How to Treat Glioma

Abstract

Methods of treating glioma with WEE1 inhibitors are disclosed.

Description

[Technical Field]

[0001] The present invention relates generally to the treatment of glioma. More specifically, the present invention relates to the use of specific WEE1 inhibitors to treat glioma in patients in need of such treatment. [Background technology]

[0002] It is estimated that more than 3 million people worldwide were diagnosed with primary brain tumors in 2020. Brain tumors account for 85% to 90% of all primary central nervous system (CNS) tumors. According to the World Health Organization 2021 classification (WHO2021), CNS tumors include many categories, including "gliomas, glioneuronal tumors, and neuronal tumors." Such tumors can be further classified by subtype and grade, for example, based on an integrated histological and molecular grading of 3 to 4, with grade 4 being the most aggressive. More than half of high-grade diffuse gliomas (also known as high-grade malignant gliomas) are malignant primary brain tumors. Approximately 60-70% of malignant gliomas are glioblastomas (GBM). GBM is the most common malignant primary brain tumor in adults and a leading cause of morbidity and mortality. Approximately 90% of GBMs are primary. In contrast to primary GBMs (95% of which are associated with isocitrate dehydrogenase (IDH) wild-type status), IDH1 gene mutations are common in secondary GBMs and tumors formerly known as anaplastic astrocytomas, which are now classified as astrocytoma IDH-mutant grade 3 tumors according to the WHO 2021 classification. The presence of IDH mutations transcends grade and generally identifies a group of tumors with a better prognosis than their IDH wild-type counterparts.

[0003] The widely accepted standard of care (SOC) for patients with newly diagnosed GBM who are in good general condition after surgical resection is temozolomide (TMZ) and concurrent radiation therapy (RT), generally followed by maintenance TMZ (Non-Patent Document 1). Additional FDA-approved treatment options for newly diagnosed high-grade gliomas include direct intracranial application of chemotherapy using biodegradable carmustine-impregnated wafers as an adjunct to surgery and the addition of alternating electric tumor treating field (TTField) therapy during TMZ treatment (Non-Patent Document 2). Unfortunately, the addition of immunotherapy or systemic targeted therapy, including bevacizumab, to the SOC of newly diagnosed high-grade gliomas has not been shown to improve overall survival (OS). Despite additional treatment, the prognosis for newly diagnosed high-grade gliomas remains poor. Almost all recurrences occur 6–9 months after first-line therapy, and the 5-year OS rate is less than 10%.

[0004] Management of recurrent GBM also remains challenging. No established second-line therapy exists, and effective treatment options are limited. Treatments may include repeated neurosurgical resection, re-irradiation, locally delivered chemotherapy using TTFields, biodegradable carmustine-impregnated wafers, bevacizumab, systemic cytotoxic chemotherapy (e.g., re-exposure to TMZ, treatment with nitrosoureas, or the combination of carboplatin and etoposide), and supportive care. However, efficacy remains limited, with response rates of ≤15%, progression-free survival (PFS-6) rates at 6 months generally ranging from 9% to 21%, and median OS of ≤30 weeks. For example, since 2009, bevacizumab has been an FDA-approved treatment option for the treatment of recurrent GBM (e.g., Non-Patent Document 3). However, bevacizumab extends PFS but not OS in patients with recurrent GBM. More generally, no clinical trials have demonstrated an improvement in OS with second-line systemic therapy (including targeted therapy or immunotherapy, see, e.g., Non-Patent Document 4) in patients who experience recurrence. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Stupp R, et al. 2005. 'Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma', New England Journal of Medicine, 352 (10): 987-96 [Non-patent document 2] Stupp R, et al. 2017. 'Effect of tumor-treating fields plus maintenance temozolomide vs. maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial', JAMA, 318: 2306-16 [Non-patent document 3] Friedman HS, et al. 2009. 'Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma', J Clin Oncol, 27: 4733-40 [Non-patent document 4] Lombardi et al. 2020. 'A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma?', Cancers, 12: 377 Summary of the Invention [Problem to be solved by the invention]

[0006] Given the poor outcomes with current therapies, there is an urgent and unmet medical challenge to develop novel therapeutic interventions to improve clinical outcomes and / or quality of life (QoL) for patients with newly diagnosed or recurrent gliomas, particularly high-grade gliomas. [Means for solving the problem]

[0007] The present invention provides a compound of formula (I) below for use in the preparation of a medicament for the treatment of glioma in a patient in need thereof:

[0008] [ka] or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating glioma in a patient in need thereof with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment of the uses or methods according to the invention, the compound of formula (I) is used in combination with temozolomide (TMZ) and / or radiation therapy. The compound of formula (I) may also be used in combination with temozolomide and radiation therapy.

[0009] In one aspect of the uses or methods according to the invention, the glioma is a glioblastoma, an astrocytoma or an oligodendroglioma. In one embodiment of the use or method according to the invention, the glioma is a high-grade glioma (grade 3 or 4).

[0010] In one embodiment of the use or method according to the present invention, the compound of formula (I) is administered on an intermittent schedule, preferably in the following (i) to (vi): (i) days 1–5, 8–10, and 15–17 of a 28-day cycle; (ii) days 1–5, 8–12, and 15–19 of a 28-day cycle; (iii) days 1–5, 8–12, 15–19, and 22–26 of a 28-day cycle; (iv) days 1–3 of each week for 6 or 7 weeks; (v) Days 1 to 5 of each week for 6 or 7 weeks; or (vi) Days 1 to 4 of each week for 6 or 7 weeks; or a continuous schedule, preferably the following: (vii) 6-week daily, 7-week daily, or 42-49-day daily schedules; It is administered orally. Dosing on days 1-5, 8-10, and 15-17 of a 28-day cycle, days 1-5, 8-12, and 15-19 of a 28-day cycle, or days 1-5, 8-12, 15-19, and 22-26 of a 28-day cycle may be preferred if the glioma progresses or recurs after initial or previous glioma treatment. For newly diagnosed gliomas, dosing on days 1-3 of each week for 6 or 7 weeks or 42-49 days, days 1-5 of each week for 6 or 7 weeks or 42-49 days, days 1-4 of each week for 6 or 7 weeks or 42-49 days, or every day for 6 weeks, every day for 7 weeks, or every day for 42-49 days may be preferred. In one embodiment of the uses or methods according to the invention, the compound of formula (I) is administered in one, two, three, four, five, six or more 28-day cycles. Typically, there is no break between any consecutive cycles, i.e., the day after one 28-day cycle can be the first day of the next consecutive cycle.

[0011] In one embodiment of the use or method according to the invention, the compound of formula (I) (i) at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and in certain embodiments, more preferably from about 90 to about 720 mg per treatment day or from about 150 to about 720 mg per treatment day; and / or (ii) as a single dose on the day of treatment, and / or (iii) at approximately the same time on each treatment day, within ± about 60 minutes, preferably within ± 60 minutes; It is administered.

[0012] In one embodiment of the uses or methods according to the invention, a compound of formula (I) is used in combination with temozolomide, wherein temozolomide is: (i) 50 to 300 mg / m on days 1 to 5 of a 28-day cycle 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day dose; (ii) 150 mg / m on days 1 to 5 of a 28-day cycle 2 / day dose; (iii) 200 mg / m on days 1 to 5 of a 28-day cycle 2 / day dose; (iv) 50 to 300 mg / m daily for 6 weeks, 7 weeks, or 42 to 49 days 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day dose, or (v) 75 mg / m daily for 6 weeks, 7 weeks, or 42 to 49 days 2 / day dose, It is administered.

[0013] If the glioma has progressed or recurred initially or after previous glioma treatment (preferably one or two prior lines of treatment, usually including temozolomide (TMZ)-based chemoradiotherapy as first-line treatment), administration of TMZ on days 1-5 of a 28-day cycle may be preferred. If the glioma is newly diagnosed, administration of TMZ daily for 6 weeks, daily for 7 weeks, or daily for 42-49 days may be preferred. In one embodiment of the uses or methods according to the present invention, when a compound of Formula (I) is used in combination with temozolomide and temozolomide is administered on the day of WEE1 inhibitor treatment, the compound of Formula (I) is optionally administered about 30 minutes to 4 hours before the administration of temozolomide. In one embodiment of the uses or methods according to the invention, when a compound of Formula (I) is used in combination with temozolomide and temozolomide is administered on the day of WEE1 inhibitor treatment, temozolomide is administered simultaneously with the administration of the compound of Formula (I). In one embodiment of the uses or methods according to the invention, the compound of formula (I) is used in combination with temozolomide and radiation therapy. Preferably, the compound of formula (I) is used in combination with temozolomide and radiation therapy for the treatment of newly diagnosed glioma.

[0014] In one embodiment of the uses or methods according to the invention, the compound of formula (I) is administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and temozolomide is administered at a dose of 50 to 300 mg / m 2 / day, preferably 75 mg / m 2 / day, daily for 6 weeks, daily for 7 weeks, or daily for 42-49 days. Preferably, this schedule is used to treat newly diagnosed glioma. In one embodiment of the use or method according to the invention, the compound of formula (I) is: (i) Days 1 to 3 of each week of 6 or 7 weeks or 42 to 49 days; (ii) days 1 to 5 of each week of 6 or 7 weeks or 42 to 49 days; (iii) Days 1 to 4 of each week for 6 or 7 weeks or 42 to 49 days; or (iv) daily for 6 or 7 weeks or 42 to 49 days and temozolomide is administered at a dose of 50 to 300 mg / m 2 / day, preferably 75 mg / m 2 / day, daily for 6 weeks, daily for 7 weeks, or daily for 42-49 days. Preferably, this schedule is used to treat newly diagnosed glioma.

[0015] In one embodiment of the use or method according to the invention, the radiation therapy is fractionated radiation therapy, and (i) a regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, more preferably 10 Gy to 60 Gy, even more preferably 60 Gy, fractionated over 5 consecutive days per week until the total radiation dose is administered, or in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days; (ii) a total dose of 60 Gy, administered on a regimen of 2 Gy per fraction per day, 5 consecutive days per week; or (iii) A total dose of 60 Gy administered over 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days.

[0016] In one embodiment of the use or method according to the invention, the glioma is newly diagnosed. In this embodiment, the compound of formula (I) is preferably administered orally: (i) Days 1–3 of each week for 6 or 7 weeks; (ii) Days 1 to 5 of each week for 6 or 7 weeks; (iii) Days 1 through 4 of each week for a period of 6 or 7 weeks, or for a period of 42 to 49 days; or (iv) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days; and / or The compound of formula (I) is preferably used in combination with temozolomide, which is (i) 50 to 300 mg / m daily for 6 weeks, 7 weeks, or 42 to 49 days 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day dose; or (ii) 75 mg / m daily for 6 weeks, 7 weeks, or 42 to 49 days 2 / day; and / or The compound of formula (I) is preferably administered in combination with temozolomide and radiation therapy, and optionally the compound of formula (I) is administered as described above, wherein temozolomide is administered at a dose of 50 to 300 mg / m 2 / day, preferably 75 mg / m 2 / day dose administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days; and / or In some cases, the radiation therapy is fractionated radiation therapy, and (i) a regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, more preferably 10 Gy to 60 Gy, even more preferably 60 Gy, fractionated over 5 consecutive days per week until the total radiation dose is administered, or in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days; (ii) a total dose of 60 Gy, administered on a regimen of 2 Gy per fraction per day, 5 consecutive days per week; or (iii) A total dose of 60 Gy administered over 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days. In one embodiment of the uses or methods according to the invention, the glioma progresses or recurs after treatment of an initial or previous glioma. In this embodiment, the compound of formula (I) is preferably administered orally by: (i) On days 1-5, 8-10, and 15-17 of a 28-day cycle, (ii) on days 1-5, 8-12, and 15-19 of a 28-day cycle; or (iii) on days 1–5, 8–12, 15–19, and 22–26 of a 28-day cycle administered, where: The compound of Formula (I) may be administered for 1, 2, 3, 4, 5, 6 or more 28 day cycles; and / or the compound of Formula (I) is administered in combination with temozolomide, wherein the temozolomide is (i) 50 to 300 mg / m on days 1 to 5 of a 28-day cycle 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day dose; (ii) 150 mg / m on days 1 to 5 of a 28-day cycle 2 / day dose; or (iii) 200 mg / m on days 1 to 5 of a 28-day cycle 2 / day dose; administered.

[0017] In one embodiment of the use or method according to the invention, the initial or previous treatment of glioma comprises radiotherapy administration and / or TMZ administration. In one embodiment of the uses or methods according to the invention, the glioma is glioblastoma. In one embodiment of the use or method according to the invention, the glioma is (IDH) wild type according to WHO2021. In one embodiment of the uses or methods according to the invention, the glioma is an astrocytoma. In one embodiment of the use or method according to the invention, the glioma is IDH mutant according to WHO2021. [Brief explanation of the drawings]

[0018] [Figure 1] 1(A) and 1(C) are graphs showing plasma and brain concentrations in healthy mice measured on day 4 after repeated administration of 30 mg / kg qd of the compound of Formula (I) (FIG. 1(A)), 30 mg / kg bid of AZD1775 (FIG. 1(B)), and 80 mg / kg qd of Zn-c3 (FIG. 1(C)), as described in Example 1. [Figure 2] FIG. 1 is a graph showing the total plasma concentration, total brain concentration, unbound CSF concentration and calculated unbound plasma concentration of a compound of Formula (I) over time following a single dose of 15 mg / kg of the compound of Formula (I) in healthy rats, as described in Example 2. [Figure 3] 3A-3D are graphs showing the in vitro efficacy of various doses of compound of formula (I) [CoF(I)] in combination with radiation therapy (RT) in GBM cell lines T98G (FIG. 3A), LN18 (FIG. 3B), SNB-19 (FIG. 3C), and U251 (FIG. 3D) as described in Example 4. [Figure 4] 4A and 4B are graphs depicting the in vivo efficacy of compound of Formula (I) [CoF(I)] as monotherapy in U87-MG-luc GBM cell line treated in mice with either 30 mg / kg or 60 mg / kg of compound of Formula (I) via subcutaneous implantation (FIG. 4A, tumor volume) or 30 mg / kg of compound of Formula (I) via intracerebral implantation (FIG. 4B, relative BLI), as described in Example 5. [Figure 5] FIG. 1 is a graph showing the in vivo efficacy of compound of formula (I) [CoF(I)] in combination with TMZ in U87-MG-luc GBM cell line implanted intracranially in mice, as described in Example 6, showing relative BLI curves at doses of 3 mg / kg TMZ, 10 mg / kg CoF(I), and the combination of 3 mg / kg TMZ + 10 mg / kg CoF(I). [Figure 6]FIG. 1 is a graph showing the probability of survival of mice bearing GL261 intracranial tumors when treated with TMZ (3 mg / kg) as monotherapy, a compound of Formula (I) (30 mg / kg) [CoF(I)] as monotherapy, or a combination of both, as described in Example 7. [Figure 7] 7A and 7B are graphs depicting the in vitro efficacy of compound of Formula (I) as monotherapy in ATRX-deficient SF188 GBM cell line: cell viability assay (FIGS. 7A and 7B) and colony formation assay (FIG. 7C), as described in Example 8. [Figure 8] FIG. 1 is a diagram of a Phase 1 Arm A clinical trial as described in Example 9. [Figure 9] FIG. 1 is a diagram of a Phase 1 Arm B clinical trial as described in Example 9. [Figure 10] 1 is a diagram of a clinical trial for the Phase 2 experimental group as described in Example 9. FIG. 2 is a diagram of a clinical trial for the Phase 2 experimental group as described in Example 9. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of glioma in a patient in need thereof. The compound of formula (I) is a WEE1 inhibitor. In one embodiment, an N-oxide or N-oxide derivative of the compound of formula (I) may be used. The compound of formula (I) was found to exhibit excellent blood-brain barrier penetration in healthy mice, rats, and monkeys. Furthermore, the compound of formula (I), either as a single agent or in combination with TMZ, was found to have excellent antitumor activity and tolerability in a murine GBM xenograft model. Furthermore, the compound of formula (I) was found to exhibit radiosensitizing effects on multiple cell lines, including GBM cell lines.

[0020] definition In order that the present invention may be more readily understood, certain terms are specifically defined below. Unless expressly defined elsewhere herein, the meanings of all other technical and scientific terms used herein will be commonly understood by one of ordinary skill in the relevant art. As used in this specification, including the appended claims, the singular forms of words such as "a," "an," and "the" (sic) include the corresponding plural references unless the context clearly dictates otherwise. Whenever an embodiment herein is described with the term "comprising," it is understood that other similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided. As used herein, the term "A and / or B" is intended to include both "A and B," "A or B," "A," and "B." Similarly, as used herein, the term "and / or" in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0021] As used herein, the term "WEE1 inhibitor" refers to a compound that inhibits the activity of WEE1 kinase, for example, with an IC50 of <10 nM in an ADP-GLO kinase assay or an IC50 of <100 nM in an enzyme profiling assay. The compound of formula (I) herein is an example of a WEE1 inhibitor. In some embodiments, a "brain-penetrating" WEE1 inhibitor refers to a WEE1 inhibitor that can cross the blood-brain barrier (whether impaired or not) and distribute into the brain. In some embodiments, the ability of a compound to cross the blood-brain barrier and distribute into the brain is reflected by its brain-to-plasma concentration ratio exceeding a certain threshold. For example, a compound represented by formula (I) may exhibit better ability to cross the blood-brain barrier and distribute into the brain than AZD1775 and Zn-c3, as evidenced by its higher brain-to-plasma concentration ratio. Therefore, a compound represented by formula (I) may be referred to as a brain-penetrating WEE1 inhibitor.

[0022] As used herein, the term "pharmaceutically acceptable salts" when referring to a compound of formula (I) refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic or organic acids. For example, acceptable salts derived from acids such as quaternary salts, acetates, carbonates, carbamates, sulfonates, and strong inorganic acids. Generally, pharmaceutically acceptable salts may be used to modify the solubility or hydrolysis characteristics of a compound or in sustained-release formulations. It will be understood that, as used herein, reference to a compound of formula (I) is meant to include pharmaceutically acceptable salts, unless otherwise specified.

[0023] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., who will be the recipient of a particular treatment. Generally, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject. As used herein, administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive (separate) administration in any order.

[0024] As used herein, the terms "treating" or "treatment" or "to treat" or "alleviating" or "palliative" and the like refer to therapeutic measures that cure, slow, or alleviate the symptoms of, and / or halt or reverse the progression or severity of, a diagnosed condition, disorder, or disease. Thus, those in need of treatment include those already diagnosed with or suspected of having a disorder. In certain embodiments, a subject is successfully "treated" for cancer by the methods of the invention if the patient exhibits one or more of the following: a reduction in the number or complete absence of cancer cells; a reduction in tumor size or burden; an inhibition or absence of cancer cell invasion into peripheral organs; an inhibition or absence of tumor metastasis; an inhibition or absence of tumor growth; a reduction in one or more symptoms associated with the particular cancer; a reduction in the need for corticosteroid doses; a reduction in morbidity and mortality; an improvement in quality of life; a reduction in tumorigenicity, tumor frequency, or tumorigenic potential; a reduction in the number or frequency of cancer stem cells in the tumor; differentiation of tumorigenic cells to a non-tumorigenic state; an increase in overall response (OR), including complete remission (CR) or partial remission (PR), an increased chance of keeping the disease under control (e.g., CR, PR, stable disease (SD)), a longer lifespan without progression and disease-free, an increased survival, a reduced risk of having progressive disease (PD), and an increased time to progression. Summarizing for a group or population of patients, successful treatment may result in endpoints such as an increase in overall response rate (ORR), best overall response rate (BOR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), time to progression (TTP), or any combination thereof.

[0025] As used herein, the term "glioma" refers to a type of primary brain tumor derived from glial cells. Examples include glioblastoma, astrocytoma, and oligodendroglioma. Gliomas can be classified, for example, according to the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), 5th Edition, 2021 (hereinafter referred to as WHO2021) (Louis DN, et al. 2021. 'The 2021 WHO Classification of Tumors of the Central Nervous System: A summary', Neuro Oncol, 23: 1231-51). In some embodiments, the WHO classification may evolve and new editions may be published and considered in the future. In certain aspects, when referring to gliomas, WHO 2021 refers to the integrated histological and molecular grading of tumors, with grades 1 and 2 generally considered "low grade" and grades 3 and 4 generally considered "high grade."

[0026] As used herein, the term "glioma treatment" refers to any treatment or therapy approved by at least one health authority, such as the FDA or EMA, or under investigation in a clinical trial for treating glioma. "Initial glioma treatment" refers to the first glioma treatment used in a given patient diagnosed with glioma, including, but not limited to, surgical resection, radiation therapy (RT), and / or temozolomide (TMZ). "Prior" or "prior glioma treatment" refers to one or more glioma treatments used in a given patient diagnosed with glioma prior to the method of the present invention. As used herein, the WHO 2021 terms "glioblastoma," "glioblastoma multiforme," or "GBM" may refer to isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic grade 4 tumors.

[0027] As used herein, the term "diffuse glioma" is used to encompass a variety of marginally tropic, infiltrating tumors of the central nervous system that appear histologically similar to glial cells, particularly astrocytes and oligodendrocytes. These range in biological behavior from nearly indolent to extremely aggressive, as reflected by grading ranging from grade 1 to grade 4. Specifically, the term "diffuse glioma" does not include focal astrocytic tumors.

[0028] As used herein, the term "astrocytoma" may refer to IDH-mutated glioma. For example, according to WHO 2021, IDH-mutated astrocytoma is classified into three WHO grades: astrocytoma, IDH mutant, WHO grade 2; astrocytoma, IDH mutant, WHO grade 3 (replacing anaplastic astrocytoma, IDH mutant, WHO grade 3); and astrocytoma, IDH mutant, WHO grade 4 (replacing the former term "glioblastoma, IDH mutant, WHO grade 4").

[0029] In one aspect, the term "ATRX deficiency" or "ATRX deficiency," when referring to a glioma, means that the α-thalassemia / mental retardation syndrome X-linked (ATRX) gene in the glioma exhibits an alteration, such as a nonsense mutation or a frameshift mutation, that results in a truncated protein and / or reduced or lost protein expression (often resulting from a genetic alteration). Such genetic alterations can be detected by known methods, including, for example, whole exome sequencing. Gene expression (or its reduction or loss) can be detected by known methods, including, for example, mass spectrometry proteomics, immunohistochemistry, Western blot, for the protein level, and / or by measuring mRNA expression levels using whole transcriptome sequencing or microarray technology.

[0030] In some embodiments, when referring to glioma, "isocitrate dehydrogenase (IDH) status" or "IDH status" or "IDH mutation status" refers to the presence or absence of a mutation in the isocitrate dehydrogenase enzyme (IDH) gene in a glioma. In humans, the IDH1, IDH2, and IDH3 genes express three isoforms of the IDH enzyme, all of which have important functions in metabolic reactions. IDH1 is found in the cytoplasm and peroxisomes, while IDH2 and IDH3 are found in the mitochondrial matrix. Mutations observed in the IDH enzyme in glioma are primarily in the cytoplasmic IDH1 and mitochondrial IDH2, most frequently at codons R132 and R172, respectively. "IDH status" in glioma generally refers to IDH1 or IDH2, and is also referred to as "IDH1 / 2 status." IDH status is "wild-type" when there are no mutations that alter enzyme activity. IDH status is "IDH mutated" or "IDH mutant" when one or more mutations that alter enzyme activity are present. Mutations in the IDH gene can be detected by known methods, including, for example, polymerase chain reaction (PCR) reactions, which can be performed on formalin-fixed, paraffin-embedded (FFPE) glioma tissue. In some instances, PCR and negative immunohistochemistry for IDH1 R132H can be used to classify glioblastoma as IDH wild-type.

[0031] In one embodiment, when referring to glioma, "MGMT status" refers to the promoter methylation status of the gene encoding the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), i.e., whether the promoter is methylated or unmethylated. Possible methods for detecting MGMT status include, but are not limited to, non-quantitative methylation-specific polymerase chain reaction (MSP) or quantitative MSP (qMSP), pyrosequencing, or methylation-sensitive multiplex ligation-dependent probe amplification (MS-MPLA). In certain embodiments, when referring to gliomas, "1p / 19q status" refers to whether the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) are deleted. Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) (1p / 19q codeletion or co-deletion) is a molecular genetic feature of oligodendroglioma, a subtype of primary brain tumor that commonly accounts for approximately 10-15% of all adult diffuse gliomas. When 1p / 19q codeletion is absent, the status is generally considered "1p / 19q intact." 1p / 19q co-deletion in gliomas can be tested by known methods, such as fluorescent in situ hybridization (FISH), which uses dual fluorescently labeled DNA probes to detect the 1p and 19q loci in interphase nuclei of individual glioma cells from FFPE glioma tissue sections transferred onto unstained slides, and changes in the 1p and 19q probe signals compared to controls are used to determine the presence of 1p / 19q co-deletion. Polymerase chain reaction-based microsatellite analysis, which can detect loss of heterozygosity (LOH) at selected loci, and next-generation sequencing (NGS)-based methods can also be used to assess 1p / 19q status. In one embodiment, when referring to a glioma, "CDKN2A / B status" refers to whether the cyclin-dependent kinase inhibitor 2A and / or 2B (CDKN2A / B) genes are altered, particularly whether homozygous deletion of CDKN2A and CDKN2B is present. CDKN2A / B are tumor suppressor gene drivers that regulate cell cycle progression. Loss of CDKN2A is thought to promote glioma formation and tumor metastasis, and homozygous deletion of CDKN2A / B has been identified as an indicator of poor prognosis, particularly in astrocytomas. In the absence of homozygous deletion of CDKN2A / B, the glioma is said to retain CDKN2A / B. Potential alterations of CDKN2A / B can be detected by known methods, such as FISH, qPCR, or NGS-based methods.

[0032] In some embodiments, when referring to glioma, "TERT promoter mutation status" or TERTp mutation status refers to whether a specific mutation exists in the promoter of the TERT gene. TERTp mutation occurs in 51% of all glioma grades. TERTp mutation can be identified using known methods that may be based on molecular characterization of tumor DNA, for example, Sanger sequencing based on tumor DNA sequencing, droplet digital PCR (ddPCR), mass spectrometry-based testing, or next-generation sequencing (NGS).

[0033] In one aspect, when referring to a glioma, "EGFR amplification status" refers to whether the epidermal growth factor receptor (EGFR) gene is amplified (EGFRamp). EGFR amplification can be detected by known methods such as fluorescent in-situ hybridization (FISH), chromosomal microarray, or real-time quantitative PCR. In one embodiment, when referring to a glioma, "chromosome 7 / 10 status" refers to whether the glioma exhibits a gain of chromosome 7 (containing the EGFR gene) combined with a loss of chromosome 10 (7+ / 10-). Chromosome 7 / 10 status can be assessed using known methods such as FISH, NGS, chromosomal microarray, or multiplex ligation-dependent probe amplification (MLPA). In the absence of microvascular proliferation and / or necrosis in diffuse gliomas, EGFR amplification, the combination of chromosome 7 and 10 (7+ / 10-), and TERT promoter mutation (pTERTmut) are frequently observed alterations in adults and are defined by WHO 2021 as molecular hallmarks of IDH wild-type glioblastoma.

[0034] In certain embodiments, when referring to gliomas, "H3.3 G34 status" or "H3K27 M status" refers to whether the glioma exhibits a histone H3.3 G34 mutation or loss of nuclear K27-trimethylated histone H3 (H3K27me3), e.g., due to an H3K27 mutation. Thus, a glioma may be H3.3 G34 wild-type, an H3.3 G34 mutant, e.g., an H3.3 G34R / V mutant, or an H3 K27M mutant, or may lack H3K27me3. H3.3 G34 mutation (e.g., H3.3 G34R / V) or H3 K27M mutation can be assessed by known methods, such as immunohistochemistry or DNA sequencing, to identify H3.3 G34-mutated diffuse hemispheric gliomas or diffuse midline gliomas, H3 K27M-mutated WHO grade 4, respectively. In glioblastoma or GBM, the H3.3 G34 status is wild-type.

[0035] The terms "recur," "recurring," and "recurrence," as used herein when referring to glioma or a patient afflicted therewith, refer to a worsening of the disease and / or signs and symptoms of the disease after a period of improvement, stabilization, or absence of the disease. The terms "progression," "progressing," or "progressive," as used herein when referring to glioma or a patient suffering therefrom, refer to when the cancer gets worse due to either growing existing lesions and / or the appearance of new lesions. As used herein, the term "WEE1 inhibitor treatment day" refers to a day on which a compound of formula (I) is administered according to the methods of the present invention. As used herein, the term "therapeutically effective amount" of a given drug when used in monotherapy, such as a "therapeutically effective amount of WEE1" or a "therapeutically effective amount of TMZ," refers to an amount of drug that is effective to "treat" a disease or disorder in a subject or patient while maintaining an acceptable safety profile. In certain embodiments, when WEE1 and TMZ (optionally, in addition to radiation therapy) are administered in combination, the therapeutically effective amounts of each may be referred to as a "therapeutically effective amount of WEE1 combined" and a "therapeutically effective amount of TMZ combined." A "therapeutically effective amount of WEE1" of a compound of Formula (I) when administered as monotherapy may differ from a "therapeutically effective amount of WEE1 combined" of a compound of Formula (I) when administered in combination with TMZ and / or radiation therapy. In the case of cancer, a therapeutically effective amount of a given drug can reduce the number of cancer cells; reduce tumor size or tumor burden; inhibit (i.e., slow to a certain extent, and in some embodiments, stop) cancer cell invasion into peripheral organs; inhibit (i.e., slow to a certain extent, and in some embodiments, stop) tumor metastasis; inhibit tumor growth to a certain extent; alleviate to a certain extent one or more symptoms associated with cancer; reduce the need for corticosteroid doses; and / or produce a favorable response, such as an increase in overall response (OR), overall response rate (ORR), best overall response (BOR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR) rate, partial response (PR) rate, or in some cases, stable disease (SD) rate, a decrease in progressive disease (PD), an increase in time to tumor progression (TTP), or any combination thereof. See the definition of "treat" herein.

[0036] As used herein, the term "RANO criteria" refers to the response assessment in neuro-oncology recommendations described in "Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group" by Wen PY, et al. 2010, J Clin Oncol 28(11): 1963-72 ("RANO 2010"). In certain embodiments, the RANO guidelines may evolve and new versions may be published and considered in the future. As used herein, the term "mRANO criteria" refers to the modified response assessment in neuro-oncology recommendations set forth in the Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials by Ellington BM, et al. 2017, Neurotherapeutics, 14(2):307-20 ("mRANO 2017"). In certain embodiments, the mRANO guidelines may evolve and new versions may be published and considered in the future.

[0037] As used herein, the term "progression-free survival" (PFS) in clinical trials refers to the time from enrollment, initial dosing, or randomization to disease progression or death from any cause, whichever occurs first. In the field of glioma, PFS is generally measured using RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria, and is generally summarized using the Kaplan-Meier method. As used herein, the term "time to tumor progression" (TTP) in clinical trials refers to the time from enrollment, initial dosing, or randomization to disease progression. In the field of glioma, TTP is generally measured using RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria.

[0038] As used herein, the terms "complete response," "complete remission," or "CR" in clinical trials indicate no detectable evidence of tumor in response to treatment. This does not necessarily mean that the cancer has been cured. Complete response in brain tumors, such as gliomas, is generally measured using the RANO criteria. For example, according to the RANO 2010 or mRANO 2017 criteria, a complete response requires the following: complete disappearance of all enhancing, measurable, and non-measurable disease sustained for at least 4 weeks; no new lesions; stable or improving non-enhancing (T2 / FLAIR) lesions; and the patient must discontinue corticosteroids or receive only physiologic replacement doses and remain clinically stable or improving. A response is considered stable disease only if there is no confirmatory scan after 4 weeks. Fluid-attenuated inversion recovery (FLAIR) is a magnetic resonance imaging (MRI) sequence that produces strong T2 weighting, suppresses CSF signal, and minimizes contrast between gray and white matter.

[0039] As used herein, the term "partial response" or "PR" in clinical trials refers to a decrease in the size or volume of one or more tumors or lesions, or a decrease in the extent of cancer in the body, in response to treatment according to RANO criteria. For example, a partial response according to the RANO 2010 or mRANO 2017 criteria requires a 50% or greater reduction compared to baseline in the sum of the perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non-measurable disease; no new lesions; stable or improved non-enhancing (T2 / FLAIR) lesions on the same or lower dose of corticosteroids compared to the baseline scan; and the patient must be on a corticosteroid dose equal to or lower than the dose at the time of the baseline scan and clinically stable or improved. If there is no confirmatory scan after 4 weeks, the response is considered stable disease only.

[0040] As used herein, the term "stable disease" or "SD" in clinical trials refers to disease without progression or recurrence. Stable disease involves neither sufficient tumor shrinkage to qualify as a partial response nor sufficient tumor growth to qualify as progressive disease based on the smallest combined diameter during the study. This can generally be measured using RANO criteria, for example, according to the RANO 2010 or mRANO 2017 criteria.

[0041] As used herein, the terms "progression," "progressive disease," or "PD" in a clinical trial or study refer to the appearance of one or more new lesions or tumors and / or overt progression of existing target and / or non-target lesions, and / or at least a 25% increase in the sum of the products of perpendicular diameters of target lesions, relative to the smallest total in the study (Note: the appearance of one or more new lesions is also considered progression). Progression is generally measured using the RANO criteria. For example, according to the RANO 2010 criteria, progression is defined by any of the following: a 25% increase in the sum of the products of perpendicular diameters of enhancing lesions on stable or increasing doses of corticosteroids (compared to baseline, in the absence of a decrease); a significant increase (not attributable to comorbid events) in T2 / FLAIR non-enhancing lesions on stable or increasing doses of corticosteroids compared to the baseline scan or best response after initiation of treatment; the appearance of any new lesions; a clear progression of non-measurable lesions; or a clear clinical deterioration not attributable to causes other than the tumor, or a reduction in corticosteroid dose. Failure to return for evaluation as a result of death or worsening condition should also be considered progression.

[0042] As used herein, the term "objective response rate" or "ORR" refers to the proportion of subjects in a study, clinical trial, or treatment group who have a partial or complete response to treatment, generally as measured using RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria. As used herein, the term "overall response" or "objective response" or "OR" refers to the response of a given patient to treatment in a study, clinical trial, or treatment group at a given endpoint, generally as measured using RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria.

[0043] As used herein, the term "best overall response" or "BOR" refers to the best recorded response for a given patient in a study, clinical trial, or treatment group from baseline assessment (enrollment, initiation of treatment, or randomization) until disease progression / recurrence (taking the lowest recorded measurement since treatment began as the reference for progressive disease) or death from any cause. Generally, BOR is measured using RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria. As used herein, the term "disease control rate" or "DCR" refers to the proportion of patients in a study, clinical trial, or treatment group who achieve a complete response, partial response, or stable disease to a therapeutic intervention, generally as measured using RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria. As used herein, the term "duration of response" (DoR) refers to the time from an early response (PR or better) to disease progression or death from any cause, generally measured using RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria. As used herein, the term "overall survival" (OS) in clinical trials refers to the time from patient enrollment, first treatment administration, or randomization to death from any cause or censoring at the date of last known survival. Improved OS includes an increase in life expectancy compared to untreated or untreated individuals or patients. Overall survival refers to the situation in which a patient remains alive for a specified period of time, such as 1 year, 5 years, etc., from the time of randomization or first treatment.

[0044] As used herein, the term "pharmaceutical formulation" or "pharmaceutical composition" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. As used herein, the term "oral dosage form" refers to any form of a pharmaceutical composition suitable for oral administration.

[0045] The term "intermittent" or "intermittent schedule," as used herein with respect to a given drug administration schedule, refers to an administration schedule that includes regular repeating periods, each of which includes one or more predetermined days on which the drug is administered and one or more other predetermined days on which the drug is not administered. The term "regular repeating period" should be understood as a period of time during which a given administration schedule is repeated one or more times during the course of glioma treatment. A regular repeating period may be a 28-day treatment cycle or one week within a 6- or 7-week treatment. For example, if the duration of a regular repeating period is n days, the predetermined days on which the drug is administered may be selected from days 1 to n-1, with the remaining days being predetermined days on which the drug is not administered. If the predetermined days of drug administration are two or more days, these predetermined days may be consecutive or non-consecutive. In the context of this application, "n" may preferably be 28 days or 7 days (one week). The intermittent schedule for the compound of Formula (I) may be, for example, administration on days 1-5, 8-10, and 15-17 of a 28-day cycle; days 1-5, 8-12, and 15-19 of a 28-day cycle; days 1-5, 8-12, 15-19, and 22-26 of a 28-day cycle; days 1-3 of each week for 6 or 7 weeks; days 1-5 of each week for 6 or 7 weeks; or days 1-4 of each week for 6 or 7 weeks. As used herein, the term "continuous" or "continuous schedule" with respect to the administration schedule of a given drug refers to an administration schedule in which the drug is administered daily for regularly repeated periods. A continuous schedule can be, for example, daily administration for one or more 28-day cycles; daily administration for 6 or 7 weeks of treatment; or daily administration for 42 to 49 days.

[0046] Therapeutic methods and uses In one embodiment of the present invention, the compound of formula (I):

[0047] [ka] or a pharmaceutically acceptable salt thereof is used in monotherapy for the treatment of glioma in patients in need thereof. In another embodiment of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with TMZ for the treatment of glioma in a patient in need thereof. In yet another embodiment of the present invention, the compounds of formula (I) or pharmaceutically acceptable salts thereof are used in combination with radiation therapy for the treatment of glioma in a patient in need thereof. In yet another embodiment of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with TMZ and radiation therapy for the treatment of glioma in a patient in need thereof.

[0048] In certain embodiments of the uses and methods of the present invention, the glioma is treated regardless of its WHO grade. In some embodiments of the uses and methods of the invention, the glioma is WHO 2021 grade 1. In other embodiments of the uses and methods of the invention, the glioma is WHO 2021 grade 2. In other embodiments of the uses and methods of the invention, the glioma is WHO 2021 grade 3. In other embodiments of the uses and methods of the invention, the glioma is WHO 2021 grade 4. In one embodiment of the uses or methods of the present invention, the glioma is treated regardless of its isocitrate dehydrogenase (IDH) status (eg, wild-type or mutant). In one embodiment of the uses or methods of the invention, the glioma is (IDH) wild type. In an alternative embodiment of the uses or methods of the invention, the glioma is (IDH) mutant. In one embodiment of the uses or methods of the present invention, gliomas are treated regardless of their MGMT status. In one embodiment of the uses or methods of the invention, the glioma presents a methylated MGMT promoter. In an alternative embodiment of the uses or methods of the invention, the glioma presents an unmethylated MGMT promoter.

[0049] In one embodiment of the uses or methods of the present invention, the glioma is treated regardless of its 1p / 19q status. In one embodiment of the uses or methods of the invention, the glioma is 1p / 19q codeficient. In an alternative embodiment of the uses or methods of the invention, the glioma is 1p / 19q intact.

[0050] In one embodiment of the uses or methods of the present invention, the glioma is treated regardless of its CDKN2A / B status.

[0051] In one embodiment of the uses or methods of the invention, the glioma has a homozygous deletion of CDKN2A / B. In an alternative embodiment of the uses or methods of the invention, the glioma retains CDKN2A / B.

[0052] In one embodiment of the uses or methods of the present invention, the glioma is treated regardless of its ATRX status. In one embodiment of the present invention, the glioma is ATRX-deficient. In another embodiment, the glioma retains ATRX. For example, the enhanced efficacy of the use or method of the present invention in treating glioma may be more pronounced in ATRX-deficient gliomas, such as when the compound of formula (I) is used as a monotherapy.

[0053] In some embodiments, the glioma is IDH wild-type and exhibits necrosis and / or microvascular proliferation. In some embodiments, the glioma is IDH wild-type in the absence of microvascular proliferation or necrosis. For example, an IDH wild-type glioma may exhibit EGFR amplification, a combination of chromosome 7 and 10 (7+ / 10-), and / or a TERT promoter mutation (pTERTmut).

[0054] In one embodiment of the uses and methods of the present invention, gliomas are treated regardless of their H3.3 G34 status. In some embodiments, the glioma is H3.3 G34 wild type. In one embodiment of the uses and methods of the present invention, gliomas are treated regardless of their H3 K27M status. In certain embodiments, the glioma is H3 K27M mutant or has a loss of H3K27me3.

[0055] The various possible molecular states and alterations in a patient's glioma may be detected or determined independently of each other, and the uses or methods of the invention may be applied to gliomas with any molecular state or alteration, particularly gliomas with a single identified molecular alteration or a combination of 2, 3, 4, 5, 6 or more identified molecular alterations. For example, IDH status and MGMT status may be determined independently of each other in the uses or methods of the invention, and the glioma may be IDH wild-type and MGMT methylated, IDH wild-type and MGMT unmethylated, IDH mutant and MGMT methylated, or IDH mutant and MGMT unmethylated.

[0056] In some embodiments of the uses or methods of the present invention, the glioma has recurred or progressed after an initial glioma treatment. In some embodiments of the uses or methods of the present invention, the glioma has recurred or progressed after a previous glioma treatment. In an alternative embodiment, the patient has not had any previous glioma treatment or has a newly diagnosed glioma. In some embodiments of the present invention, the glioma is a glioblastoma. For example, the glioma can be GBM, isocitrate dehydrogenase (IDH) wild-type, and grade 4 according to WHO 2021. In certain other aspects of the invention, the glioma is an astrocytoma. For example, the glioma can be an astrocytoma IDH mutant, grade 2, 3, or 4 according to WHO2021, preferably grade 3 according to WHO2021. In certain other aspects of the invention, the glioma is an oligodendroglioma. For example, the glioma can be an IDH-mutant and 1p / 19q-codeficient, grade 2 or 3 oligodendroglioma according to WHO 2021.

[0057] In one embodiment, the use or method of treatment according to the present invention exhibits advantageous properties for enhancing efficacy in treating glioma, such as improving OS, PFS, OR, ORR, BOR, DOR, DC and / or DCR, with an acceptable safety profile and no adverse effects on patient quality of life, as assessed by the RANO 2010 or mRANO 2017 criteria, compared to SOC. In the same or other embodiment, the use or method of treatment according to the present invention may reduce the need for steroid administration in patients suffering from glioma.

[0058] Dose, schedule and route of administration As used herein, the term "about" refers to a ±10% deviation from the indicated value. Individual values ​​should be understood to describe ranges between any of the stated values.

[0059] Compounds represented by formula (I) In the uses and methods of the present invention, the compound of Formula (I) may be administered at a dose ranging from about 30 to about 1000 mg of the free base per treatment day, preferably from about 30 to about 720 mg of the free base per treatment day. In one embodiment, the compound of Formula (I) may be administered at a dose ranging from about 90 to about 720 mg of the free base, or from about 150 to about 720 mg of the free base per treatment day. For example, the compound of Formula (I) may be administered at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 130, about 150, about 200, about 220, about 250, about 260, about 300, about 320, about 350, about 360, about 400, about 420, about 450, about 460, about 500, about 520, about 550, about 600, about 620, about 650, about 700, about 720, about 750, about 800, about 820, about 850, about 900, about 920, about 950 or about 1000 mg of free base per treatment day. Preferably, the compound of formula (I) may be administered at a dose of 30, 60, 75, 90, 100, 120, 130, 150, 200, 220, 250, 260, 300, 320, 350, 360, 400, 420, 450, 460, 500, 520, 550, 600, 620, 650, 700, 720, 750, 800, 820, 850, 900, 920, 950 or 1000 mg of the free base per day of treatment. In more specific embodiments, the compound of Formula (I) may be administered at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg of free base per treatment day. Preferably, the compound of Formula (I) may be administered at a dose of 30, 60, 75, 90, 100, 120, 150, 200, 250, 260, 300, 350, 360, 400, 450, 460, 500, 520, 550, or 720 mg of free base per treatment day. In a preferred embodiment, a therapeutically effective amount of WEE1 or a combination of WEE1 may be administered.

[0060] In one embodiment of the invention, the compounds of Formula (I) are administered orally. In certain embodiments of the present invention, the compound of formula (I) is administered as a single dose per treatment day (QD) or twice per treatment day (BID). In one embodiment, the compound of Formula (I) is administered on an intermittent schedule. In some embodiments, the compound of Formula (I) is administered on days 1-5, 8-10, and 15-17 of a 28-day cycle. In these embodiments, the compound of Formula (I) may be administered for 1, 2, 3, 5, 4, 5, 6, or more cycles. In some embodiments, treatment with the compound of Formula (I) may continue for two years, or until disease progression, unacceptable toxicity, patient withdrawal, physician-initiated discontinuation, initiation of subsequent anti-neoplastic therapy, completion of the clinical trial, or death. In some embodiments, treatment with the compound of Formula (I) may continue for up to two years. In some embodiments, the compound of Formula (I) may be administered on days 1-5, 8-10, and 15-17 of a 28-day cycle at the doses per treatment day indicated above.

[0061] In some embodiments, the compound of Formula (I) is administered on days 1-5, 8-12, and 15-19 of a 28-day cycle. In these embodiments, the compound of Formula (I) may be administered for 1, 2, 3, 5, 4, 5, 6, or more cycles. In some embodiments, treatment with the compound of Formula (I) may continue for two years, or until disease progression, unacceptable toxicity, patient withdrawal, physician-initiated withdrawal, initiation of subsequent anti-neoplastic therapy, completion of the clinical trial, or death. In some embodiments, treatment with the compound of Formula (I) may continue for up to two years. In some embodiments, the compound of Formula (I) may be administered on days 1-5, 8-12, and 15-19 of a 28-day cycle, at the doses per treatment day listed above.

[0062] In some embodiments, the compound of Formula (I) is administered on days 1-5, 8-12, 15-19, and 22-26 of a 28-day cycle. In these embodiments, the compound of Formula (I) may be administered for 1, 2, 3, 5, 4, 5, 6, or more cycles. In some embodiments, treatment with the compound of Formula (I) may continue for two years, or until disease progression, unacceptable toxicity, patient withdrawal, physician-initiated discontinuation, initiation of subsequent anti-neoplastic therapy, completion of the clinical trial, or death. In some embodiments, treatment with the compound of Formula (I) may continue for up to two years. In some embodiments, the compound of Formula (I) may be administered on days 1-5, 8-12, 15-19, and 22-26 of a 28-day cycle, at the doses per treatment day listed above.

[0063] In some embodiments, the compound of Formula (I) is administered on days 1-3 of each week for several weeks, particularly 6 or 7 weeks. In other embodiments, the compound of Formula (I) may be administered on days 1-3 of each week for 42 to 49 days, such as 42, 43, 44, 45, 46, 47, 48, or 49 days. In some embodiments, the compound of Formula (I) may be administered at the dose per day of treatment indicated above for 6 weeks, 7 weeks, or 42-49 days.

[0064] In some embodiments, the compound of Formula (I) is administered on days 1-5 of each week for several weeks, particularly 6 or 7 weeks. In other embodiments, the compound of Formula (I) may be administered on days 1-5 of each week for 42 to 49 days, such as 42, 43, 44, 45, 46, 47, 48, or 49 days. In some embodiments, the compound of Formula (I) may be administered at the doses per day of treatment indicated above for 6 weeks, 7 weeks, or 42-49 days.

[0065] In some embodiments, the compound of Formula (I) is administered on days 1-4 of each week for several weeks, particularly 6 or 7 weeks. In other embodiments, the compound of Formula (I) may be administered on days 1-4 of each week for 42 to 49 days, such as 42, 43, 44, 45, 46, 47, 48, or 49 days. In some embodiments, the compound of Formula (I) may be administered at the doses per day of treatment indicated above for 6 weeks, 7 weeks, or 42-49 days.

[0066] In some embodiments, one or more drug holidays are included in the 6-week schedule for the compound of Formula (I), for example, each of which includes one or more drug holidays of 1 week. A drug holiday should be understood as a period during which the compound of Formula (I) is not administered. The drug holiday does not affect the administration of TMZ and / or radiation therapy, which continues according to the schedule and at the doses specified above or below. The 6-week schedule for the compound of Formula (I) can be any 6-week schedule described above or below for the compound of Formula (I). For example, the compound of Formula (I) can be administered on days 1 to 3 of weeks 1, 2, 4, and 5, where weeks 3 and 6 are drug holidays (when the compound of Formula (I) is not administered). Alternatively, the compound of Formula (I) can be administered on days 1 to 3 of weeks 1, 2, 3, 5, and 6, where week 4 is a drug holiday (when the compound of Formula (I) is not administered). In those embodiments that include one or more drug holidays, the compound of formula (I) may be administered at the doses per treatment day indicated above.

[0067] In other embodiments of the present invention, the compound of Formula (I) is administered on a continuous schedule. For example, the compound of Formula (I) is administered daily for several weeks, particularly 6 or 7 weeks. In some embodiments, the compound of Formula (I) may be administered daily for 42 to 49 days, for example, 42, 43, 44, 45, 46, 47, 48, or 49 days. In some embodiments, the compound of Formula (I) may be administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, at the doses per day of treatment indicated above. The compound of formula (I) (optionally in combination with TMZ on a schedule defined herein) may be preferably administered on days 1-5, 8-10, and 15-17 of a 28-day cycle, or on days 1-5, 8-12, and 15-19 of a 28-day cycle, or on days 1-5, 8-12, 15-19, and 22-26 of a 28-day cycle when the glioma being treated is initially or has recurred after a previous glioma treatment (second (or more) line of treatment). The compound of formula (I) (optionally in combination with TMZ and / or radiation therapy on a schedule defined herein) may be preferably administered daily for 6 weeks, daily for 7 weeks, or for 42-49 days when the glioma being treated is newly diagnosed (first line treatment). It may be more preferred that the compound of formula (I) (optionally in combination with TMZ and / or radiation therapy in a schedule defined herein) be administered on days 1-3 of each week for 6 or 7 weeks, or on days 1-5 of each week for 6 or 7 weeks, or on days 1-4 of each week for 6 or 7 weeks if the glioma being treated is newly diagnosed (first line treatment).

[0068] In certain embodiments of the invention, the compound of formula (I) is administered, for example, at about the same time each treatment day in a given cycle, for example, about ±60 minutes, preferably ±60 minutes, from the same time each treatment day. In a more specific embodiment, the compound of formula (I) is administered in the morning, for example, between 5:00 a.m. and noon. In one embodiment of the uses or methods according to the invention, the compound of formula (I) is administered after fasting, preferably after a 4 hour fasting period. In the same or other embodiments, administration of the compound of formula (I) may be followed by fasting, preferably by 2 hours of fasting. In an alternative embodiment of the uses and methods according to the present invention, the compound of formula (I) is administered in the fed state. In yet another alternative embodiment of the use or method according to the present invention, the compound of formula (I) is administered regardless of the patient's food status.

[0069] Temozolomide (TMZ) In one embodiment of the methods of the present invention, when TMZ is administered in combination with a compound of Formula (I), or in combination with a compound of Formula (I) and radiation therapy, TMZ is administered at a dose of about 50 to about 300 mg / m 2 / day, preferably about 50 to about 250 mg / m 2 / day, more preferably about 50 to about 200 mg / m 2 The dose may be administered in the range of 100 mg / day. In a preferred embodiment, a therapeutically effective amount of TMZ or a combination of TMZ may be administered. In one embodiment, TMZ is about 75 mg / m 2 / day, about 150mg / m 2 / day, or approximately 200 mg / m 2 TMZ may be administered at a dose of 75 mg / m 2 / day, 150mg / m 2 / day, or 200 mg / m 2 It may be administered at a dose of 100 mg / day. In one embodiment, TMZ may be administered on days 1 to 5 of a 28-day cycle. In another embodiment, TMZ may be administered on days 1 to 5, days 8 to 10, and days 15 to 17 of a 28-day cycle. The 28-day cycle may be the same as that for the compound represented by formula (I). TMZ may be administered for 1, 2, 3, 4, 5, 6 or more cycles. In some embodiments, TMZ treatment may continue for 2 years. In some embodiments, TMZ treatment may continue for up to 2 years.

[0070] In still other embodiments, TMZ may be administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days. In some preferred embodiments, TMZ is administered at a dose of 50-300 mg / m on days 1-5 of a 28-day cycle. 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 TMZ may be administered at doses ranging from 150 mg / m on days 1 to 5 of a 28-day cycle. 2 / day or 200 mg / m 2 In these embodiments, TMZ may be administered at a dose of 1 / day. In these embodiments, TMZ may be administered for 1, 2, 3, 4, 5, 6 or more cycles. In some embodiments, TMZ treatment may continue for 2 years. In some embodiments, TMZ treatment may continue for up to 2 years. This TMZ schedule may be preferred when the glioma being treated is initially or has recurred after a previous glioma treatment, and the compound of Formula (I) is administered on the administration days defined above, particularly days 1 to 5 of a 28-day cycle. In another preferred embodiment, TMZ is 50 to 300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 TMZ may be administered at a dose of 75 mg / m daily for 6 weeks, 7 weeks, or 42 to 49 days. 2The TMZ may be administered at a dose of 1 / day daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days. This TMZ schedule is preferred when the glioma being treated is newly diagnosed, with the compound of formula (I) being administered on the administration dates defined above, particularly daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days. For the treatment of newly diagnosed gliomas, radiation therapy, as further defined below, may be additionally administered. In another embodiment, TMZ is administered at a dose of 50-300 mg / m on days 1-5, 8-10, and 15-17 of a 28-day cycle. 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 Preferably, TMZ is administered at a dose ranging from 75 mg / m on days 1-5, 8-10, and 15-17 of a 28-day cycle. 2 / day, 150mg / m 2 / day, or 200 mg / m 2 This TMZ schedule may be used when the glioma being treated recurs after initial or prior glioma therapy, and the compound of formula (I) is administered on the same administration day, i.e., both the compound of formula (I) and TMZ are administered on days 1-5, 8-10, and 15-17 of a 28-day cycle. TMZ may be administered on the same days as the compound of formula (I), or may be administered on a different schedule as defined below.

[0071] In one embodiment, TMZ is administered on a different schedule than the compound of Formula (I). In one example, when the compound of Formula (I) is administered on days 1 to 5, days 8 to 10, and days 15 to 17 of a 28-day cycle, TMZ may be administered on days 1 to 5 of the 28-day cycle. In another example, when the compound of Formula (I) is administered on days 1 to 5, days 8 to 12, and days 15 to 19 of a 28-day cycle, TMZ may be administered on days 1 to 5 of the 28-day cycle. In yet another example, when the compound of Formula (I) is administered on days 1 to 5, days 8 to 12, days 15 to 19, and days 22 to 26 of a 28-day cycle, TMZ may be administered on days 1 to 5 of the 28-day cycle. The dosages of the compound of Formula (I) and TMZ per administration day may be as defined above. This schedule may be preferable when the glioma being treated is initially treated or has recurred after previous glioma treatment. In yet another example, when the compound of Formula (I) is administered on days 1 to 3 of each week for 6 or 7 weeks, or for 42 to 49 days, TMZ may be administered daily for the 6, 7, or 42 to 49 days; when the compound of Formula (I) is administered on days 1 to 5 of each week for 6 or 7 weeks, or for 42 to 49 days, TMZ may be administered daily for the 6, 7, or 42 to 49 days; when the compound of Formula (I) is administered on days 1 to 4 of each week for 6 or 7 weeks, or for 42 to 49 days, TMZ may be administered daily for the 6, 7, or 42 to 49 days. The dosages of the compound of Formula (I) and TMZ on the administration days may be as defined above. These schedules with a duration of 6 or 7 weeks or 42 to 49 days may be preferred when the glioma being treated is newly diagnosed. In another embodiment, TMZ is administered on the same schedule as the compound of formula (I). In one example, when the compound of formula (I) is administered daily for 6 weeks, 7 weeks, or 42 to 49 days, TMZ may also be administered daily for the 6 weeks, 7 weeks, or 42 to 49 days. The daily doses of the compound of formula (I) and TMZ on the days of administration may be as defined above. This schedule may be preferable when the glioma being treated is newly diagnosed. In another example, if the compound of Formula (I) is administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle, TMZ may also be administered on days 1 to 5, 8 to 10, and 15 to 17 of the 28-day cycle. The daily doses of the compound of Formula (I) and TMZ on the days of administration may be as defined above. This schedule may be preferable when the glioma being treated is initially or has recurred after a previous glioma treatment.

[0072] Certain TMZ schedules that can be used in combination with compounds of formula (I) in the uses and methods according to the present invention include the following: (a) 75 mg TMZ / m 2 / day daily for 6 weeks, daily for 7 weeks, or daily for 42-49 days; (b) 150 mg TMZ / m on days 1–5 of each 28-day cycle 2 / day; (c) 200 mg TMZ / m on days 1 to 5 of each 28-day cycle 2 / day; (d) 50 mg TMZ / m 2 / day, daily, until progression; (e) 28-day cycle with 1 week of TMZ (e.g., 120 mg / m2 per day, daily for 7 days) / 1 week off (7 days without TMZ administration); (f) 28-day cycles of 3 weeks of TMZ (e.g., 80 mg / m2 / day daily for 21 days) / 1 week off (7 days without TMZ); or (g) 75 mg TMZ / m every week on days 1 to 5 for 6 or 7 weeks or for 42 to 49 days 2 / day; Examples include: In certain embodiments, it may be desirable to express the amount of TMZ administered in mg per day of treatment. In such embodiments, the daily dose is expressed as the mg / m 2The blood pressure can be calculated based on the blood glucose level per day and the patient's body surface area (BSA), which can be calculated using methods known to those skilled in the art, such as the Du Bois method (see, e.g., Dubois D, Dubois EF. A formula to estimate the approximate surface area if height and weight are known. Arch Intern Med. 1916; 17:863-871) or the Mosteller formula (see, e.g., Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987; 317:1098). Table 1 below shows the 2 / day, 150mg / m 2 / day, or 200 mg / m 2 This provides an overview of how the dose / day can be converted to mg per day of treatment depending on the BSA. For example, for a patient with a BSA of 2.0, a dose of 75 mg / m 2 / day dosage means that a total of 150 mg of TMZ may be administered. Table 1: Calculation of daily dose of TMZ by body surface area (BSA)

[0073] [Table 1] In one embodiment of the present invention, TMZ is administered orally. In another embodiment of the present invention, TMZ is administered intravenously by infusion. The dose of TMZ administered as an intravenous infusion (e.g., over 90 minutes) is generally the same as the dose of an oral formulation. Of course, in some embodiments, TMZ can be used in the form of a pharmaceutically acceptable salt, in which case the dosage, amount, or concentration references herein for TMZ, which are references to the free base, can be appropriately adapted taking into account the molecular weight of each salt.

[0074] Radiation therapy In some embodiments of the methods of the present invention, radiation therapy is used in combination with a compound of Formula (I) alone or in combination with a compound of Formula (I) and TMZ. If the glioma being treated is newly diagnosed, radiation therapy is generally preferred (first-line treatment). The radiation therapy used may be any suitable type of radiation therapy, such as 3D conformal radiation therapy (3DCRT), intensity modulated radiation therapy (IMRT), focal radiation therapy, or fractionated radiation therapy. In some embodiments, the radiation therapy is fractionated radiation therapy. In preferred embodiments, radiation therapy is administered five consecutive days per week until the total radiation dose is administered. In other preferred embodiments, radiation therapy is administered in equal proportions over a period of six weeks, seven weeks, or 42 to 49 days. It will be appreciated that radiation therapy need not be administered daily. In one example, when the compound of formula (I) is administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, radiation therapy can be administered in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days. In a further example, when the compound of formula (I) and TMZ are administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, radiation therapy can be administered in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days. The dosage of the compound of formula (I) and / or TMZ per each administration day can be as defined above. Alternatively, when the compound of formula (I) is administered on days 1 to 3 of each week for 6 or 7 weeks or for 42 to 49 days, the radiation therapy may be administered in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days. In a further example, when the compound of formula (I) is administered on days 1 to 3 of each week for 6 or 7 weeks or for 42 to 49 days, and TMZ is administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, the radiation therapy may be administered in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days. The dosage of the compound of formula (I) and / or TMZ per each administration day may be as defined above. Alternatively, when the compound of formula (I) is administered on days 1 to 5 of each week for 6 or 7 weeks or for 42 to 49 days, the radiation therapy may be administered in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days. In a further example, when the compound of formula (I) is administered on days 1 to 5 of each week for 6 or 7 weeks or for 42 to 49 days, and TMZ is administered daily for 6 weeks, 7 weeks, or for 42 to 49 days, the radiation therapy may be administered in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days. The dosage of the compound of formula (I) and / or TMZ per administration day may be as defined above. Alternatively, if the compound of formula (I) is administered on days 1 to 4 of each week for 6 or 7 weeks or for 42 to 49 days, the radiation therapy may be administered in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days. In a further example, if the compound of formula (I) is administered on days 1 to 4 of each week for 6 or 7 weeks or for 42 to 49 days, and TMZ is administered daily for 6 weeks, 7 weeks, or for 42 to 49 days, the radiation therapy may be administered in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days. The dosage of the compound of formula (I) and / or TMZ per administration day may be as defined above.

[0075] In the same or other embodiments, radiation therapy is administered in a regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, more preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, fractionated over 5 consecutive days per week, or equally divided over a period of 6 weeks, 7 weeks, or 42 to 49 days until a total radiation dose is administered. In particularly preferred embodiments, radiation therapy is administered in a regimen of 2 Gy per fraction daily, 5 consecutive days per week for a total dose of 60 Gy, over a period of 6 weeks, 7 weeks, or 42-49 days, and / or a total dose of 60 Gy over 30 fractions.

[0076] In certain embodiments, the administration schedules described herein, for example, when involving radiation therapy, can be understood to encompass administration schedules interrupted (continuous or non-continuous) for one or several days. The interruption can be due, for example, to a malfunction of the radiation therapy device. On such an interruption day, RT, the compound of Formula (I), and TMZ are discontinued if scheduled to be administered on that day. The interrupted administration day can be added to the end of the treatment period. For example, administration can be interrupted on day 1 of a 6-week (42-day) treatment period, and then a missed administration day can be added during the 7th week (after day 42), preferably on day 1 of the 7th week (day 43). If several days of administration are missed, the total treatment period can be extended by the number of missed administration days, up to a maximum of 7 weeks (49 days). The specific handling of missed administration days will be determined by the treating physician or the team of physicians surrounding the glioma patient, depending on their expertise and the patient's condition.

[0077] Combination Therapy with Compounds of Formula (I) In some embodiments of the present invention in which a compound of Formula (I) is used in combination with TMZ and / or radiation therapy, if TMZ and / or radiation therapy is administered on the day of WEE1 inhibitor treatment, then the compound of Formula (I) is administered prior to the TMZ and / or radiation therapy on the day of WEE1 inhibitor treatment. In one embodiment, when TMZ is administered on a WEE1 inhibitor treatment day, administration of TMZ is initiated about 30 minutes to 4 hours, preferably about 30 minutes to 1 hour, after administration of the compound represented by Formula (I). In an alternative embodiment, when TMZ is administered on a WEE1 inhibitor treatment day, TMZ is administered at bedtime, such as between 9:00 PM and midnight. In certain embodiments of the present invention in which a compound of Formula (I) is administered in combination with both TMZ and radiation therapy on a WEE1 inhibitor treatment day, when TMZ and / or radiation therapy are administered on said WEE1 inhibitor treatment day, TMZ administration is initiated about 30 minutes to 4 hours, preferably about 30 minutes to 1 hour, after administration of the compound of Formula (I), and radiation therapy is initiated about 1 hour after the end of TMZ administration. In certain embodiments of the present invention in which a compound of Formula (I) is administered in combination with radiation therapy alone, if radiation therapy is administered on the day of WEE1 inhibitor treatment, radiation therapy is initiated about 30 minutes to 4 hours, preferably about 30 minutes to 1 hour, after administration of the compound of Formula (I).

[0078] Glioma patients may require steroid support. In one embodiment of the present invention, the patient in need thereof is administered a steroid in the context of glioma treatment, e.g., in the context of initial or prior glioma treatment. In one embodiment of the present invention, the glioma patient in need thereof is administered a combination treatment of a compound represented by Formula (I) and TMZ, a compound represented by Formula (I) and TMZ and RT, or a compound represented by Formula (I) and RT, and a steroid. In one embodiment, the steroid is a corticosteroid, such as, but not limited to, dexamethasone or prednisone. In one embodiment, the maximum daily dose of dexamethasone is 8 mg, preferably 4 mg, or the maximum daily dose of prednisone is 40 mg, preferably 25 mg. Glioma patients may require anticonvulsant support, for example in the event of seizures. In one embodiment of the present invention, a glioma patient in need thereof is administered a combination treatment of a compound of Formula (I) and TMZ, a compound of Formula (I) and TMZ and RT, or a compound of Formula (I) and RT, and an anticonvulsant. In one embodiment, the anticonvulsant does not have enzyme-inhibiting or enzyme-inducing properties, such as, but not limited to, lacosamide, gabapentin, or pregabalin. In one embodiment of the invention, for example, when a patient receives concurrent TMZ and RT treatment, a Pneumocystis pneumonia (PCP) prophylactic and a combination treatment of a compound of Formula (I) with TMZ and RT are administered to the patient.

[0079] In certain aspects of the uses or methods according to the present invention, for example (but not limited to) when glioma is newly diagnosed, the combination treatment schedule or regimen may be defined as an alternative or supplement to the following: (a) a compound of Formula (I) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days in combination with TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, in conjunction with radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days; (b) a compound of Formula (I) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, in combination with TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, administered during 6 weeks, 7 weeks, or 42 to 49 days of radiation therapy, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per day of treatment, preferably about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per day of treatment; (c) a compound of Formula (I) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days in combination with TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; and TMZ: 50-300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 Administered at a dose of / day; (d) a compound of Formula (I) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days in combination with TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; TMZ: 50-300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day and a fractionation regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, more preferably 10 Gy to 60 Gy, even more preferably 60 Gy, fractionated over 5 consecutive days per week until a total radiation dose is administered, or in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, most preferably a fractionation regimen of 2 Gy per daily fraction, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6 weeks, 7 weeks, or 42 to 49 days; (e) a compound of Formula (I) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days in combination with TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; TMZ is 75 mg / m 2 / day, and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days; (f) a compound of Formula (I) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; (g) a compound of Formula (I) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550 or about 720 mg per treatment day; and a fractionation regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, more preferably 10 Gy to 60 Gy, even more preferably 60 Gy, fractionated over 5 consecutive days per week until a total radiation dose is administered, or in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, most preferably a fractionation regimen of 2 Gy per daily fraction, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6 weeks, 7 weeks, or 42 to 49 days; (h) a compound of Formula (I) administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein: wherein the free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction once daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days. In some embodiments, an intermittent schedule may be used if unacceptable toxicity is observed with continuous administration (ie, daily).

[0080] In certain aspects of the uses or methods according to the present invention, for example (but not limited to) when glioma is newly diagnosed, the combination treatment schedule or regimen may be defined as an alternative or supplement to the following: (aa) a compound of formula (I) administered on days 1 to 3 of each week for 6 or 7 weeks or for 42 to 49 days daily for 6, 7 weeks or for 42 to 49 days, in combination with TMZ administered daily for 6, 7 weeks or for 42 to 49 days, and radiation therapy for 6, 7 weeks or for 42 to 49 days; (bb) a compound of Formula (I) administered on days 1-3 of each week for 6 or 7 weeks or for 42 to 49 days daily for 6, 7 weeks, or for 42 to 49 days, in combination with TMZ administered daily for 6, 7 weeks, or for 42 to 49 days, and radiation therapy for 6, 7 weeks, or for 42 to 49 days, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per day of treatment, preferably about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per day of treatment; (cc) a compound of formula (I) administered on days 1-3 of each week for 6 or 7 weeks or for 42-49 days in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, and radiation therapy for 6, 7 weeks, or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; and TMZ: 50-300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 Administered at a dose of / day; (dd) a compound of formula (I) administered on days 1-3 of each week for 6 or 7 weeks or for 42-49 days in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, and radiation therapy for 6, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; TMZ: 50-300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days; (ee) a compound of formula (I) administered on days 1-3 of each week for 6 or 7 weeks or for 42-49 days in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, and radiation therapy for 6, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; TMZ is 75 mg / m 2 / day, and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days; (ff) a compound of Formula (I) administered on days 1-3 of each week for 6 or 7 weeks or for 42-49 days in combination with radiation therapy for 6 weeks, 7 weeks, or 42-49 days, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; (gg) a compound of formula (I) administered on days 1-3 of each week for 6 or 7 weeks or for 42-49 days in combination with radiation therapy for 6 weeks, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550 or about 720 mg per treatment day; and a fractionation regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, more preferably 10 Gy to 60 Gy, even more preferably 60 Gy, fractionated over 5 consecutive days per week until a total radiation dose is administered, or in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, most preferably a fractionation regimen of 2 Gy per daily fraction, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6 weeks, 7 weeks, or 42 to 49 days; (hh) a compound of formula (I) administered on days 1 to 3 of each week for 6 or 7 weeks or for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks or for 42 to 49 days, wherein: wherein the free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction once daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days.

[0081] In certain aspects of the uses or methods according to the present invention, for example (but not limited to) when glioma is newly diagnosed, the combination treatment schedule or regimen may be defined as an alternative or supplement to the following: (aaa) a compound of formula (I) administered on days 1 to 5 of each week for 6 or 7 weeks or for 42 to 49 days daily for 6, 7 weeks or for 42 to 49 days, in combination with TMZ administered daily for 6, 7 weeks or for 42 to 49 days, and radiation therapy for 6, 7 weeks or for 42 to 49 days; (bbb) a compound of Formula (I) administered on days 1-5 of each week for 6 or 7 weeks or for 42-49 days daily for 6, 7 weeks, or for 42-49 days, in combination with TMZ administered daily for 6, 7 weeks, or for 42-49 days, and radiation therapy for 6, 7 weeks, or for 42-49 days, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per day of treatment, preferably about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per day of treatment; (ccc) a compound of formula (I) administered on days 1-5 of each week for 6 or 7 weeks or for 42-49 days daily for 6, 7 weeks or for 42-49 days in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, with radiation therapy for 6, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; and TMZ: 50-300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 Administered at a dose of / day; (ddd) a compound of formula (I) administered on days 1-5 of each week for 6 or 7 weeks or for 42-49 days daily for 6, 7 weeks or for 42-49 days, in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, with radiation therapy for 6, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; TMZ: 50-300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days; (eee) a compound of formula (I) administered on days 1-5 of each week for 6 or 7 weeks or for 42-49 days daily for 6, 7 weeks or for 42-49 days in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, with radiation therapy for 6, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; TMZ is 75 mg / m 2 / day, and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days; (fff) a compound of Formula (I) administered on days 1 to 5 of each week for 6 or 7 weeks or for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; (ggg) a compound of formula (I) administered on days 1 to 5 of each week for 6 or 7 weeks or for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks or for 42 to 49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550 or about 720 mg per treatment day; and a fractionation regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, more preferably 10 Gy to 60 Gy, even more preferably 60 Gy, fractionated over 5 consecutive days per week until a total radiation dose is administered, or in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, most preferably a fractionation regimen of 2 Gy per daily fraction, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6 weeks, 7 weeks, or 42 to 49 days; (hhh) a compound of formula (I) administered on days 1 to 5 of each week for 6 or 7 weeks or for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks or for 42 to 49 days, wherein: wherein the free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction once daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days.

[0082] In certain aspects of the uses or methods according to the present invention, for example (but not limited to) when glioma is newly diagnosed, the combination treatment schedule or regimen may be defined as an alternative or supplement to the following: (aaaa) a compound of formula (I) administered on days 1 to 4 of each week for 6 or 7 weeks or for 42 to 49 days daily for 6, 7 weeks or for 42 to 49 days, in combination with TMZ administered daily for 6, 7 weeks or for 42 to 49 days, and radiation therapy for 6, 7 weeks or for 42 to 49 days; (bbbb) a compound of Formula (I) administered on days 1-4 of each week for 6 or 7 weeks or for 42 to 49 days daily for 6, 7 weeks, or for 42 to 49 days, in combination with TMZ administered daily for 6, 7 weeks, or for 42 to 49 days, and radiation therapy for 6, 7 weeks, or for 42 to 49 days, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per day of treatment, preferably about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per day of treatment; (cccc) a compound of formula (I) administered on days 1-4 of each week for 6 or 7 weeks or for 42-49 days daily for 6, 7 weeks or for 42-49 days, in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, and radiation therapy for 6, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; and TMZ: 50-300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 Administered at a dose of / day; (dddd) a compound of formula (I) administered on days 1-4 of each week for 6 or 7 weeks or for 42-49 days daily for 6, 7 weeks or for 42-49 days, in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, with radiation therapy for 6, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; TMZ: 50-300 mg / m 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days; (eeee) a compound of formula (I) administered on days 1-4 of each week for 6 or 7 weeks or for 42-49 days daily for 6, 7 weeks or for 42-49 days, in combination with TMZ administered daily for 6, 7 weeks or for 42-49 days, and radiation therapy for 6, 7 weeks or for 42-49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; TMZ is 75 mg / m 2 / day, and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days; (ffff) a compound of Formula (I) administered on days 1 to 4 of each week for 6 or 7 weeks or for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably about 30 to about 720 mg per treatment day, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; (gggg) A compound of formula (I) administered on days 1 to 4 of each week for 6 or 7 weeks or for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks or for 42 to 49 days, wherein: The free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550 or about 720 mg per treatment day; and a fractionation regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, more preferably 10 Gy to 60 Gy, even more preferably 60 Gy, fractionated over 5 consecutive days per week until a total radiation dose is administered, or in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, most preferably a fractionation regimen of 2 Gy per daily fraction, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6 weeks, 7 weeks, or 42 to 49 days; (hhhh) a compound of formula (I) administered on days 1 to 4 of each week for 6 or 7 weeks or for 42 to 49 days in combination with radiation therapy for 6 weeks, 7 weeks or for 42 to 49 days, wherein: wherein the free base of the compound of formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably from about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; and Radiation therapy is administered in a fractionation regimen of 2 Gy per fraction once daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions, or a total dose of 60 Gy over 30 fractions, for example, over a period of 6, 7 weeks or 42 to 49 days.

[0083] In an alternative embodiment of any one of the above combination therapies comprising a compound of Formula (I), such as items a) to h), aa) to hh), aaa) to hhh), and aaaa) to hhhh), one or more drug holidays are included in a 6-week schedule for the compound of Formula (I), for example, one or more drug holidays each week. A drug holiday should be understood as a period during which the compound of Formula (I) is not administered. The drug holiday does not affect the administration of TMZ and / or radiation therapy, which continues according to the schedule and at the doses specified above or below. For example, in an alternative embodiment of items aa) to hh), the compound of Formula (I) may be administered on days 1 to 3 of weeks 1, 2, 4, and 5, where weeks 3 and 6 are drug holidays (when the compound of Formula (I) is not administered). Alternatively, the compound of formula (I) may be administered on days 1 to 3 of weeks 1, 2, 3, 5, and 6, with week 4 being a washout period (when the compound of formula (I) is not administered). In certain embodiments of any of the above paragraphs a) through h), aa) through hh), aaa) through hhh), and aaaa) through hhhh), or alternative embodiments including a drug holiday, the free base of the compound of Formula (I) may preferably be administered at a dose ranging from about 90 to about 720 mg. In other embodiments of any of the above items a) to h), aa) to hh), aaa) to hhh), and aaaa) to hhhh), or alternative embodiments including a drug holiday, the free base of the compound of Formula (I) may be administered preferably at a dose ranging from about 30 to about 200 mg, or from 60 to 200 mg.

[0084] In other alternative embodiments of any one of the above combination therapies comprising a compound of Formula (I), such as items a)-h), aa)-hh), aaa)-hhh), and aaaa)-hhhh), TMZ may not be administered daily, but may be administered on days 1-5 of each week for 6 or 7 weeks, or on days 1-5 of each week for 42-49 days, preferably at a dose of 75 mg TMZ / m 2 / day on days 1-5 of each week for 6 or 7 weeks, or on days 1-5 of each week for 42-49 days. In any of the above paragraphs a) through h), aa) through hh), aaa) through hhh), and aaaa) through hhhh), or in alternative embodiments including a drug holiday, a 6-week, 7-week, or 42-49-day combination treatment regimen including a compound of Formula (I) may be followed by maintenance therapy with TMZ, optionally with alternating current electrical tumor treating fields (TTFields). In a more specific embodiment, a 6-week, 7-week, or 42-49-day combination treatment regimen including a compound of Formula (I) may be followed by one or more 28-day cycles of maintenance therapy with TMZ, with TMZ administered on days 1 through 5 of each 28-day cycle. For example, the TMZ maintenance treatment comprises six cycles, e.g., 28 days. Optionally, alternating current electrical tumor treating fields (TTFields) may be added to the TMZ maintenance treatment. Optionally, a 4- to 6-week rest period is observed before initiating TMZ maintenance treatment. In certain embodiments of any of the above combination therapies comprising a compound of Formula (I), including items a) through h), aa) through hh), aaa) through hhh), and aaaa) through hhhh), optionally followed by TMZ maintenance therapy, the glioma is newly diagnosed. In more specific embodiments, the newly diagnosed glioma is WHO 2021 grade 4. In the same or other specific embodiments, the newly diagnosed glioma is IDH wild-type.

[0085] In certain embodiments of the uses or methods according to the present invention, for example (but not limited to), when glioma recurs after treatment of glioma, the combination treatment may be defined as the following alternative or complementary items: (k) the compound of formula (I) is administered in combination with TMZ on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle; (l) a compound of Formula (I) in combination with TMZ is administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day; (m) A compound of Formula (I) is administered in combination with TMZ on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle, wherein the free base of the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg per treatment day, preferably about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg per treatment day, and TMZ is 50 to 300 mg / m on days 1 to 5 of each 28-day cycle 2 / day, preferably 50-250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, and even more preferably 150-200 mg / m 2 / day dose, or 50 mg / m daily until progression 2 / day dose, or e.g., 120 mg / m on days 1–7 of each 28-day cycle 2 / day, or e.g., 80 mg / m on days 1–21 of each 28-day cycle 2 / day, administered; (n) A compound of Formula (I) administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle, wherein the compound of Formula (I) is administered at a dose ranging from about 30 to about 1000 mg of the free base per treatment day, preferably about 30 to about 720 mg, and most preferably at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550, or about 720 mg of the free base per treatment day; 150–200 mg / m on days 1–5 of each 28-day cycle 2 / day, or 50 mg / m daily until progression 2 / day dose, or e.g., 120 mg / m on days 1–7 of each 28-day cycle 2 / day, or e.g., 80 mg / m on days 1–21 of each 28-day cycle 2 It is administered at 100 mg / day.

[0086] In alternative embodiments from any one of the above items k) to n), the compound of formula (I) may additionally be administered on days 11-12 and 18-19 of a 28-day cycle, i.e., the compound of formula (I) may be administered on days 1-5, 8-12, and 15-19 (additional WEE1 inhibitor treatment days) of a 28-day cycle. In further alternative embodiments derived from any one of the above items k) to n), the compound of formula (I) may be further administered on days 11 to 12, 18 to 19, and 22 to 26 of a 28-day cycle, i.e., the compound of formula (I) may be administered on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle (further WEE1 inhibitor treatment days). In some embodiments of any of items k) through n) above, or any one of the embodiments in which additional WEE1 inhibitor treatment is administered, the compound of Formula (I) may be administered at a dose preferably ranging from about 150 to about 720 mg of the free base, or from about 200 to about 720 mg of the free base. In any of the above items k)-n) or any one of the embodiments involving additional WEE1 inhibitor treatment days, the compound of Formula (I) may be administered in 1, 2, 3, 4, 5, 6 or more 28-day cycles. For example, the compound of Formula (I) may be administered for up to 2 years.

[0087] In specific embodiments of any of the above combination therapies involving a compound of Formula (I) and TMZ, such as items k) through n), at any number of cycles, or with any number of additional WEE1 inhibitor treatment days, the glioma has recurred after the initial glioma treatment. In some aspects, the initial glioma treatment is TMZ-based. The glioma may also have recurred after up to two prior glioma treatments, one of which is TMZ-based. In a more specific embodiment, the recurrent glioma is grade 4 according to WHO 2021. In the same or other specific embodiments, the recurrent glioma is IDH wild-type. In an alternative more specific embodiment, the recurrent glioma is grade 3 according to WHO 2021. In the same or other specific embodiment, the recurrent glioma is IDH mutant. As noted above, in certain aspects, the dosing schedules described herein may be understood to encompass dosing schedules that are interrupted for one or several days (continuous or non-continuous), for example, when including radiation therapy.

[0088] In one embodiment of the present invention, the combination of a compound of formula (I) with either TMZ or radiation therapy, or both, exhibits synergistic effects in the treatment of glioma. In particular, in certain embodiments, the combination of a compound of Formula (I) with either TMZ or radiation therapy exhibits synergistic effects with an acceptable safety profile in the treatment of glioma, and in certain embodiments, the triple combination of a compound of Formula (I) with TMZ and radiation therapy exhibits synergistic effects with an acceptable safety profile in the treatment of glioma.

[0089] Pharmaceutical Composition Pharmaceutical compositions of the present invention suitable for oral administration (oral dosage forms) may be provided in solid or liquid form. Suitable solid oral dosage forms include capsules, tablets, powders, or granules, each containing a predetermined amount of the active ingredient. Suitable liquid oral dosage forms include solutions, emulsions, or suspensions. The pharmaceutical compositions of the present invention may also be in the form of sustained-release formulations. Any inert ingredient commonly used as a carrier or diluent may be used as a pharmaceutically acceptable excipient in the solid oral dosage form of the present invention, such as gums, starches, sugars, cellulosic materials, acrylates, or mixtures thereof. Preferred diluents include, for example, microcrystalline cellulose and anhydrous lactose. The composition may further comprise a disintegrant (e.g., croscarmellose sodium, sodium starch glycolate) and a lubricant (e.g., magnesium stearate), and may further comprise one or more additives selected from a binder (e.g., hydroxypropyl cellulose), a glidant (e.g., silicon dioxide), a buffer (e.g., citric acid), a surfactant (e.g., Tween 80), a solubilizer (e.g., cyclodextrin), a plasticizer (e.g., triacetin), an emulsifier (e.g., sodium lauryl sulfate), a stabilizer (e.g., povidone, ascorbic acid), a thickener (e.g., hydroxypropyl methylcellulose), a sweetener (e.g., sucrose), a film-forming agent (e.g., cellulosic systems, polymers), a colorant (e.g., iron oxide), a flavoring, or any combination thereof.

[0090] The oral pharmaceutical composition of the present invention can be prepared by any pharmaceutical method, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0091] Compounds represented by formula (I) In one embodiment of the present invention, the compound of formula (I) is formulated into a pharmaceutical composition in an oral dosage form. In a more specific embodiment, the compound of formula (I) is in the form of a solid oral dosage form such as a tablet or capsule (which may include powder, granules, or mini-tablets). The capsule may be a soft capsule or a hard capsule. For example, a compound of formula (I) may be formulated in a capsule, such as a hard gelatin capsule containing mini-tablets. Each mini-tablet may contain 10 mg of active ingredient. The following capsule strengths are available: 20, 30, 60, 100, 130, 150, and 200 mg of active ingredient (free base). Intermediate capsule strengths can be readily produced to cover alternative dosage levels.

[0092] In some embodiments, the solid oral dosage forms are packaged in blisters and / or bottles. In some embodiments, 1, 2, 3, 4, 5, or 6 unit dosage forms are administered per ingestion of the compound of Formula (I). Preferably, 1 to 4 unit dosage forms are administered per ingestion of the compound of Formula (I). For example, when formulated as a capsule containing mini-tablets, the excipients in each mini-tablet may include microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, sodium starch glycolate, anhydrous colloidal silica, and / or magnesium stearate. Alternative excipients may be used in bioequivalent oral dosage forms.

[0093] Temozolomide In one embodiment of the present invention, TMZ is formulated into a pharmaceutical composition that is an oral dosage form. In a more specific embodiment, the pharmaceutical composition containing TMZ is a capsule, such as a hard capsule. TMZ capsules may contain lactose, anhydrous lactose, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, and / or stearic acid. Bioequivalent oral dosage forms may use alternative excipients. Each capsule for oral use may contain 5 to 250 mg of temozolomide, for example, 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide. The inactive ingredients of the TMZ capsules may be, for example: TMZ 5mg: Lactose anhydrous (132.8mg), colloidal silicon dioxide (0.2mg), sodium starch glycolate (7.5mg), tartaric acid (1.5mg), and stearic acid (3mg). TMZ 20 mg: Lactose anhydrous (182.2 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (11 mg), tartaric acid (2.2 mg), and stearic acid (4.4 mg). TMZ 100mg: Lactose anhydrous (175.7mg), colloidal silicon dioxide (0.3mg), sodium starch glycolate (15mg), tartaric acid (3mg), and stearic acid (6mg). TMZ 140mg: Lactose anhydrous (246mg), colloidal silicon dioxide (0.4mg), sodium starch glycolate (21mg), tartaric acid (4.2mg), and stearic acid (8.4mg). TMZ 180mg: Lactose anhydrous (316.3mg), colloidal silicon dioxide (0.5mg), sodium starch glycolate (27mg), tartaric acid (5.4mg), and stearic acid (10.8mg). TMZ 250mg: Lactose anhydrous (154.3mg), colloidal silicon dioxide (0.7mg), sodium starch glycolate (22.5mg), tartaric acid (9mg), and stearic acid (13.5mg).

[0094] For each dosage form and strength, alternative bioequivalent excipients may be used in the oral dosage form. For example, each of the capsule strengths listed above may contain lactose, sodium starch glycolate (type B), tartaric acid, and stearic acid as excipients. The capsule body may be made of, for example, gelatin. The cap may also be made of gelatin, and the color of the capsule cap may vary based on the dosage strength. The capsule body and cap may be printed with pharmaceutical brand inks that may contain shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and / or iron (III) oxide or iron oxide.

[0095] In another embodiment of the present invention, TMZ is formulated into an injectable pharmaceutical composition, for example, TMZ is formulated as an injectable powder containing 5 to 250 mg of temozolomide, for example, a 100 mg injectable powder. As an example, a vial may contain 100 mg of sterile, pyrogen-free temozolomide lyophilized powder for intravenous injection. Inactive ingredients may be mannitol (600 mg), L-threonine (160 mg), polysorbate 80 (120 mg), sodium citrate dihydrate (235 mg), and hydrochloric acid (160 mg). For each dosage form and strength, alternative excipients may be used in bioequivalent IV dosage forms.

[0096] In certain embodiments of the present invention, an oral dosage form, such as a solid oral dosage form, may incorporate both a compound of formula (I) and TMZ as active ingredients. Of course, in some embodiments, TMZ may be used in the form of a pharmaceutically acceptable salt, and in such embodiments, the dosage, amount, or concentration indicators for etoposide herein, which are indicators for the free base, may be appropriately adapted taking into account the molecular weight of each salt. Embodiments of the present disclosure can be further defined and illustrated by reference to the following non-limiting examples. For example, it will be apparent to those skilled in the art that many modifications or variations to the materials and methods described can be practiced without departing from the scope of the present disclosure. [Example]

[0097] Determination of the concentrations of the compound of formula (I), AZD1775 and Zn-c3 in brain tissue of healthy mice after repeated administration Healthy male Nu / Nu mice were orally treated with either (i) a single dose of 30 mg / kg of the compound of formula (I) (25 mice total, 3 mice per time point), (ii) 30 mg / kg of the compound of formula (I) given once daily for 4 consecutive days (27 mice total, 3 mice per time point), (iii) 30 mg / kg of AZD-1775 (adavosertib, purchased from Combi-Blocks, San Diego, USA) given twice daily for 3 consecutive days, with one dose on the fourth day (27 mice total, 3 mice per time point), or (iv) 80 mg / kg of Zn-c3 (purchased from EOS Med Chem, Jina City, China) given once daily for 4 consecutive days (27 mice total, 3 mice per time point). The doses used for each compound were previously reported as active dose levels. The compound of formula (I) was formulated as a suspension in 0.5% methylcellulose containing 1% Tween 80 and administered at a concentration of 3.0 mg / mL. AZD-1775 was formulated as a suspension in 0.5% methylcellulose in water at a dose concentration of 3.0 mg / mL, and Zn-c3 was prepared in 20% HP-β-CD(2-hydroxypropyl)-β-cyclodextrin in water and administered as a solution at a dose concentration of 8 mg / mL. The administration volume for all formulations was 10 mL / kg.

[0098] At designated time points, mice were euthanized by carbon dioxide inhalation, and blood samples were collected by cardiac puncture into K2EDTA-containing tubes. The tubes were inverted several times, placed on ice, and centrifuged (6000 rpm for 5 minutes at 4°C) within 30 minutes of collection to obtain plasma. Plasma samples were flash-frozen in dry ice and stored at -80°C until analysis. Brains were collected, weighed, and flash-frozen in dry ice until further analysis. To obtain brain homogenates, water was first added to each brain (brain weight:water volume = 1:4), and then the brains were homogenized in an H-Speed ​​homogenizer (time procedure: 10 seconds, with 10-second intervals between each homogenization, for a total of 3-5 times; homogenizer washing procedure: water-methanol-ethanol-water, 10 seconds each). Brain homogenate samples were transferred to individual tubes and stored at -80°C before analysis.

[0099] Mouse plasma and brain samples were analyzed as follows. For each analytical batch of plasma and brain samples, standards and quality control (QC) samples were freshly prepared in blank male Nu / Nu mouse plasma (containing K2EDTA anticoagulant) and brain homogenate. Aliquots of each standard, QC, control blank, and test sample were diluted with the internal standard (for compound of formula (I), 0.01% CI 0.01-0.02) in methanol / acetonitrile (1:1, v / v). 13 CD6-the compound of formula (I), AZD-1775, and Zn-c3 (terfenadine) were added. The samples were mixed for 1 minute and centrifuged at 4000 rpm at 4°C for 15 minutes. The supernatant was transferred and diluted with MeOH / water (1:1, v / v, containing 0.1% FA) before injection into LC-MS / MS.

[0100] Chromatographic separation was achieved on a Shimadzu LC-20AD using a Kinetex 2.6μ C18 100A column (50mm*3.00mm) for the compound of formula (I) and AZD-1775 samples, and an ACE 5 C4 column (50mm*2.1mm) for the Zn-c3 sample, with gradient elution using the following conditions: flow rate 0.7mL / min; run time: 3.0min; mobile phase: A: 5mM NHOAc (0.1% FA), B: acetonitrile (0.1% FA).

[0101] Detection was achieved using an AB Sciex 5500 using electrospray MS / MS in positive ion multiple reaction monitoring mode (MRM). The MRM channels were 511.29 / 98 for the compound of formula (I), 501.47 / 442.20 for AZD-1775, and 527.36 / 468.10 for Zn-c3. The MRM channels for the internal standards were 518.17 / 102.10 ( 13 For CD6 (compound represented by formula (I)), AZD-1775 and Zn-c3, the results were 472.40 / 436.40 (terfenadine).

[0102] The plasma and brain concentrations measured at each time point, the nominal sample collection time, and the intended dosage were used for pharmacokinetic analysis. The PK parameters of all test compounds were determined by non-compartmental analysis using WinNonlin Version 8.0 (Pharsight). The results are summarized in Table 2 below. Table 2

[0103] [Table 2] FIG. 1 shows three graphs depicting plasma and brain concentrations measured on day 4 after repeated administration of 30 mg / kg qd of the compound of formula (I) (FIG. 1(A)), 30 mg / kg bid of AZD1775 (FIG. 1(B)), and 80 mg / kg qd of Zn-c3 (FIG. 1(C)). The results of Example 1 demonstrate that compound of formula (I) can cross the blood-brain barrier (BBB) ​​and distribute into the brain. Furthermore, the data show that the brain distribution profile of compound of formula (I) is favorable compared to AZD1775 and Zn-C3, as reflected by the higher brain-to-plasma exposure ratio of compound of formula (I) (more than 10-fold higher than AZD1775; more than 7-fold higher than Zn-C3). [Example]

[0104] Determination of the concentrations of the compound of formula (I) in brain tissue and cerebrospinal fluid of healthy rats after a single dose Healthy male Wistar Han rats were orally treated with a single 15 mg / kg dose of the compound of formula (I) (24 rats total, 3 rats per time point). The compound of formula (I) was formulated as a suspension in 0.5% methylcellulose containing 1% Tween 80 and administered at a concentration of 1.5 mg / mL in a dose volume of 10 mL / kg. At the designated time points (0.5, 1, 2, 4, 8, 24, 32, and 48 hours post-dose), rats were euthanized by carbon dioxide inhalation. Blood, CSF, and brain samples were then collected as follows: Blood samples were collected by cardiac puncture into K2EDTA-containing tubes. The tubes were inverted several times, placed on ice, and centrifuged (6000 rpm for 5 minutes at 4°C) within 30 minutes of collection to obtain plasma. Plasma samples were quickly frozen in dry ice and stored at -80°C until analysis. CSF samples were collected using a scalp needle to puncture the foramen magnum. CSF samples were acidified with 10% formic acid (final sample concentration 0.5% formic acid) and stored at -80°C until further analysis. Brains were collected, weighed, and quickly frozen in dry ice until further analysis. To obtain brain homogenates, water was first added to each brain (brain weight:water volume = 1:4), and then the brains were homogenized in an H-Speed ​​homogenizer (time procedure: 10 seconds, with 10-second intervals between each homogenization, for a total of 3-5 times; homogenizer washing procedure: water-methanol-ethanol-water, 10 seconds each). Brain homogenate samples were transferred to individual tubes and stored at -80°C before analysis.

[0105] Samples were analyzed as follows: For each analytical batch of plasma and brain samples, standards and quality control (QC) samples were freshly prepared in blank male Wistarhan plasma (containing K2EDTA anticoagulant) and brain homogenate. Acidified (containing 0.5% formic acid) artificial CSF was used as a standard and quality control for CSF samples. In addition, one set of blank male Wistarhan CSF was included as a QC sample. An aliquot of each standard, QC, control blank, and test sample was diluted with the internal standard ( 13 CD6 (compound of formula (I)) was added. The sample was mixed for 1 minute and centrifuged at 4000 rpm at 4°C for 15 minutes. The supernatant was decanted and diluted with MeOH / water (1:1, v / v, containing 0.1% FA) before injection into LC-MS / MS.

[0106] Chromatographic separation was achieved on a Shimadzu LC-20AD (for plasma and brain samples) or Shimadzu LC-30AD (for CSF samples) using a Kinetex 2.6μC18 100A column (50mm x 3.00mm; for plasma and brain samples) or an ACE 5 C4 column (50mm x 2.1mm; for CSF samples). The following conditions were applied: flow rate: 0.7mL / min; run time: 3.0min; mobile phase: A: 5mM NHOAc (0.1% FA), B: acetonitrile (0.1% FA).

[0107] Detection was achieved using an AB Sciex 5500 utilizing electrospray MS / MS in positive ion multiple reaction monitoring mode (MRM). The MRM channel was 511.29 / 98 for the compound of formula (I) and 511.29 / 98 for the internal standard 13 For CD6-compound of formula (I), it was 518.17 / 102.10. The plasma, CSF, and brain concentrations measured at each time point, the nominal sample collection time, and the intended dosage were used for pharmacokinetic analysis. PK parameters of all test compounds were determined by non-compartmental analysis using WinNonlin Version 8.0 (Pharsight). The results are summarized in Table 3 below. Table 3

[0108] [Table 3] FIG. 2 graphically depicts the total plasma concentration, total brain concentration, unbound CSF concentration and calculated unbound plasma concentration of a compound of formula (I) over time. The results of Example 2 demonstrate that in rats, the compound of formula (I) can cross the blood-brain barrier and distribute to the brain. Furthermore, the results show that the compound of formula (I) can cross the blood-CSF barrier and distribute into the CSF. [Example]

[0109] Determination of drug concentrations in monkey brain after 91 days of daily oral administration The compound of formula (I) was administered orally by gavage to three female cynomolgus monkeys once daily for 91 days. The dose volume was 5 mL / kg, and the vehicle was an aqueous solution of 0.5% (w / v) methylcellulose (cps 400) and 1% (w / v) Tween 80. The dose of the compound of formula (I) was 10 mg / kg, a dose level evaluated as the minimal no-adverse-effect level (NOAEL) in this study based on conventional toxicology evaluation. Animals were necropsied 24 hours after the final dose and after an overnight fasting period. Brain tissue (left forebrain) samples were collected from each animal and flash-frozen in liquid nitrogen. They were stored frozen at temperatures below -50°C. Blood samples were collected from the femoral vein into tubes containing K2EDTA, inverted completely approximately 10 times, and placed on crushed wet ice until centrifuged at approximately 4°C for 10 minutes at 2300 g. The resulting plasma was separated, transferred to polypropylene tubes, and frozen at below −50° C. Tissue and plasma samples were shipped frozen on dry ice to their respective analysis sites.

[0110] Monkey plasma samples were analyzed by incubating the compound of formula (I) and N 32 The content of the compound of formula (I) was analyzed as follows: Plasma samples were fortified with human K2-EDTA plasma (1:9 monkey:human volume ratio) before extraction. All solution preparations and dilutions were carried out in "low binding" quality polypropylene tubes and deep-well plates under sodium vapor light. Analytes and internal standards ( 13 CD6 - a compound of formula (I) and D7-N 32The α-desmethyl-compound of formula (I) was extracted by protein precipitation with 5 M aqueous urea (40 μL per 50 μL plasma) and then analyzed by LC-MS / MS. Chromatographic separation was achieved on a Synergi Polar-RP, 80-augmented, 4 μm 75 × 2.00 mm column (Phenomenex) using a gradient elution of a mixture of 0.1% formic acid in water as eluent A and 0.1% formic acid in acetonitrile as eluent B (5% B from 0.50 to 0.50 min, 42% B from 4.5 to 5.50 min, 95% B from 5.60 to 5.70 min, 100% B from 5.70 to 6.40 min, 100% B from 6.50 min, 5% B from 7.00 min; 800 μL / min, 70 °C). Detection was achieved on an AB Sciex 6500+ mass spectrometer utilizing electrospray MS / MS in positive ion multiple reaction monitoring mode (MRM). 32 The lower limits of quantitation for the -desmethyl-compound of formula (I) were 5.00 ng / mL and 2.50 ng / mL, respectively.

[0111] Monkey brain tissue samples were treated with a compound of formula (I) and N 32 The content of N-desmethyl-compound of formula (I) was analyzed as follows: Tissue samples were homogenized in human plasma (1 mg tissue per 10 μL plasma) at +4° C. using a Precelly Evolution system. The analytes (compound of formula (I) and N-desmethyl-compound of formula (I)) were analyzed as follows: 32 -desmethyl-compound represented by formula (I)) was used as an internal standard ( 13 CD6 - a compound of formula (I) and D7-N 32The compounds were extracted by protein precipitation using methanol / acetonitrile (9:1, v:v) containing 1-desmethyl-N-(N-desmethyl-)-compound of formula (I) and then analyzed by UHPLC-MS / MS. Chromatographic separation was achieved on an HSS T3 1.8 μm, 2.1 × 100 mm column (Waters) with gradient elution (20% B from 0 to 0.50 min, 90% B from 1.80 to 2.30 min, 20% B at 2.60 min) using a mixture of 0.1% formic acid in water as eluent A and 0.1% formic acid in acetonitrile as eluent B (0.6 mL / min, room temperature). Detection was achieved on a Xevo TQ-S mass spectrometer (Waters) using electrospray MS / MS in positive ion multiple reaction monitoring mode (MRM). Compounds of formula (I) and N-(N-desmethyl-)-compounds of formula (I) were analyzed. 32 The limits of quantitation for the -desmethyl-compounds were 55.00 ng / g tissue and 22.00 ng / g tissue, respectively. The results are shown in Table 4 below. Table 4

[0112] [Table 4] Compounds of formula (I) and N 32 For both -desmethyl metabolites, 24 hours after the final dose, brain concentrations were not negligible compared to plasma concentrations, indicating that both compounds are capable of crossing the blood-brain barrier. [Example]

[0113] In vitro efficacy of compounds of formula (I) in combination with radiation therapy (RT) in GBM cell lines GBM tumor cells (T98G, LN18, SNB-19, and U251) were grown as adherent monolayers at 37°C in a humidified atmosphere (5% CO2, 95% air). For experimental use, tumor cells were detached from culture flasks by treatment with trypsin-versene for 5 minutes in calcium- or magnesium-free Hanks' medium and neutralized by the addition of complete medium. Cells were counted, and viability was assessed using a 0.25% trypan blue exclusion assay. All cell lines were seeded at three densities for evaluation of proclonogenic effects in 1.9 ml cell culture medium in 6-well plates (Ref. #152795, Nunc, Dutcher) under conditions for monolayer colony formation. The cell densities were 500, 100, or 200 cells per well for the GL261 and LN-18 cell lines, 1500, 2000, and 2500 cells per well for the SNB-19 cell line, and 250, 500, and 1000 cells per well for the T98G cell line. At 24 h after seeding (D1), treatment was performed by adding 20-fold concentrated compound or vehicle solution to obtain final concentrations of 0.1 μM to 5.0 μM of the compound of formula (I) [CoF(I) in Figure 3]. 0.1% DMSO vehicle was added as a control. Immediately after compound treatment, plates were irradiated at 1, 2, and 4 Gy. Irradiation was performed using a SARRP irradiation system (Xstrahl Life Science). Mock irradiation was performed on plates corresponding to non-irradiated controls. On days 2 and 7 following treatment and irradiation, the culture medium was replaced with fresh medium without the compound of formula (I) in all plates. After 14 days of culture, colonies were stained by incubation with 500 μl of an aqueous solution containing 0.05% (w / v) methylene blue (Ref. M4159, Sigma) for 2 h, followed by counting. Colonies were counted using a colony counter pen (Ref#045855, Dutscher, Brumath, France). The survival rate was calculated for each condition using the formula given below and plotted on a semi-logarithmic graph using a linear-quadratic model. The curve was weighted by 1 / y 2Statistical testing was performed using a further sum-of-squares F-test, with the H0=1 curve fitting exactly to all data. All analyses were performed using GraphPad Prism 7 (GraphPad Inc., La Jolla, CA).

[0114]

number

[0115] In vivo efficacy of compound of formula (I) as monotherapy in U87-MG-luc GBM cell line Male athymic nude mice received 1 × 10 cells in Matrigel A) subcutaneously (sc) or B) intracerebrally (ic). 5Each animal was injected with 1000 U87-MG-luc cells. The intravital implanted animals were imaged weekly using an in vivo imaging system (IVIS) to monitor tumor establishment and growth throughout the study period. For subcutaneously implanted animals, tumor growth was monitored twice weekly by caliper measurement, and tumor volume was calculated using the formula V = (L × W × W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension), and W is tumor width (the longest tumor dimension perpendicular to L). After confirmation of tumor establishment, animals were randomly assigned to three (A, sc) or two (B, i) treatment groups (n = 8 animals per group) consisting of vehicle (0.5% methylcellulose, 1% Tween 80 PO, and saline IV) or compound of formula (I) [CoF(I)] formulated as a suspension in 0.5% methylcellulose and 1% Tween 80. Treatment was administered over a 28-day cycle, with the compound of formula (I) administered orally once daily (QD) at a dose of either 30 mg / kg (both A and B) or 60 mg / kg (A only). During routine monitoring, animals were monitored for tumor growth and any effects of treatment on behavior, including mobility, food and water consumption, weight gain / loss three times a week, eye / hair tangles, and other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal. The results are shown in Figure 4. Treatment of subcutaneously implanted U876-MG-luc tumors with 30 mg / kg or 60 mg / kg of the compound of formula (I) resulted in tumors that were significantly smaller than vehicle controls at the end of the treatment period (p=0.0009 and p<0.0001, respectively, at day 28). Treatment of brain-implanted U876-MG-luc tumors with 30 mg / kg of a compound of formula (I) resulted in tumors that were significantly smaller than vehicle controls at the end of the treatment period (p=0.0023 at day 28). No significant weight loss was observed throughout the study, indicating that treatment with the compound of formula (I) at all dose levels was well tolerated. Thus, compounds of formula (I) used in monotherapy for the treatment of subcutaneous or brain-implanted GBM tumors were well tolerated and provided significant antitumor activity. [Example]

[0116] In vivo efficacy of compound of formula (I) in combination with temozolomide in U87-MG-luc GBM cell line The cerebellum of male athymic nude mice was treated with 1 × 10 5 U87-MG-luc cells were injected into the mice. Animals were imaged and tumor establishment and growth was monitored weekly throughout the study using an in vivo imaging system (IVIS) to detect tumor bioluminescence (BLI) with photons. After tumor establishment was confirmed, animals were randomly assigned to eight treatment groups: vehicle (0.5% methylcellulose, 1% Tween 80 PO and saline IV), compound of formula (I) [CoF(I)] (formulated as a suspension in 0.5% methylcellulose and 1% Tween 80) administered orally once daily (QD) at 3 mg / kg, 10 mg / kg, or 30 mg / kg in monotherapy, temerozomide [TMZ] administered orally once daily (QD) at 3 mg / kg in monotherapy, and combinations of TMZ and compound of formula (I) at various doses over a 28-day cycle (n = 6 animals per group for monotherapy groups and n = 8 animals per group for combination groups). In the combination groups, compound of formula (I) was administered 2 hours before TMZ. During routine monitoring, animals were monitored for tumor growth and any effects of treatment on behavior such as mobility, food and water consumption, weight gain / loss three times a week, eye / hair matting, and other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0117] Treatment of brain-implanted U876-MG-luc tumors with 3 mg / kg or 10 mg / kg of the compound of Formula (I) as monotherapy did not result in any significant antitumor activity as determined by mean relative BLI, but treatment with 30 mg / kg of the compound of Formula (I) resulted in tumors significantly smaller than vehicle controls (p=0.0133 at day 36), consistent with the results presented in Example 5 (B ic). Because U876-MG-luc is a TMZ-sensitive tumor model, treatment with TMZ resulted in a significant antitumor response (p=0.0066 vs. vehicle at day 36) that persisted throughout the monitoring period, with three of six treated animals experiencing a complete response.

[0118] Furthermore, treatment of U87MG-luc tumors with compound of Formula (I) in combination with TMZ also resulted in significant antitumor activity compared to vehicle controls (p<0.001 for all doses of compound of Formula (I) at day 28), which was sustained up to day 160. Furthermore, combination treatment with 10 mg / kg and 30 mg / kg doses of compound of Formula (I) demonstrated significant antitumor activity compared to standard of care TMZ treatment throughout the treatment period (p=0.0213 and p=0.0174 at day 28, respectively) (Figure 5 shows that a 10 mg / kg dose of compound of Formula (I) in combination with TMZ was sufficient to achieve a significant antitumor effect). Treatment in each combination group resulted in durable responses throughout the monitoring period, with 3 out of 8 (3 mg / kg compound of formula (I)), 6 out of 8 (10 mg / kg compound of formula (I)), and 5 out of 7 (30 mg / kg compound of formula (I)) animals experiencing a complete response (defined as a BLI value of 0). TMZ at 3 mg / kg, the compound of Formula (I) at 3, 10, and 30 mg / kg as monotherapy, and the compound of Formula (I) in combination with temozolomide were also well tolerated at all doses tested, with no significant changes in animal weight compared to pretreatment levels over the course of the 28-day treatment period. All groups maintained their weight following the treatment period and showed no post-treatment intolerance. [Example]

[0119] In vivo evaluation of compounds of formula (I) as monotherapy or in combination with TMZ on survival of mice bearing GL261 intracranial tumors GL261 cells were harvested in logarithmic growth phase and resuspended in phosphate-buffered saline (PBS). Female C57 / BL6 mice were seeded with 1 × 1 × 10 cells in Matrigel. 5 GL261 cells (10 μL of cell suspension) were inoculated via intracranial injection. The injection site was determined based on the intersection of the midline suture and the caudal transverse suture according to the protocol. The tip of a 25-gauge needle was placed 1 mm cranial and 1 mm to the right or left of the intersection, and 10 μL of the GL261 glioma cell suspension was injected into the space. Intracranial injections were performed 5 days before the start of treatment. The compound of Formula (I) [CoF(I)] and temozolomide were orally (po) administered at a dose volume of 10 mL / kg, adjusted to each animal's most recent body weight (BW). The compound of Formula (I) was administered once daily for 14 days (qd x 14) or 28 days (qd x 28). Temozolomide was administered once daily for 5 days (qd x 5). In the combination therapy group, the compound of Formula (I) was administered 2 hours before temozolomide. Five days after GL261 tumor cell implantation (referred to as day 1 of the study), mice were divided into 8 groups (n = 8) according to BW. Treatment began on day 1, and mice in group 1 received vehicle orally daily for 14 days and served as controls for efficacy analysis. Group 2 received 30 mg / kg of the compound of Formula (I) orally daily for 14 days; Group 3 received 3 mg / kg of temozolomide orally daily for 5 days; and Group 4 received 30 mg / kg of temozolomide orally daily for 14 days in combination with 3 mg / kg of temozolomide orally daily for 5 days. The study endpoint was death or moribund due to glioma progression or the end of the study, whichever occurred first (i.e., an event). The median time to event (TTE) was calculated for each group. The median TTE of treated mice was expressed as a percentage of the median TTE of control mice (%T / C), and the lifespan extension (ILS) was expressed as ILS = %T / C - 100%, where T = median TTE treated and C = median TTE control. Therefore, if T = C, ILS = 0%. The maximum %ILS in this study is 296%, based on the ratio between the study endpoint and the median TTE in the control group (22.5 days) (Teicher, Beverly A. Tumor models in cancer research. New York: Humana Press Springer, 2011). For the 30 mg / kg compound of Formula (I) in combination with temozolomide, the median TTE was 30.0 days, corresponding to a 33% ILS. Overall survival in the combination group was improved compared to the temozolomide monotherapy regimen (p<0.01) (Figure 6). [Example]

[0120] In vitro efficacy of compound of formula (I) as monotherapy in ATRX-deficient GBM cell lines SF188 cells were transfected with ATRX siRNA (siATRX_1 or siATRX_2), either individually (A) or as a pool (B and C), or with control siRNA (siCon), and ATRX deficiency was assessed by determining relative ATRX protein levels by Western blot. Control and ATRX-deficient SF188 cells were then treated with compounds of formula (I) at concentrations ranging from 0 to 1.5 μM (Figure 7A) and 400 nM (Figure 7B), and drug sensitivity was assessed by ATP-based cell viability assay or colony formation assay.

[0121] For cell viability assessment, SF188 cells were seeded into 96-well culture plates at 100–500 cells per well in 100 μl of medium. After overnight incubation, 100 μl of culture medium containing a compound of Formula (I) was added to each well at the desired final concentration. After 72 hours, cell viability was assessed using CellTiter-Glo 2.0 according to the manufacturer's instructions. Each condition was tested in triplicate or quadruplicate, and the average viability is shown as a percentage of vehicle-treated cells. For colony formation assessment (Figure 7C), SF188 cells were seeded into 6-well plates at 100 cells per well in 1 ml of culture medium. After overnight incubation, 1 ml of culture medium containing a compound of Formula (I) was added to each well at the desired final concentration up to 400 nM. Ten days after treatment, cell colonies were fixed with 70% ethanol for 30 minutes, washed with distilled water, and stained with Coomassie blue. The number of colonies in each well was counted manually. Each colony consisted of >50 cells (corresponding to six doublings from a single cell). Colony formation efficiency was determined by normalizing colony numbers to vehicle-treated cells.

[0122] In a colony formation assay (Figure 7C), treatment with compound of Formula (I) significantly reduced cell viability, demonstrating antitumor activity. In cell viability assays (Figures 7A and 7B), treatment with compound of Formula (I) significantly reduced the viability of SF188 cells treated with ATRX siRNA, and significantly improved this response to compound of Formula (I), with an IC50 less than half that of control siRNA (Figure 7A). Cell viability of ATRX-deficient SF188 cells was significantly reduced after treatment with 400 nM compound of Formula (I) (p<0.01) (Figure 7B). Western blotting demonstrated that treatment with siRNA ATRX pool 1 (ATRX_1) or pool 2 (ATRX_2) significantly reduced ATRX protein levels (Figure 7B, bottom). [Example]

[0123] Phase 1 / 2 clinical trials involving a compound of formula (I) (herein referred to as the investigational drug) The clinical trial will be a Phase 1 / 2 multicenter, open-label, non-randomized controlled trial in adult participants with glioma, as described below. Phase 1 (dose escalation) It consists of two arms: Arm A The study population for this arm is as follows (according to WHO2021): GBM isocitrate dehydrogenase (IDH) wild-type, grade 4, or - Astrocytoma, IDH variant, grade 3 All participants must have received temozolomide (TMZ)-based chemoradiotherapy as first-line treatment. Participants will receive the following: study drug (escalating doses) on days (D) 1-5, D8-10, and D15-17 of each cycle, and TMZ (150 mg / m) on days (D) 1-5. 2 / day); administered orally once daily in 28-day cycles. Treatment will continue for up to two years or until disease progression, unacceptable toxicity, participant withdrawal, investigator-determined discontinuation, initiation of subsequent antineoplastic therapy, study termination, or death, whichever occurs first. The starting dose of study drug is 150 mg, based on the dose level determined to be safe in ongoing Phase 1 studies: Study 101, which includes the study drug in combination with carboplatin, and Study 102, which includes the study drug in monotherapy.

[0124] Arm B The study population for this arm is adult participants with confirmed, newly diagnosed GBM IDH wild-type, grade 4 (WHO 2021). Participants will receive the following: study drug (escalating doses) and TMZ (75 mg / m) with concurrent administration of radiation therapy (RT; conventional fractionation regimen of 2 Gy per fraction once daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions). 2 Patients will receive a continuous daily dose of 100 mg / day (100 mg / day) orally once daily for 6 weeks. The starting dose of study drug is 90 mg, based on available data from the dose levels determined to be safe in the ongoing Phase 1 studies: Study 101, which includes the study drug in combination with carboplatin, and Study 102, which includes the study drug in monotherapy. New data, including data from Arm A of this clinical trial, will be evaluated to confirm the proposed starting dose. After a 4-6 week rest period following the end of study treatment, maintenance therapy with TMZ for 5 days (D1-D5) repeated every 28 days, with or without further administration of alternating Electrical Tumor Treating Fields (TTFields Optune®) therapy, may be administered at the investigator's discretion per standard of care (SOC). Arm B will begin after at least two dose levels have been found safe in Arm A. Dose recommendations for study drug during the dose escalation phase will be provided independently for Arms A and B. The maximum tolerated dose (MTD) and / or recommended phase 2 dose (RP2D) to be used in Part 2 will be determined based on Safety Monitoring Committee (SMC) recommendations. After the end-of-treatment (EOT) visit, Phase 1 participants will be followed for safety and antitumor activity until disease progression or, in the absence of disease progression, initiation of subsequent antineoplastic therapy, withdrawal of consent, loss to follow-up, death, or end of study, whichever occurs first.

[0125] Phase 2 will begin once the RP2D for Arm A of Phase 1 is determined as recommended by the SMC. Phase 2 is a multicenter, open-label, externally controlled study comparing the efficacy and safety of the study drug when administered in combination with TMZ versus SOC in adult participants with a confirmed diagnosis of GBM IDH wild-type, grade 4 (WHO 2021) who have progressed or experienced disease recurrence after first-line TMZ-based chemoradiation therapy. The comparison will be conducted using a group sequential design, comparing participants assigned to treatment with the study drug and TMZ with patients in the external control arm (ECA). Phase 2 consists of two arms. Experimental Arm The study population consisted of adult participants with a confirmed diagnosis of GBM IDH wild-type, grade 4 (WHO 2021) who had progressed or experienced disease recurrence after first-line TMZ-based chemoradiotherapy. Participants enrolled in this group received the following: study drug on RP2D on Day 5, Days 8-10, and Days 15-17, and TMZ (150 mg / m on Days 1-5). 2 Patients will receive oral once-daily doses of 100mg / day in 28-day cycles. Treatment will continue for up to 2 years or until disease progression, unacceptable toxicity, participant withdrawal, investigator-determined discontinuation, study termination, or death, whichever occurs first. ECA The study population consists of adult participants with a confirmed diagnosis of GBM IDH wild-type, grade 4 (WHO 2021) who have progressed or experienced disease recurrence after first-line TMZ-based chemoradiotherapy. ECA includes only patient-level data from patients treated with SOC therapy from a recently completed historical clinical trial (HCT). Propensity score methods will be used to balance baseline and disease-specific prognostic factors for ECA patients with study drug participants. The safety and efficacy of participants assigned to treatment with the study drug and TMZ in Phase 2 will be compared with patients with ECA. At the end-of-treatment (EOT) visit, participants in the experimental arm will be followed for safety and antitumor activity until disease progression, or in the absence of disease progression, initiation of subsequent antineoplastic therapy, withdrawal of consent, loss to follow-up, death, or study termination, whichever occurs first. Additionally, participants will be followed for OS. In Phase 1 Arm A and Phase 2 experimental arms, a treatment cycle is defined as 28 days. Abbreviations used in tables and text: AE = adverse event; AUC = area under the drug blood concentration-time curve; AUC24 = area under the drug blood concentration-time curve over 24 hours; AUClast = area under the drug blood concentration-time curve up to the last measured concentration; BOR = best overall response; CL / F=apparent clearance; Cmax=maximum plasma concentration; CSF = cerebrospinal fluid; Ctrough = trough plasma concentration; CV = coefficient of variation; DC = disease control; DCR = disease control rate; DOR = duration of response; DLT=dose-limiting toxicity; DOR = duration of response; ECG = electrocardiogram; ECHO = echocardiogram; EOT = end of treatment; FACTBr=Functional Assessment of Cancer Therapy Brain; GBM = glioblastoma; Gd-based = Gadolinium-based (used as a contrast agent in MRI) ka = absorption rate constant; KPS = Karnofsky Performance Status; KPS is a functional impairment assessment tool. It is a standard way of measuring participants' ability to perform usual tasks with cancer. Scores range from 0 (death) to 100 (no evidence of disease). A higher score means that the participant is better able to perform daily activities. LVEF=left ventricular ejection fraction; mRANO = Modified Response Assessment in Neuro-Oncology; i.e., recommendations set out in "Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials" by Ellington BM, et al. 2017, Neurotherapeutics, 14(2):307-20. NCI-CTCAE 5.0=National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0; OR = objective response; ORR = objective response rate; OS=overall survival; PD=progressive disease; PFS = progression-free survival; PK = pharmacokinetic(s); QoL = quality of life; RANO = Response Assessment in Neuro-Oncology; i.e., recommendations as set out in Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group by Wen PY, et al. 2010, J Clin Oncol 28(11): 1963-72. RP2D = recommended phase 2 dose; RT=radiotherapy; SOC=standard of care; t1 / 2=apparent terminal half-life; TEAE = treatment-emergent adverse events; tmax = time to Cmax; TMZ = temozolomide; Vd = volume of distribution; Vd / F = apparent Vd The primary objectives and evaluation items (including endpoints) of the clinical trial include:

[0126] [Table 5] Secondary objectives and objectives (including endpoints) of clinical trials include:

[0127] [Table 6] TIFF2026506642000011.tif91170Exploratory objectives of the clinical trial include:

[0128] [Table 7] The study population for this clinical trial was as follows: Phase 1: -Arm A: Adult participants (age 18 years or older) with a confirmed diagnosis of GBM IDH wild-type, grade 4, or astrocytoma, IDH mutant, grade 3 (WHO 2021) who have received first-line TMZ-based chemoradiotherapy and have progressed or relapsed after up to two prior lines of therapy. Arm B: Adult participants (18 years or older) with confirmed, newly diagnosed GBM IDH wild-type, grade 4 (WHO2021).

[0129] Phase 2: - Experimental arm: Adult participants (age 18 years or older) with a confirmed diagnosis of GBM IDH wild-type, grade 4 (WHO 2021) who have progressed or experienced disease recurrence after first-line TMZ-based chemoradiotherapy. -ECA: Adult patients with confirmed GBM IDH wild-type, grade 4 (WHO 2021) who have progressed or experienced disease recurrence after first-line TMZ-based chemoradiation. ECA consists of patients treated with standard therapy from HCT. Inclusion criteria: For both Phase 1 (Arms A and B) and Phase 2, inclusion criteria include: - (Both) Willingness to provide archived or fresh tumor specimens, if available. Receipt of a tumor specimen is not required for initiation of study treatment. -(Both) Adequate bone marrow, liver, and kidney function: Absolute neutrophil count (ANC) ≥ 1500 / μL, platelets ≥ 100,000 / μL, hemoglobin ≥ 9 g / dL or 5.6 mmol / L, and no blood transfusion within the last 2 weeks after initiating study treatment. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN for participants with liver metastases; serum total bilirubin ≤ 1.5 × ULN; alkaline phosphatase (ALP) < 2.5 × ULN or ≤ 5 × ULN for participants with liver metastases. • Calculated creatinine clearance ≥ 50 mL / min (minutes) (as determined by the Chronic Kidney Disease-Epidemiology Collaboration [CKD EPI] formula). ● Coagulation status: INR or prothrombin time ≤ 1.5 × ULN; activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN. - (Both) Life expectancy of at least 3 months in the investigator's best judgment. - (Both) Participants receiving corticosteroids must be receiving a stable or tapering dose of ≤4 mg dexamethasone (or ≤25 mg prednisone) daily for 7 days prior to the start of study treatment. - (Both) Participants with seizures must be appropriately managed on a stable regimen of antiepileptic medication. Note: Anticonvulsants with enzyme-inhibiting or -inducing properties are prohibited. -(Both) Measurable or non-measurable disease by RANO criteria using Gd-based contrast-enhanced brain magnetic resonance imaging (MRI). - (Both) Willingness to use highly effective contraceptive methods.

[0130] Further specific inclusion criteria for Phase 1 Arm A: -(A) Participants must have one of the following histopathologically proven diagnoses (WHO2021): GBM IDH wild-type grade 4, which may include secondary GBM (i.e., progressing from low-grade glioma) ●Astrocytoma, IDH variant, grade 3 -(A) A maximum of two prior lines of therapy, the first of which must be TMZ-based chemoradiation therapy (TMZ concurrent with RT). -(A) Documented disease recurrence or progression by diagnostic biopsy or Gd-enhanced brain MRI according to RANO criteria. Progressive disease (PD) on the most recent treatment regimen is required. Unless study treatment initiation occurs within 28 days of the diagnostic brain MRI, a subsequent brain MRI must be obtained within 10 days before initiation of study treatment. -(A) Surgery after initial disease progression is permitted. To avoid interpreting postoperative changes as residual enhancing disease, a postoperative brain MRI must be available within 72 hours after surgery. A subsequent brain MRI documenting disease progression by RANO criteria must be obtained within 10 days before the start of study treatment. Surgery must occur at least 2 weeks before the start of study treatment, and participants must have recovered. -(A) Karnofsky Performance Status (KPS) ≥ 60. Further specific inclusion criteria for Phase 1 Arm B: (B) Participants must have a new histopathologically proven diagnosis of GBM, IDH wild-type, grade 4 (WHO 2021), which may include secondary GBM (i.e., progressing from a low-grade glioma) if previous treatment was surgery alone. The histologic diagnosis may be obtained from either brain biopsy or surgical resection. - (B) Initiation of study treatment is planned at least 2 weeks after diagnostic biopsy or within 3 to 7 weeks after maximal surgical resection (subtotal or gross total resection). (B) For participants who have undergone tumor resection, a postoperative brain MRI performed within 72 hours is recommended. Subsequent brain MRIs must be obtained within 10 days before the start of study treatment. - (B) For participants who have had only a diagnostic biopsy, a subsequent brain MRI must be obtained 10 days before the start of study treatment, unless the start of study treatment is within 28 days of the diagnostic brain MRI. -(B) KPS ≥ 70. Further specific inclusion criteria for Phase 2: - (Phase 2) Participants must have a histopathologically proven diagnosis of GBM, IDH wild-type, grade 4 (WHO2021). -(Phase 2) Prior first-line treatment with TMZ-based chemoradiotherapy (TMZ concurrent with RT), i.e., a maximum of one prior line of treatment. - (Phase 2) First disease recurrence or progression documented by diagnostic biopsy or Gd-enhanced brain MRI per RANO criteria. Subsequent brain MRI must be obtained within 10 days before the start of study treatment. -(Phase 2) KPS≧60. Exclusion criteria: For both Phase 1 (Arms A and B) and Phase 2, exclusion criteria include: - (Both) History of other malignancies requiring active treatment within the last 2 years prior to the first dose of study treatment, excluding superficial bladder cancer, low-risk prostate cancer adequately treated with active surveillance, ductal carcinoma in situ or other carcinoma in situ, and non-melanoma skin cancer (basal cell / squamous cell skin cancer) treated with curative intent. -(Both) Current use of investigational drugs. -(Both) Known contraindications to undergoing Gd-enhanced MRI. - (Both) Major surgery for other conditions within 4 weeks prior to the first dose of study treatment. - (Both) History of myocardial infarction or stroke within 6 months, congestive heart failure greater than New York Heart Association (NYHA) class II, unstable angina, unexplained recurrent syncope, cardiac arrhythmia requiring treatment, or known family history of sudden death from cardiac causes before age 50, or any cardiac toxicity experienced after previous chemotherapy. -(Both) LVEF less than 55%. (Both) Baseline QTcF interval >450 ms, history of congenital long QT syndrome, or clinically significant conduction abnormality, or any conduction abnormality that may increase the risk of TdP or QTc interval prolongation. - (Both) Concomitant use of medications with a known risk of QTc prolongation / TdP. If such medications are used by the participant, there must be a washout period of at least 5 half-lives of the drug prior to the first dose of study treatment. - (Both) Concomitant use of drugs or herbal products that are inhibitors or inducers of CYP3A4, strong inhibitors of CYP2D6, or other drugs (e.g., proton pump inhibitors, H2 receptor antagonists) listed in the Prohibited Substances section of the protocol (Section 6.3.3). If such drugs are used by the participant, there must be a washout period of at least 5 half-lives of the drug (4 weeks for irreversible CYP inhibitors and CYP inducers) before the first dose of study treatment. -(Both) Clinically significant gastrointestinal abnormalities affecting drug absorption (e.g., ulcer disease, gastrointestinal dysfunction, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, major small intestinal resection or total gastrectomy, or inflammatory bowel disease). - (Both) Any infection requiring the use of systemic antibiotics or antivirals within 1 week prior to the start of study treatment. - (Both) Immunization with live or live attenuated vaccines within 28 days prior to study inclusion. - (Both) Unable or unwilling to swallow oral medications. - (Both) Exposure to high levels of UV light, e.g., occupational exposure to sunlight or sunbathing. - (Both) chemotherapy, monoclonal antibody / biologic, investigational treatment, or RT with curative intent within 28 days prior to starting study treatment - (Both) Unresolved AE or toxicity from prior treatment > Grade 1, excluding hemoglobin (≥ 9 g / dL or 5.6 mmol / L). Note: Participants with Grade ≤ 2 alopecia or endocrinopathy (e.g., hypothyroidism due to immune checkpoint inhibitors) controlled by replacement therapy are exceptions and may be eligible for the study. -(Both) Hypersensitivity to the study drug, TMZ, dacarbazine, or any of the excipients found in the formulation for the study drug or TMZ. -(Both) Known history of infection with human immunodeficiency virus (HIV) or positive HIV 1 / 2 serology at screening. - (Both) Known active HCV or HBV infection or positive serology at screening, defined as: HBV screening tests: both HBV sAg and anti-HepB core IgG. NOTE: Participants with a positive anti-HepB core IgG and a negative HBsAg test must have a negative HBV DNA test. HCV screening test: both HCV antibodies by polymerase chain reaction (PCR) and positive viral load HCV ribonucleic acid (RNA) -(Both) Presence of extracranial metastases, leptomeningeal disease, infratentorial components, or primary spinal tumor. - (Both) Evidence of intracranial or intratumoral hemorrhage by brain MRI. Participants with resolved postoperative changes, petechiae, or hemosiderin are eligible. - Participants with (both) clinical or radiological signs of hernia. -(Both) Prior exposure to any WEE1 inhibitor. Specific exclusion criteria for Phase 1 Arm A: - (A) Prior treatment with more than two lines of therapy for GBM, IDH wild-type, grade 4, or astrocytoma, IDH-mutant, grade 3. Note: Only one prior line of systemic therapy is permitted; combination therapy with TMZ and RT with or without subsequent TMZ maintenance therapy is considered one line. Prior surgery, radiation, or local delivery of a therapeutic agent (i.e., carmustine-containing wafers [GLIADEL®]) for first recurrence is permitted. (A) Prior treatment with bevacizumab or other VEGF inhibitors or VEGF receptor signaling inhibitors. -(A) Previous TMZ-related hematologic event leading to discontinuation of TMZ during concurrent chemoradiotherapy. Specific exclusion criteria for Phase 1 Arm B: - (B) For GBM, prior radiation, chemotherapy, biotherapy, interstitial brachytherapy, implant chemotherapy, therapeutic agents delivered by local injection or convection-enhanced delivery. -(B) Prior treatment that would result in overlap of radiation fields. Specific exclusion criteria for Phase 2: -(Phase 2) Prior treatment with ≥2 lines of systemic therapy for GBM, IDH wild-type, grade 4. Combination therapy with TMZ and RT, with or without subsequent TMZ maintenance therapy, is considered 1 line -(Phase 2) Prior treatment with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor signaling inhibitors. - (Phase 2) Previous TMZ-related hematologic event leading to discontinuation of TMZ during concurrent chemoradiation therapy.

[0131] The investigational drugs used in this clinical trial are as follows: The study drug will be formulated as 20, 30, 60, 100, 130, and 150 mg hard gelatin capsules containing 10 mg mini-tablets (excipients: microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, sodium starch glycolate, anhydrous colloidal silica, and magnesium stearate). Intermediate capsule strengths can be produced to cover alternative dose levels. Study medication will be taken orally on an empty stomach (i.e., participants must be fasted [only water is allowed] for at least 4 hours prior to ingestion and 2 hours after ingestion). Concurrent RT for Phase 1 Arm B will be delivered using intensity-modulated radiation therapy (IMRT) or three-dimensional (3D) conformal radiation (conventional fractionation regimen, 2 Gy per fraction per day, 5 consecutive days per week, total dose of 60 Gy over 30 fractions) for 6 weeks. RT will be administered approximately 1 hour after TMZ ingestion. TMZ is formulated as 5, 20, 100, 140, 180, and 250 mg capsules to be administered orally.

[0132] In Phase 1 (Group A), participants received TMZ (150 mg / m ) once daily on days 1–5 of a 28-day cycle. 2 / day) orally. TMZ will be administered approximately 1 hour after the study drug. In Phase 1 (Group B), TMZ (75 mg / m) was administered approximately 30 minutes to 1 hour after administration of the study drug. 2 / day) will be administered orally once daily for 6 weeks, concomitantly with RT (only the first 5 days of each week). In Phase 2, participants in the experimental group received oral administration of the study drug at RP2D on D1-5, D8-10, and D15-17, and TMZ (150 mg / m ) on D1-5, once daily in a 28-day cycle, as follows: 2 / day). TMZ will be administered approximately 1 hour after the study drug.

[0133] Treatment duration Phase 1 (dose escalation): Participants in Arm A will be treated for up to two years or until disease progression, unacceptable toxicity, participant withdrawal, investigator-determined discontinuation, subsequent antineoplastic treatment, study termination, or death, whichever occurs first. For Arm B, participants will be considered to have completed the study treatment period if they receive the study drug daily for six weeks (42 days) in combination with TMZ and RT. Following a four- to six-week break after the end of study treatment, it is up to the investigator's discretion to initiate five-day (D1-D5) maintenance treatments with TMZ, repeated every 28 days, with or without the addition of alternating current electric fields (TTFields Optune®) administered by SOC. TMZ maintenance treatment will follow the study treatment period. Phase 2 : Phase 2 participants will be treated for up to two years or until disease progression, unacceptable toxicity, participant withdrawal, investigator-determined withdrawal, study termination, or death, whichever occurs first. It is estimated that up to 89 evaluable participants will be enrolled in this study. Figures 8, 9 and 10 provide study diagrams showing Phase 1 Arm A, Phase 1 Arm B and Phase 2 experimental arms, respectively. In these figures, the following abbreviations are used: AE = adverse event; C = cycle; D = day; DLT = dose-limiting toxicity study; EOS = end of study; EOT = end of treatment; mRANO = modified Response Evaluation in Neuro-Oncology; PO = oral; RANO = Response Evaluation in Neuro-Oncology; SAE = serious adverse event; SFU = safety follow-up; TMZ = temozolomide; TTFields = tumor treating fields; W = week. Specificities of Phase 1 Arm A (Figure 8): EOT: 20 days after the last dose of study treatment. SFU: After safety follow-up, all SAEs (regardless of causality assessment) and non-serious AEs considered related to study treatment, as assessed by the investigator, will be collected until the participant's EOS. 1 Subsequent cycles will be for a maximum of 2 years or until disease progression documented by RANO and confirmed by mRANO, unacceptable toxicity, participant withdrawal, investigator decision to discontinue, subsequent antineoplastic treatment, study termination, or death, whichever occurs first. One cycle is defined as 28 days. Specificities of Phase 1 Arm B (Figure 9): EOT: 20 days after the last dose of study treatment. SFU: After safety follow-up, all SAEs (regardless of causality assessment) and non-serious AEs considered related to study treatment, as assessed by the investigator, will be collected until the participant's EOS. After completion of study treatment and a 4-6 week rest period, maintenance therapy with TMZ for 5 days (D 1-5) repeated every 28 days, with or without the addition of alternating Electrical Tumor Treating Fields (TTFields Optune®) therapy, can be administered at the investigator's discretion according to standard of care. Specificity of Phase 2 experimental groups (Figure 10): EOT: 20 days after the last dose of study treatment. SFU: After safety follow-up, all SAEs (regardless of causality assessment) and non-serious AEs considered related to study treatment, as assessed by the investigator, will be collected until the participant's EOS. 1 Subsequent cycles will be for a maximum of 2 years or until disease progression documented by RANO and confirmed by mRANO, unacceptable toxicity, participant withdrawal, investigator decision to discontinue, subsequent antineoplastic treatment, study termination, or death, whichever occurs first. One cycle is defined as 28 days. [Example]

[0134] Phase 1 / 2 clinical trials involving a compound of formula (I) (referred to herein as the investigational drug) A clinical trial was conducted as described above in Example 9, which is a Phase 1 / 2 multicenter, open-label, non-randomized controlled trial in adult participants with glioma, with a new Phase 1 Arm C (dose escalation) as follows: The study population for Group C was adult participants with a confirmed diagnosis of newly diagnosed GBM IDH wild-type, grade 4 (WHO 2021). Participants received a continuous daily dose of TMZ (75 mg / m) for 6 weeks with concurrent administration of radiation therapy (RT; conventional fractionation regimen of 2 Gy per fraction daily, 5 consecutive days per week, for a total dose of 60 Gy over 30 fractions). 2 / day, orally, once daily). Participants will also receive oral once-daily ascending doses of study medication for 6 weeks on a schedule chosen from the following options: Study drug (escalating doses) on days (D) 1-3 of each week; or • Study medication (escalating doses) on days 1-5 of each week (D). The starting dose of the study drug is based on available data from dose levels determined to be safe in ongoing Phase 1 studies, i.e., Study 101, which includes the study drug in combination with carboplatin, and Study 102, which includes the study drug in monotherapy, and preliminary data from the study described in Example 9. Such starting doses may be 60 mg or 90 mg, with dose reductions down to 30 mg being considered if necessary. If unacceptable toxicity is observed on the above study drug schedule for Group C, one or more drug holidays (1 week each) for study drug alone may be introduced into the 6-week schedule. After a 4-6 week rest period following the end of study treatment, maintenance therapy with TMZ for 5 days (D1-D5) repeated every 28 days, with or without the addition of alternating Electrical Tumor Treating Fields (TTFields Optune®) therapy, can be administered at the investigator's discretion according to standard of care (SOC). [Example]

[0135] The compound represented by formula (I) (test drug) is present in CSF, and is shown to effectively cross the blood-brain barrier and be distributed in the brain in patients with glioma. In the clinical trial described in Example 9, cerebrospinal fluid (CSF) stabilized with 0.5% formic acid and corresponding plasma samples collected on K2 EDTA were obtained from three patients in Arm A on Day 11 of Cycle 1 (i.e., two patients on 150 mg study drug and one patient on 200 mg study drug) and one patient in Arm B on Day 1 of Week 3 (i.e., Day 15 after daily dosing with 90 mg study drug). Test drug (parent, active moiety) and its active metabolite N 32 -desmethyl-test drug was measured using an LC-MS / MS method. Results are provided in ng per mL of plasma or CSF and then analyzed using the study drug (511.45 g / mol) and N 32 -desmethyl- was converted to nmol / L using the molecular weight of the study drug (497.42 g / mol). In plasma, the active metabolites accounted for approximately 10% of the parent drug, and both compounds were moderately bound to plasma proteins: 91.7% for the parent drug and N 32 -desmethyl-test drug: 87.1%. Therefore, the test drug and N 32 The unbound (or free) fraction of desmethyl-test drug is calculated. In CSF, the total protein concentration varies between 0.2% and 0.5% of the total protein concentration in blood (H. Reiber, Clinica Chimica Acta, 2001; Schilde LM et al., PLoS ONE, 2018), and therefore, the concentrations measured in CSF essentially correspond to the free fraction of the compound. For each of the four patients, the CSF / plasma ratio of a given compound (test drug parent or metabolite) was calculated using the CSF concentration of the compound (nmol / L) and the unbound or free fraction of the compound in plasma (nmol / L). The raw data and results are shown in Tables 5 and 6. Table 5

[0136] [Table 8] Table 6

[0137] [Table 9] The total active moiety (test drug and N 32 The CSF / plasma ratio for the 100 mg / mL -desmethyl-test drug) was approximately 1 / 3, demonstrating relatively high levels in the CSF and therefore good drug penetration in the patient's brain. N 32 The CSF / plasma ratio for the -desmethyl-test drug concentrations was approximately 5%, whereas the ratio for the parent drug was 33-42%, indicating a particularly high propensity for brain penetration of the test drug.

Claims

1. 2. A compound of formula (I) below for use in the treatment of glioma in a patient in need thereof: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof.

2. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with temozolomide (TMZ) and / or radiation therapy.

3. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the glioma is glioblastoma, astrocytoma, or oligodendroglioma.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the glioma is a high-grade glioma (grade 3 or 4).

5. The compound of formula (I) is administered on an intermittent schedule or in one of the following (i) to (vi): (i) days 1-5, 8-10, and 15-17 of a 28-day cycle; (ii) days 1-5, 8-12, and 15-19 of a 28-day cycle; (iii) days 1-5, 8-12, 15-19, and 22-26 of a 28-day cycle; (iv) days 1 to 3 of each week for 6 or 7 weeks; (v) Days 1 to 5 of each week for 6 or 7 weeks; or (vi) days 1 to 4 of each week for 6 or 7 weeks; or a continuous schedule, or the following: (vii) daily for 6 weeks, daily for 7 weeks, or daily for 42-49 days; 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is orally administered in an amount of 100 mg / kg or more.

6. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, administered over 1, 2, 3, 4, 5, 6 or more 28 day cycles.

7. The compound of formula (I) (i) at a dose ranging from about 30 to about 1000 mg per treatment day or from about 30 to about 720 mg per treatment day; and / or (ii) as a single dose on the day of treatment, and / or (iii) at approximately the same time on each treatment day 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is administered to a patient in need thereof.

8. The compound of formula (I) is used in combination with temozolomide, wherein temozolomide is: (i) 50 to 300 mg / m on days 1 to 5 of a 28-day cycle ２ / day, 50-250mg / m ２ / day or 50-200 mg / m ２ / day dose; (ii) 150 mg / m on days 1 to 5 of a 28-day cycle ２ / day dose; (iii) 200 mg / m on days 1 to 5 of a 28-day cycle ２ / day dose; (iv) 50 to 300 mg / m daily for 6 weeks, 7 weeks, or 42 to 49 days ２ / day, 50-250mg / m ２ / day, or 50-200 mg / m ２ / day dose, or (v) 75 mg / m daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days ２ / day dose, 8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, which is administered.

9. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein when the compound of formula (I) is used in combination with temozolomide and temozolomide is administered on a WEE1 inhibitor treatment day, the compound of formula (I) is optionally administered about 30 minutes to 4 hours before administration of temozolomide.

10. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein when the compound of formula (I) is used in combination with temozolomide and temozolomide is administered on a WEE1 inhibitor treatment day, temozolomide is administered simultaneously with administration of the compound of formula (I).

11. 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, in combination with temozolomide and radiation therapy.

12. Administered according to any one of (iv), (v), (vi) or (vii) of claim 5, wherein temozolomide is administered at a dose of 50 to 300 mg / m ２ / day or 75 mg / m ２ 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, administered at a dose of 100 mg / day daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days.

13. The radiation therapy is fractionated, and (i) a regimen of 1 Gy to 100 Gy, 2 Gy to 80 Gy, 10 Gy to 60 Gy, or 60 Gy, fractionated over 5 consecutive days per week until the total radiation dose is administered, or in equal proportions over a period of 6 weeks, 7 weeks, or 42 to 49 days; (ii) a total dose of 60 Gy, given on a regimen of 2 Gy per fraction per day, 5 consecutive days per week; or (iii) a total dose of 60 Gy over 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days; 13. The compound of claim 11 or 12, or a pharmaceutically acceptable salt thereof, for administration.

14. 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in treating newly diagnosed glioma, wherein the compound is as defined in (iv), (v), (vi) or (vii) of claim 5, embodiment (iv) or (v) of claim 8, or any one of claims 11 to 13.

15. 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in treating glioma that has progressed or recurred after initial or previous glioma treatment, wherein the compound is used as defined in any one of (i) to (iii) of claim 5, claim 6 or embodiment (i), (ii) or (iii) of claim 8.

16. 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein the initial or previous treatment for glioma comprises administering radiation therapy.

17. 17. The compound or pharmaceutically acceptable salt thereof of claim 15 or 16, wherein the treatment of the initial or previous glioma comprises the administration of radiation therapy.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein the glioma is glioblastoma.

19. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein the glioma is (IDH) wild-type according to WHO 2021.

20. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein the glioma is astrocytoma.

21. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein the glioma is an IDH mutant according to WHO2021.

Images