dosage may include a daily dose of temozolomide of about 90 milligrams / square meter, about 90 milligrams / square meter to about 100 milligrams / square meter, about 90 milligrams / square meter to about 101 milligrams / square meter, about 90 milligrams / square meter to about 150 milligrams / square meter, about 90 milligrams / square meter to about 200 milligrams / square meter, about 100 milligrams / square meter to about 101 milligrams / square meter, about 100 milligrams / square meter to about 150 milligrams / square meter, about 100 milligrams / square meter to about 200 milligrams / square meter, about 101 milligrams / square meter to about 150 milligrams / square meter, about 101 milligrams / square meter to about 200 milligrams / square meter, or about 150 milligrams / square meter to about 200 milligrams / square meter. In some cases, the composition, kit, or method can include a daily dose of temozolomide of 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, the composition, kit, or method can include a daily dose of temozolomide of 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, the composition, kit, or method can include a daily dose of temozolomide of 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, temozolomide can be in a solid form. In some cases, temozolomide can be in a powder form. In some cases, temozolomide can be in the form of a liquid solution (e.g., an aqueous solution) at a concentration (e.g., weight % free base equivalent) or dosage amount (e.g., grams free base equivalent per square meter) described herein, for example. In some cases, temozolomide can be formulated for oral administration (e.g., as an oral liquid or as an oral solid such as a pill or tablet). In some cases, temozolomide can be formulated for intravenous delivery. In some cases, temozolomide can be formulated for intraperitoneal delivery. In some cases, temozolomide can be formulated for parenteral delivery. In some cases, temozolomide can be formulated for transdermal delivery. In some cases, temozolomide can be formulated for subcutaneous delivery. In some cases, temozolomide may be formulated for intramuscular delivery.

[0033] In some cases, the composition, kit, or method can include a dosage amount of lomustine of about 50 milligrams per square meter to about 150 milligrams per square meter. In some cases, the composition, kit, or method provides a stimulant having a stimulant concentration of about 50 milligrams / square meter to about 75 milligrams / square meter, about 50 milligrams / square meter to about 90 milligrams / square meter, about 50 milligrams / square meter to about 100 milligrams / square meter, about 50 milligrams / square meter to about 110 milligrams / square meter, about 50 milligrams / square meter to about 120 milligrams / square meter, about 50 milligrams / square meter to about 150 milligrams / square meter, about 75 milligrams / square meter to about 90 milligrams / square meter, about 75 milligrams / square meter to about 100 milligrams / square meter, about 75 milligrams / square meter to about 110 milligrams / square meter, about 75 milligrams / square meter to about 120 milligrams / square meter, or about 75 milligrams / square meter to about 150 milligrams / square meter. The dosage amount of lomustine may be about 90 milligrams / m², about 90 milligrams / m² to about 100 milligrams / m², about 90 milligrams / m² to about 110 milligrams / m², about 90 milligrams / m² to about 120 milligrams / m², about 90 milligrams / m² to about 150 milligrams / m², about 100 milligrams / m² to about 110 milligrams / m², about 100 milligrams / m² to about 120 milligrams / m², about 100 milligrams / m² to about 150 milligrams / m², about 110 milligrams / m² to about 120 milligrams / m², about 110 milligrams / m² to about 150 milligrams / m², or about 120 milligrams / m² to about 150 milligrams / m². In some cases, the composition, kit, or method can include a lomustine dosage amount of 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, the composition, kit, or method can include a lomustine dosage amount of 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, the composition, kit, or method can include a lomustine dosage amount of 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, the composition, kit, or method can include a daily dose of lomustine of about 50 milligrams per square meter to about 150 milligrams per square meter. In some cases, the composition, kit, or method provides a stimulant having a stimulant concentration of about 50 milligrams / square meter to about 75 milligrams / square meter, about 50 milligrams / square meter to about 90 milligrams / square meter, about 50 milligrams / square meter to about 100 milligrams / square meter, about 50 milligrams / square meter to about 110 milligrams / square meter, about 50 milligrams / square meter to about 120 milligrams / square meter, about 50 milligrams / square meter to about 150 milligrams / square meter, about 75 milligrams / square meter to about 90 milligrams / square meter, about 75 milligrams / square meter to about 100 milligrams / square meter, about 75 milligrams / square meter to about 110 milligrams / square meter, about 75 milligrams / square meter to about 120 milligrams / square meter, or about 75 milligrams / square meter to about 150 milligrams / square meter. The dosage may include a daily dose of lomustine of about 90 milligrams / m², about 90 milligrams / m² to about 100 milligrams / m², about 90 milligrams / m² to about 110 milligrams / m², about 90 milligrams / m² to about 120 milligrams / m², about 90 milligrams / m² to about 150 milligrams / m², about 100 milligrams / m² to about 110 milligrams / m², about 100 milligrams / m² to about 120 milligrams / m², about 100 milligrams / m² to about 150 milligrams / m², about 110 milligrams / m² to about 120 milligrams / m², about 110 milligrams / m² to about 150 milligrams / m², or about 120 milligrams / m² to about 150 milligrams / m². In some cases, the composition, kit, or method can include a daily dose of lomustine of 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, the composition, kit, or method can include a daily dose of lomustine of 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, the composition, kit, or method can include a daily dose of lomustine of 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, lomustine can be in solid form. In some cases, the lomustine can be in powder form. In some cases, lomustine can be in the form of a liquid solution (e.g., an aqueous solution) at a concentration (e.g., weight percent free base equivalent) or dosage amount (e.g., grams free base equivalent per square meter) described herein. In some cases, lomustine can be formulated for oral administration (e.g., as an oral liquid or as an oral solid such as a pill or tablet).

[0036] In some cases, the composition can contain one or more pharmaceutically acceptable additives. In some cases, the one or more pharmaceutically acceptable additives can be selected from preservatives, sweeteners, thickeners, buffers, liquid carriers, isotonicity agents, wetting agents, solubilizers, emulsifiers, acidifiers, alkalizers, carrying agents, chelating agents, colorants, complexing agents, solvents, suspending agents, viscosity-increasing agents, flavors, fragrances, oils, penetration enhancers, polymers, hardening agents, proteins, carbohydrates, bulking agents, and / or lubricants. In some cases, the one or more additives can be selected from sodium benzoate, saccharin sodium dihydrate, glycerol, and / or propylene glycol. In some cases, the composition can contain eflornithine or a salt thereof, one or more pharmaceutically acceptable additives, and up to 100% water in the amounts of the concentrations or dosages described herein. In some cases, the composition can include temozolomide in a concentration or dosage amount described herein, one or more pharmaceutically acceptable excipients, with up to 100% water. In some cases, the composition can include lomustine in a concentration or dosage amount described herein, one or more pharmaceutically acceptable excipients, with up to 100% water.

[0037] The 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 include 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 additives and auxiliaries that facilitate processing of the active compound into a pharmaceutically usable preparation.

[0038] The specific embodiment of the formulation of the pharmaceutical composition disclosed herein can be determined by the selected route of administration.In some cases, compositions intended for administration to a subject by injection can be formulated in aqueous solution in a physiologically compatible buffer, such as Hanks' solution, Ringer's solution, or physiological saline buffer.For example, for transmucosal administration, penetrants appropriate to the barrier to be permeated can be used in the formulation.

[0039] The compound can be easily formulated by combining one or more compounds (e.g., eflornithine or its salt and drugs such as temozolomide) with one or more pharmaceutically acceptable carriers for oral administration. Such carriers can, for example, allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, solutions, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing a solid additive with the active ingredient (drug), milling the resulting mixture as needed, and processing the mixture of granules after adding suitable additives, 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, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gums, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0040] In some embodiments, dragee core can be provided with suitable coating.For this purpose, concentrated sugar solution can be used, for example, where concentrated sugar solution comprises gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and suitable organic solvent or solvent mixture as needed.For identification or to characterize different combinations of active agent, dyes or pigments can be added to tablet or dragee coating.

[0041] Pharmaceutical preparations that can be used orally can include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers can be added. Formulations for oral administration can be prepared and / or utilized (e.g., according to the instructions in the kits disclosed herein) in dosages suitable for such administration. The compositions can also take the form of tablets or lozenges formulated in a conventional manner, which can be useful for buccal administration.

[0042] Pharmaceutical preparations 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 can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. If necessary, the suspension can also contain suitable stabilizers or modifiers that increase the solubility or dispersibility of the composition, allowing 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 a solid additive, optionally milling the resulting mixture, and processing the mixture into tablets or dragee cores, if desired, after adding suitable additives. Suitable additives are, inter alia, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegration-regulating substances such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may also be added.

[0043] Other ingredients, such as stabilizers, can be used, 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-α-naphthylamine, or lecithin. Chelators, such as EDTA, can also be used in the compositions (e.g., pharmaceutical compositions) disclosed herein. Other ingredients, such as lubricants, colorants, or flavoring agents in tablets or pills, can be used. Pharmaceutical additives used in the 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 glycol, and physiologically compatible solvents. In some embodiments, other pharmaceutical additives can be used as well. 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 media, carrier, or agent is incompatible with the active ingredient or ingredients, its use in the compositions according to the present invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions, particularly the compositions described herein.

[0044] subject 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 using one or more steps of the methods described herein) based on one or more criteria. In some cases, the one or more criteria can be the clinical condition of the subject. For example, a subject identified, selected for treatment, and / or administered a treatment or therapy 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., 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 an oligodendroglioma, anaplastic oligodendroglioma, or anaplastic ependymoma.

[0045] In some cases, the subject (e.g., the subject's glioma) may have a genetic mutation. In some cases, the genetic mutation may affect the severity, treatment resistance, progression rate, and / or progression mechanism or pathway, or the risk thereof in the subject, of the tumor. In some cases, the mutation (e.g., driver mutation) in one or more of IDH1, IDH2, CDKN2A / B, PTEN, ERCC1, MGMT, p53, EGFR, ATRX, SMARCA4, and / or BRAF genes may affect the severity, treatment resistance, progression rate (e.g., to a higher grade tumor classification), and / or progression mechanism or pathway, or the risk thereof in the subject, of the tumor. In some cases, the compositions, methods, regimens, or kits described herein may be effective in reducing the rate of progression, increasing overall survival, and / or increasing progression-free survival in a subject or tumor, where 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 example, the compositions, regimens, methods, or kits described herein may be effective in treating a subject's glioma that has a mutation in the IDH1 gene (e.g., and / or one or more of the other genes disclosed herein). In some cases, the subject or glioma may 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, the compositions, methods, regimens, or kits described herein may be effective in reducing the rate of progression, 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 example, the compositions, regimens, methods, or kits described herein may be effective for treating gliomas of subjects who are wild-type for the IDH1 gene (e.g., and / or one or more of the other genes disclosed herein).In some cases, mutations in IDH1 can increase cell cycle arrest.In some cases, subjects with IDH1 wild-type gliomas may be at a higher risk of tumor progression and / or metastasis than subjects with IDH1 mutations (e.g., subjects with IDH1 mutant gliomas), for example, in some cases, where IDH1 mutations increase cell cycle arrest.In some cases, IDH1 wild-type gliomas may be more difficult to treat with current therapies than IDH1 mutant gliomas.This is because, for example, the lack of mutations in the IDH1 gene may allow tumor cells to proliferate and / or migrate at a faster rate and / or more extensively in IDH1 wild-type gliomas than in IDH1 mutant gliomas. The compositions, methods, regimens, and / or kits disclosed herein comprising eflornithine or a salt thereof (e.g., in combination with one or more additional agents, e.g., antineoplastic agents such as temozolomide, or a therapy such as radiation therapy) may be advantageous for reducing the growth rate, tumor stage progression, and / or metastasis in IDH1 mutant gliomas and IDH1 wild-type gliomas. In some embodiments, the use of eflornithine or a salt thereof may be advantageous for treating an IDH1 mutant tumor (e.g., glioma) in a subject. This is because, for example, eflornithine or a salt thereof may, in some cases, further inhibit cell cycle progression in tumor (e.g., glioma) cells beyond the effect of IDH1 mutation on cell cycle progression of the tumor cells, which may, in some cases, enable one or more antineoplastic agents (e.g., temozolomide and / or lomustine) of the compositions, methods, regimens, or kits disclosed herein to adversely affect tumor cell viability (e.g., by increasing the time to progression, reducing the rate of proliferation, and / or reducing the rate of migration or metastasis in a subject).In some cases, the advantage of including eflornithine or a salt thereof in the compositions, methods, regimens, or kits disclosed herein (e.g., in combination with one or more additional agents, for example, anti-cancer agents such as temozolomide, or a therapy such as radiation therapy) may be particularly beneficial in treating a subject's IDH1 wild-type tumor (e.g., glioma). This is because, for example, the tumor (e.g., glioma) may not be hindered by any inhibitory effect that IDH1 mutations would otherwise have on tumor cell cell cycle progression. As a result, the lack of IDH1 mutations in a subject or its tumor may allow an IDH1 wild-type tumor to grow, migrate, metastasize, and / or progress (e.g., to a more severe stage) at a faster rate than an IDH1 mutant tumor, for example, in some cases, shortening the time an anti-cancer agent must destroy tumor cells before they can grow or migrate. The inclusion of eflornithine or a salt thereof in the compositions, methods, regimens, or kits disclosed herein can inhibit cell cycle progression in IDH1 wild-type tumor cells, which may, in some cases, allow antineoplastic agents or other therapies more opportunity to destroy tumor cells (e.g., by slower growth, migration, progression, and / or metastasis) before the tumor cells proliferate, migrate, progress to a more severe stage (e.g., a higher tumor classification grade), and / or metastasize to a different location. In some cases, tumors (e.g., gliomas) can be identified for treatment using the compositions, methods, regimens, or kits disclosed herein based (e.g., at least in part) on the tumor's epigenetic status. For example, the compositions, methods, regimens, or kits disclosed herein may be advantageous in treating tumors that have O6-methylguanine DNA methyltransferase (MGMT) methylation (e.g., IDH1 wild-type status, with or without one or more genetic mutations disclosed herein), e.g., as confirmed by historical standard of care testing.

[0046] In some cases, the subject has previously received anti-cancer therapy.In some cases, the subject has previously received chemotherapy (for example, temozolomide, lomustine, or another anti-cancer agent) or radiation therapy (for example, external beam radiation therapy).In some cases, the subject may not be receiving concurrent radiation therapy or additional chemotherapy during treatment.In some cases, eflornithine or its salt and / or temozolomide can be administered concurrently with radiation therapy.

[0047] In some cases, the subject's tumor (e.g., a glioma such as an astrocytoma or glioblastoma) may be relapsed or refractory (e.g., "relapsed / 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 with a relapsed or refractory tumor (e.g., a glioma, e.g., an astrocytoma or glioblastoma). A recurrent or refractory (e.g., "recurrent / refractory") tumor or glioma (e.g., a recurrent or refractory astrocytoma or a recurrent or refractory glioblastoma) can be, for example, one that has recurred in a subject after a previous (e.g., initial) treatment or therapy, e.g., where the previous treatment or therapy includes 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., a treatment including an antibody or other targeted binding composition, eflornithine or a salt thereof, or a cell-based anti-cancer treatment including, e.g., CAR-T cells). In some cases, the compositions, methods, regimens, or kits disclosed herein (e.g., comprising eflornithine or a salt thereof, temozolomide, and / or lomustine) can reduce the rate of progression, reduce the rate of growth, and / or reduce the risk of metastasis in recurrent or refractory tumors (e.g., recurrent or refractory gliomas, e.g., recurrent or refractory astrocytomas and / or recurrent or refractory glioblastomas). In some cases, the compositions, methods, regimens, or kits disclosed herein (e.g., comprising eflornithine or a salt thereof, temozolomide, and / or lomustine) can increase progression-free survival or overall survival in subjects with recurrent or refractory tumors (e.g., recurrent or refractory gliomas, e.g., recurrent or refractory astrocytomas and / or recurrent or refractory glioblastomas).For example, the compositions, methods, regimens, or kits disclosed herein (e.g., comprising eflornithine or a salt thereof, temozolomide, and / or lomustine) may improve progression-free survival or overall survival in subjects with recurrent or refractory tumors (e.g., recurrent or refractory gliomas, e.g., recurrent or refractory astrocytoma and / or recurrent or refractory glioblastoma) by 1 day to 28 days, less than 1 month, 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, or 1 month to 30 days. 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, 12-72 months, 18-24 months, 18-30 months, 18-36 months, 18-48 months, 18-60 months, 18-72 months, 24-30 months, 24-36 months, 24-48 months, 24-60 months, 24-72 months, 30-36 months, 30-48 months, 30-60 months, 30-72 months, 36-48 months, 36-60 months, 36-72 months, 48-60 months, 48-72 months, 60-72 months, 1 month, 3 months, 6 months, 12 months, 18 months, 24 months The term may be increased by 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, or by 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, the subject's glioma is not recurrent or refractory during at least a portion of the treatment period.

[0048] In some cases, the subject's glioma is selected from grade 2 astrocytoma, grade 3 astrocytoma, grade 4 astrocytoma, or grade 4 glioblastoma. In some cases, the glioma may contain a mutation. In some cases, the glioma may contain a mutation in the IDH1 gene. In some cases, the glioma may be an IDH1 wild-type glioma. In some cases, the compositions, methods, regimens, or kits disclosed herein can be used to treat central nervous system (CNS) tumors (e.g., gliomas), where the CNS tumor has a mutation in the IDH1 gene and may be a grade 3 central nervous system (CNS) tumor according to 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, where the CNS tumor has a mutation in the IDH1 gene and a wild-type allele of the CDKN2A / B gene, which may be a grade 3 astrocytoma, IDH-1 mutant, according to the WHO 2021 classification system. In some cases, a composition, method, regimen, or kit disclosed herein can be used to treat a CNS tumor, where the CNS tumor has a mutation in the IDH1 gene and one or more mutations (e.g., homozygous deletions) in the CDKN2A / B gene, which may be classified as a grade 4 astrocytoma, IDH-1 mutant, according to the WHO 2021 classification system. In some cases, the compositions, methods, regimens, or kits disclosed herein can be used to treat a CNS tumor, where the CNS tumor is wild-type for IDH1, which may be classified as a grade 3 anaplastic astrocytoma according to the WHO 2016 classification system, or a grade 4 glioblastoma, IDH-1 wild-type, according to the WHO 2021 classification system.

[0049] RANO criteria (e.g., Response Assessment in Neuro-Oncology criteria for Gliomas) can be used to measure disease progression and response in subjects (e.g., where progression can be defined as worsening enhancement and / or distinct 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 blood-brain barrier integrity, where microstructural disruption may indicate active tumor) and / or assessment of tumor size enhancement or increase (e.g., using T2-weighted MRI imaging or T2-weighted fluid-attenuated inversion recovery (T2-weighted FLAIR) MRI imaging).

[0050] To evaluate the effectiveness of the compositions, methods, regimens, or kits disclosed herein, progression-free survival can be determined.In some cases, progression-free survival can be evaluated by establishing a target baseline using RANO criteria before treatment.Progression can be determined by one or more of the following methods: recurrence / progression can be determined by the increase in T2 hyperintensity, gadolinium enhancement, or both, for example, where T2 hyperintensity progression can be determined by the increase in size of T2 hyperintensity on T2-weighted and / or T2-weighted FLAIR images (for example, the expansion into the brain and / or the presence of new lesions), and where gadolinium enhancement progression can be determined by the increase in size of one or more gadolinium enhancement lesions seen on T1-weighted images.

[0051] To evaluate the efficacy of a composition, method, regimen, or kit disclosed herein, the objective response rate (ORR) can be determined. In some cases, the RANO criteria can be used to measure the ORR during the study. In some cases, the ORR response category can be based on MRI using the RANO criteria for glioblastoma (GBM). In some cases, the ORR can be estimated based on the crude proportion of patients whose best overall response during the course of study treatment is a complete response (CR) or a partial response (PR). In some cases, the clinical benefit rate (CBR) can be determined to evaluate the efficacy of a composition, method, regimen, or kit disclosed herein. In some cases, the CBR can be estimated based on the crude proportion of patients whose best overall response during the course of study treatment is a combination of a complete response (CR), a partial response (PR), and stable disease (SD).

[0052] In some cases, plasma concentrations of L-eflornithine (or a salt thereof) and / or D-eflornithine (or a salt thereof) can be determined to assess the efficacy and / or safety of the compositions, methods, regimens, or kits disclosed herein.

[0053] kit Disclosed herein is a kit comprising one or more pharmaceutical compositions, for example, together with instructions for the use of the one or more pharmaceutical compositions.The instructions of the kit can include instructions for the use of one or more pharmaceutical compositions in the treatment of a condition of a subject (for example, the treatment of glioma in a subject described herein).In some cases, the instructions can include one or more steps of the method or regimen described herein.In some cases, the kit can include a composition comprising eflornithine or a salt thereof, together with instructions for its use (for example, administration).For example, the kit can include a composition comprising eflornithine or a salt thereof, together with instructions for its use in the treatment of a condition such as glioma (for example, by the method or regimen disclosed herein).In some cases, the kit can include a composition comprising temozolomide, together with instructions for its use (for example, administration).For example, the kit can include a composition comprising temozolomide, together with instructions for its use in the treatment of a condition such as glioma (for example, by the method or regimen disclosed herein). In some cases, a kit can include a composition comprising lomustine along with instructions for its use (e.g., administration). For example, a kit can include a composition comprising lomustine along with instructions for use in treating a condition such as glioma (e.g., by a method or regimen set forth herein).

[0054] In some cases, the instructions include instructions for preparing a composition described herein (e.g., a composition for use in treating glioma, which may include, for example, an aqueous solution containing eflornithine or a salt thereof and / or temozolomide). In some cases, the instructions for preparing a composition described herein may include instructions indicating the amount of solid (e.g., a solid included in the kit) to be added to a solvent (e.g., to create a composition described herein, e.g., an aqueous solution) and / or how to accomplish the same. In some cases, the solvent is water. In some cases, the solvent is hydrophobic. In some cases, the solvent includes an alcohol and / or an oil. In some cases, the kit described herein may include one or more solvents, for example, a solvent selected from water, an alcohol, or an oil.

[0055] In some cases, the kit may include one or more dispensing devices and / or one or more liquid and / or solid pharmaceutical formulations (e.g., powders, solutions, suspensions) containing one or more compositions described herein (e.g., containing eflornithine or a salt thereof or temozolomide). For example, the kit may include 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 contain eflornithine or a salt thereof (e.g., less than 400 ml of an eflornithine oral liquid formulation, 400-450 ml of eflornithine or a salt thereof in an oral liquid formulation, 450 ml of eflornithine or a salt thereof in an oral liquid formulation, or more than 500 ml of eflornithine or a salt thereof in an oral liquid formulation). In some cases, the cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and / or tablets of the kit can contain a dose of eflornithine or a salt thereof (e.g., a dose amount described herein, e.g., a daily dose amount). In some cases, the cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and / or tablets of the kit can contain a precise dose of eflornithine or a salt thereof (e.g., a dosage amount described herein, e.g., a daily dose amount). In some cases, the kit can contain multiple 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 contains a dose of eflornithine or a salt thereof (e.g., a dosage amount described herein, e.g., a daily dose amount). In some cases, the kit can include 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 contains a precise 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 contain temozolomide. In some cases, the cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and / or tablets of the kit can contain a dose of temozolomide (e.g., a dose amount described herein, e.g., a daily dose amount). In some cases, the cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and / or tablets of the kit can contain a precise dose of temozolomide (e.g., a dose amount described herein, e.g., a daily dose amount). In some cases, the kit can include 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 contains a dose of temozolomide (e.g., a dose amount described herein, e.g., a daily dose amount). In some cases, the kit can include 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, dragees, and / or tablets contains a precise dose of temozolomide. In some cases, temozolomide can be provided in one or more capsules for oral administration, for example, where one or more capsules (e.g., each capsule) contain 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 contain lomustine.In some cases, the cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and / or tablets of the kit can contain a dose of lomustine (e.g., a dose amount described herein, e.g., a daily dose amount).In some cases, the cups, bottles, ampoules, syringes, pouches, wafers, pills, dragees, and / or tablets of the kit can contain an exact dose of lomustine (e.g., a dose amount described herein, e.g., a daily dose amount). In some cases, the kit can include 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 contains a dose of lomustine (e.g., a dose amount described herein, e.g., a daily dose amount). In some cases, the kit can include 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, dragees, and / or tablets contains a precise dose of lomustine.

[0059] In some cases, it may be advantageous to provide a kit containing one or more dispensing devices and / or one or more compositions, each of which contains one dose of eflornithine or a salt thereof, one dose of temozolomide, one dose of lomustine, one dose of lomustine and eflornithine or a salt thereof, one dose of temozolomide and eflornithine or a salt thereof, and / or one dose of lomustine and temozolomide.This is because, for example, it can reduce the complexity of subject preparation and / or self-administration of treatment, improve compliance with the methods or regimens described herein, and improve the efficacy of the regimens.

[0060] In some cases, a kit, method, or regimen can include multiple doses (e.g., where the doses include eflornithine or a salt thereof, temozolomide, and / or lomustine). In some cases, two or more of the multiple 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 amounts 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., eflornithine, temozolomide, or lomustine) of a first dose of a kit, method, or regimen can be different from that of a second dose of a kit, method, or regimen. In some cases, in the first dose of a kit, method or regimen, the amount of the dose of one or more components of the first dose may be greater than the amount of the dose of the same one or more components of the second dose, for example, where the second dose is administered to the subject after the first dose.In some cases, in the first dose of a kit, method or regimen, the amount of the dose of one or more components of the first dose may be less than the amount of the dose of the same one or more components of the second dose, for example, where the second dose is administered to the subject after the first dose.In some cases, the instructions for the kit may include instructions regarding the order of administration of two or more doses of the kit (for example, where two or more doses are labeled to indicate the identity or order of the doses).

[0061] definition The terms "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a polypeptide" includes one or more polypeptides.

[0062] As used herein, the terms "about" and "approximately," when modifying a quantity specified by a numerical value or range, indicate reasonable deviations from that numerical value and values ​​known to one of ordinary skill in the art, e.g., ±20%, ±10%, or ±5%, within the intended meaning of the stated value. [Example]

[0063] Example 1 Subject selection including assessment of IDH1 genetic background This example describes the selection of a subject population for treatment with eflornithine or a salt thereof and temozolomide.

[0064] For example, a tissue sample 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 with a glioma, such as an astrocytoma or glioblastoma, for treatment with eflornithine or a salt thereof and temozolomide according to the compositions or methods described herein. Mutation analysis is performed on the tissue sample. Subjects with mutations in the IDH1 gene are treated with eflornithine (or a salt thereof) and temozolomide according to the methods or regimens described herein (e.g., as described in one of Examples 2-4). In some cases, subjects who are wild-type for IDH1 are treated in a separate group with eflornithine (or a salt thereof) and temozolomide according to the methods or regimens described herein (e.g., as described in one of Examples 2-4). Optionally, the subject may have a glioma that is refractory or recurrent after previous temozolomide treatment (and / or previous radiation therapy).

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

[0066] The target was 2.3 g / m 2administered orally every 8 hours daily for 2 weeks during the treatment period, followed by a 2-week period during the treatment period during which the subject does not receive eflornithine. Temozolomide is administered to the subject at a dose of 150 mg / m once daily for 5 days during the treatment period. 2 On the days when eflornithine is administered to the subject, temozolomide is not administered to the subject.

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

[0068] The target is 2.8g / m 2 administered orally every 8 hours daily for 2 weeks during the treatment period, followed by a 2-week period during the treatment period during which the subject does not receive eflornithine. Temozolomide is administered to the subject at a dose of 150 mg / m once daily for 5 days during the treatment period. 2 On the days when eflornithine is administered to the subject, temozolomide is not administered to the subject.

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

[0070] The target is 1.75 g / m 2 administered orally every 8 hours daily for 2 weeks during the treatment period, followed by a 2-week period during the treatment period during which the subject does not receive eflornithine. Temozolomide is administered to the subject at a dose of 150 mg / m once daily for 5 days during the treatment period. 2 On the days when eflornithine is administered to the subject, temozolomide is not administered to the subject.

[0071] Example 5 Treatment of subject cohort with eflornithine and temozolomide This example describes the treatment of a population of subjects for treatment with eflornithine or a salt thereof and temozolomide.

[0072] Subjects with newly diagnosed glioblastoma after radiation therapy are selected for treatment with eflornithine and temozolomide.

[0073] Dosing for both study medications (eflornithine and temozolomide) is based on body surface area calculated per institutional guidelines on study day 1. During the course of the study, doses will be adjusted for subjects with a 10% or greater change in body weight used to calculate dose. Subject cohort dosing is as follows:

[0074] Cohort-1: (Dose Level-1): Eflornithine dosing for 14 days out of 28 days (Days 1-14: eflornithine 1.75 g / m 2 , given orally every 8 hours.

[0075] Cohort 1 (dose level 1): Eflornithine was administered for 14 days out of 28 days (Days 1-14: eflornithine 2.3 g / m 2 , given orally every 8 hours.

[0076] Cohort 2: (Dose Level 2): ​​Eflornithine dosing for 14 days out of 28 days (Days 1-14: eflornithine 2.8 g / m 2 , given orally every 8 hours.

[0077] All cohorts: Days 15-19: Temozolomide (TMZ) 150 mg / m 2 , once daily for 5 days, with the possibility of dose escalation; days 20-28: no therapy.

[0078] Subjects are treated with one or more 28-day treatment period cycles as described above, for a maximum of 12 28-day treatment period cycles (eg, for a maximum of 48 weeks).

[0079] Dose escalation from Cohort 1 to Cohort 2 (dose level 2) can proceed if all subjects in Cohort 1 have completed 56 days (eg, two consecutive cycles) of treatment.

[0080] Dose de-escalation from Cohort 1 to Cohort-1 (dose level-1) can proceed if two or more subjects experience a dose-limiting toxicity (DLT) event during the first 56 days of treatment (e.g., the first two cycles of treatment), which may include grade 4 neutropenia, grade 3 or higher febrile neutropenia, grade 4 thrombocytopenia, or grade 4 anemia.

[0081] While the present invention has been described in conjunction with the detailed description thereof, it should be understood that the foregoing description is intended to illustrate, but 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. Furthermore, the section headings, materials, methods, and examples are illustrative and are not necessarily intended to be limitations on the scope of the invention.

Claims

1. 1. A regimen for treating a subject having glioma, comprising: and administering eflornithine or a salt thereof and temozolomide to the subject during the treatment period, wherein the eflornithine or salt thereof is administered at a dose of 6.9 g / m ２ (grams / square meter) to 9.0 g / m ２ for 14 days or more of the treatment period, and the temozolomide is administered at a daily dose of 150 mg / m ２ (milligrams / square meter) to 200 mg / m ２ is administered for 5 days or more of said treatment period.

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

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

4. The eflornithine or salt thereof is administered in an amount of 2.3 g / m per dose. ２ ~4.0g / m ２ 4. The regimen of claim 1 or claim 3, wherein the medicament is administered to the subject in three separate doses in an amount of free base equivalent of 100 mg / kg of medicament.

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

6. The temozolomide is administered at a dose of 150 mg / m ２ 10. The regimen of any one of the preceding claims, wherein the subject is administered a single dose per day of

7. 1. A regimen for treating a subject having glioma, comprising: administering eflornithine or a salt thereof and temozolomide to the subject during a treatment period, wherein the eflornithine or salt thereof is administered at a dose of at least 4.5 g / m ２ (grams / square meter) and 6.9 g / m ２ and the temozolomide is administered at a daily dose of less than 150 mg / m free base equivalent for 14 days or longer of the treatment period. ２ (milligrams / square meter) to 200 mg / m ２ is administered for 5 days or more of said treatment period.

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

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

10. The eflornithine or salt thereof has a density of at least 1.5 grams per square meter (g / m ２ ) and a free base equivalent of 2.3 grams per square meter (g / m ２ 10. The regimen of claim 7 or claim 9, wherein the compound is administered to the subject in an amount of less than 100 mg / kg of hydroxybenzoates (200 mg / kg) or ...

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

12. The temozolomide is administered at a dose of 150 mg / m ２ 12. The regimen of any one of claims 7 to 11, wherein the subject is administered a single dose per day of

13. 13. The regimen of any one of claims 1 to 12, wherein the subject has previously been treated with chemotherapy or radiation therapy.

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

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

16. 15. The regimen of any one of claims 1 to 14, wherein the eflornithine or a salt thereof or the temozolomide is administered concurrently with radiation therapy.

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

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

19. 18. The regimen of any one of claims 1 to 17, wherein the daily administration of eflornithine or a salt thereof overlaps with the daily administration of temozolomide for 1 to 3 days.

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

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

22. 22. The regimen of claim 21, wherein the treatment holiday is one week or longer.

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

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

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

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

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

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

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

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

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

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

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

34. 10. The regimen of any one of the preceding claims, repeated sequentially for three months or longer.

35. A regimen for treating a subject with glioma, comprising administering to the subject eflornithine or a salt thereof and temozolomide during a first-line treatment period, wherein the eflornithine or salt thereof is administered at a dose of at least 2.3 grams per square meter (g / m ２ ) free base equivalent dose, and temozolomide is administered at a dose of 50 mg / m ２ (milligrams / square meter) to 90 mg / m ２ The regimen is administered in a dose amount of.

36. The eflornithine or a salt thereof is administered in a dose of 6.9 g / m ２ ~9.0g / m ２ 36. The regimen of claim 35, wherein the medicament is administered at a daily dose of the free base equivalent of 14 or more of the first-line treatment period.

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

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

39. The eflornithine or salt thereof is administered in an amount of 2.3 g / m per dose. ２ ~3.0g / m ２ 39. The regimen of claim 38, wherein the compound is administered to the subject in three separate doses in an amount of free base equivalent of

40. The temozolomide is administered at a dose of 150 mg / m ２ 40. The regimen of any one of claims 35 to 39, wherein the subject is administered a single dose per day of

41. A regimen for treating a subject with glioma, comprising administering eflornithine or a salt thereof and temozolomide to the subject during a first-line treatment period, wherein the eflornithine or salt thereof is administered at a dose of at least 1.5 grams per square meter (g / m ２ ) and a free base equivalent of 2.3 grams per square meter (g / m ２ ) and temozolomide is administered at a dose of less than 50 mg / m ２ (milligrams / square meter) to 90 mg / m ２ The regimen is administered in a dose amount of.

42. The eflornithine or salt thereof is administered in a dose of at least 4.5 g / m ２ and a free base equivalent of 6.9 g / m ２ 42. The regimen of claim 41, wherein the first-line treatment is administered at a daily dose of less than 14 days of the first-line treatment period.

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

44. 43. The regimen of claim 41 or claim 42, wherein the eflornithine or its salt is administered to the subject three times per day.

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

46. The temozolomide is administered at a dose of 150 mg / m ２ 46. ​​The regimen of any one of claims 41 to 45, wherein the subject is administered a single dose per day of

47. 47. The regimen of any one of claims 41 to 46, wherein the subject has not received chemotherapy prior to the first-line treatment period.

48. 48. The regimen of any one of claims 41 to 47, wherein the subject did not receive radiation therapy prior to the first-line treatment period.

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

50. 50. The regimen of any one of claims 41 to 49, wherein the eflornithine or salt thereof or the temozolomide is administered concurrently with radiation therapy.

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

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

53. The temozolomide is administered at a dose of 150 mg / m ２ ~200 mg / m ２ for 5 days or more of said subsequent treatment period.

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

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

56. 54. The regimen of any one of claims 51 to 53, wherein the eflornithine or a salt thereof is administered during the subsequent treatment period at the same dosage amount as during the first-line treatment period.

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

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

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

60. 60. The regimen of claim 59, wherein the treatment holiday is one week or longer.

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

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

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

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

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

66. 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 of the 28 day subsequent treatment period.

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

68. 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 when temozolomide is not administered to the subject.

69. 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 during which temozolomide is also administered to the subject.

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

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

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

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

74. 74. The regimen of any one of claims 51-73, wherein the subsequent treatment periods are repeated sequentially for 3 months or longer.

75. 10. 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. 10. The regimen of any one of the preceding claims, wherein the glioma is not a recurrent glioma.

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

78. 77. The regimen of any one of claims 1 to 76, wherein the glioma is an IDH1 wild-type glioma.

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