DEBIO-0123 in combination with temozolomide and radiotherapy for treatment of glioma

Abstract

Methods of treating glioma using a WEE1 inhibitor are disclosed.

Description

Technical Field

[0001] The present invention generally relates to the treatment of gliomas. More particularly, the present invention relates to the use of specific WEE1 inhibitors for the treatment of gliomas in patients in need thereof. Background Art

[0002] It is estimated that in 2020, more than 300,000 people worldwide were diagnosed with primary brain tumors. Brain tumors account for 85% to 90% of all primary central nervous system (CNS) tumors. According to the World Health Organization 2021 classification (WHO 2021), CNS tumors include many categories, including those called "gliomas, glioneuronal tumors, and neuronal tumors." These tumors can be further classified by subtype and grade, for example, based on an integrated histological and molecular grade, from 3 to 4, with grade 4 being the most aggressive.

[0003] High-grade diffuse gliomas (also called high-grade gliomas) account for more than half of malignant primary brain tumors. Approximately 60% to 70% of all malignant gliomas are glioblastomas (GBM). GBM is the most common malignant primary brain tumor in adults and represents the leading cause of morbidity and mortality. Primary GBM accounts for approximately 90% of all GBMs. Compared to primary GBM (95% of which is associated with isocitrate dehydrogenase (IDH) wild-type status), IDH1 gene mutations are common in secondary GBMs and tumors previously called anaplastic astrocytomas, which are now classified as astrocytoma IDH-mutant grade 3 tumors according to the WHO 2021 classification. Within these grades, the presence of IDH mutations generally identifies a group of tumors with a better prognosis than their IDH wild-type counterparts.

[0004] Following surgical resection, the generally accepted standard of care (SOC) for patients with newly diagnosed GBM who are in good general condition consists of radiation therapy (RT) and concurrent temozolomide (TMZ), usually followed by maintenance TMZ (Stupp R, et al. 2005. 'Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma', New England Journal of Medicine, 352(10):987-96).

[0005] For newly diagnosed high-grade gliomas, additional FDA-approved treatment options have been included: direct intracranial administration of chemotherapy using biodegradable carmustine-impregnated wafers as an adjunct to surgery, and the addition of alternating electrical tumor treating field (TTField) therapy during maintenance TMZ treatment (Stupp R, et al. 2017. 'Effect of tumor-treating fields plus maintenance temozolomidevs. maintenance temozolomide alone on survival in patients with glioblastoma: arandomized clinical trial', JAMA, 318: 2306-16). Unfortunately, the addition of immunotherapy or systemic targeted therapy, including bevacizumab, to the SOC of patients with newly diagnosed high-grade gliomas has not been shown to improve overall survival (OS). Despite additional treatment, the prognosis for patients with newly diagnosed high-grade gliomas remains poor. Almost all relapses occur 6 to 9 months after first-line treatment, and the 5-year OS is less than 10%.

[0006] The management of recurrent GBM has also been challenging. There is no established second-line treatment, and effective treatment options are limited. Treatment may include repeated nerve surgical resection, repeated irradiation, TTField, chemotherapy with local delivery of biodegradable carmustine-impregnated wafers, bevacizumab, systemic cytotoxic chemotherapy (such as re-exposure to TMZ, treatment with nitrosoureas, or a combination of carboplatin and etoposide), and supportive care. However, their effectiveness remains limited, with response rates ≤15%, 6-month progression-free survival (PFS-6) rates typically ranging from 9% to 21%, and median OS ≤30 weeks.

[0007] For example, bevacizumab has been an FDA-approved treatment option for recurrent GBM since 2009 (see, for example, Friedman HS, et al. 2009. 'Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma ', J Clin Oncol, 27: 4733-40). However, bevacizumab prolongs PFS in patients with recurrent GBM, but does not prolong OS. More generally, in patients experiencing recurrence, no clinical trials have shown that second-line systemic therapy improves OS (the second-line systemic therapy includes targeted therapy or immunotherapy, see, for example, Lombardi et al. 2020. 'A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma? ', Cancers, 12: 3775).

[0008] Given the poor outcomes of current treatments, there is an urgent unmet medical need to develop new therapeutic interventions to improve clinical outcomes and / or quality of life (QoL) in patients with newly diagnosed or recurrent gliomas, and particularly in patients with high-grade gliomas. Summary of the Invention

[0009] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0010]

[0011] For use in treating glioma in a patient in need thereof or for use in preparing a medicament for treating glioma in a patient in need thereof.

[0012] The present invention also relates to methods for treating glioma in a patient in need thereof using a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In some aspects of the uses or methods according to the invention, the compound of formula (I) is used in combination with temozolomide (TMZ) and / or radiotherapy.The compound of formula (I) may also be used in combination with both temozolomide and radiotherapy.

[0014] In some aspects of the uses or methods according to the invention, the glioma is a glioblastoma, an astrocytoma or an oligodendroglioma.

[0015] In some aspects of the uses or methods according to the invention, the glioma is a high-grade glioma (grade 3 or 4).

[0016] In some aspects of the uses or methods according to the invention, the compound of formula (I) is administered orally as follows,

[0017] Intermittent schedule, preferably selected from any one of (i) to (vi):

[0018] i. On days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle,

[0019] ii. on days 1 to 5, 8 to 12, and 15 to 19 of a 28-day cycle,

[0020] iii. on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle,

[0021] iv. on days 1 to 3 of each week for 6 or 7 weeks or 42 to 49 days,

[0022] v. On days 1 through 5 of each week for 6 or 7 weeks or 42 through 49 days, or

[0023] vi. On days 1 to 4 of each week for 6 or 7 weeks or 42 to 49 days, or a continuous schedule, preferably

[0024] vii. Daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days.

[0025] When the glioma has progressed or recurred after initial or previous glioma treatment, it may be preferably administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle, on days 1 to 5, 8 to 12, and 15 to 19 of a 28-day cycle, or on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. If the glioma is newly diagnosed, it may be preferably administered on days 1 to 3 of each week for 6 or 7 weeks or 42 to 49 days; on days 1 to 5 of each week for 6 or 7 weeks or 42 to 49 days; on days 1 to 4 of each week for 6 or 7 weeks or 42 to 49 days; or daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days.

[0026] In some aspects of the use or method according to the invention, the compound of formula (I) is administered in 1, 2, 3, 4, 5, 6 or more 28-day cycles. Generally speaking, there is no break between any consecutive cycles, i.e. the day following the previous 28-day cycle can be the first day of the consecutive cycle.

[0027] In some aspects of the uses or methods according to the invention, the compound of formula (I) is administered as:

[0028] i. a dosage range of about 30 to about 1000 mg / treatment day, preferably about 30 to about 720 mg / treatment day, and in some embodiments more preferably about 90 to about 720 mg / treatment day or about 150 to about 720 mg / treatment day, and / or

[0029] ii. a single dose on treatment day, and / or

[0030] iii. At approximately the same time on each treatment day, eg, the same time ± about 60 minutes, preferably ± 60 minutes.

[0031] In some aspects of the uses or methods according to the invention, the compound of formula (I) is used in combination with temozolomide, and temozolomide is administered as follows:

[0032] i. On days 1 to 5 of a 28-day cycle, the dose is 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably the dose is 50 to 200 mg / m 2 / sky,

[0033] ii. 150 mg / m2 on days 1 to 5 of a 28-day cycle 2 / sky,

[0034] iii. 200 mg / m2 on days 1 to 5 of a 28-day cycle 2 / sky,

[0035] iv. Dosage ranges from 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days, or

[0036] v.Dose is 75mg / m 2 / day, daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days.

[0037] When the glioma has progressed or recurred after initial or previous glioma treatment, TMZ may be preferably administered on day 1 to day 5 of a 28-day cycle, preferably 1 or 2 prior lines of treatment, typically including temozolomide (TMZ)-based chemoradiation therapy as first-line treatment. If the glioma is newly diagnosed, TMZ may be preferably administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days.

[0038] In some aspects of the uses or methods according to the invention, the compound of formula (I) is used in combination with temozolomide and, on a WEE1 inhibitor treatment day, if temozolomide is administered on said WEE1 inhibitor treatment day, the administration of the compound of formula (I) is carried out before the administration of temozolomide, optionally by a period of about 30 minutes to 4 hours before.

[0039] In some aspects of the uses or methods according to the invention, the compound of formula (I) is used in combination with temozolomide, and on WEE1 inhibitor treatment days, if temozolomide is administered on said WEE1 inhibitor treatment days, the administration of temozolomide is concomitant with the administration of the compound of formula (I).

[0040] In some aspects of the use or method according to the present invention, the compound of formula (I) is used in combination with temozolomide and radiotherapy. Preferably, the compound of formula (I) is used in combination with temozolomide and radiotherapy for the treatment of newly diagnosed gliomas.

[0041] In some aspects of the use or method 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 50 to 300 mg / m 2 / day, preferably 75mg / m 2The dose of 1 mg / day is administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days. Preferably, the schedule is for the treatment of newly diagnosed gliomas.

[0042] In some aspects of the uses or methods according to the invention, the compound of formula (I) is administered as:

[0043] i. on days 1 to 3 of each week for 6 or 7 weeks or 42 to 49 days,

[0044] ii. on days 1 to 5 of each week for 6 or 7 weeks or 42 to 49 days,

[0045] iii. on days 1 to 4 of each week for 6 or 7 weeks or 42 to 49 days, or

[0046] iv. Daily for 6 or 7 weeks or 42 to 49 days

[0047] Temozolomide is administered at a dose of 50 to 300 mg / m 2 / day, preferably 75 mg / m 2 The regimen is for the treatment of newly diagnosed gliomas.

[0048] In some aspects of the uses or methods according to the invention, the radiotherapy is fractionated radiotherapy and is administered as:

[0049] i. a regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided into 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks or 42 to 49 days,

[0050] ii. a regimen of 2 Gy per day, 5 consecutive days per week, for a total of 60 Gy, or

[0051] iii. 60 Gy total dose in 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days.

[0052] In some aspects of the uses or methods according to the present invention, the glioma is newly diagnosed. In these aspects, the compound of formula (I) is preferably administered orally as follows:

[0053] i. on days 1 to 3 of each week for 6 or 7 weeks or 42 to 49 days,

[0054] ii. on days 1 to 5 of each week for 6 or 7 weeks or 42 to 49 days,

[0055] iii. on days 1 to 4 of each week for 6 or 7 weeks or 42 to 49 days, or

[0056] iv. daily for 6 or 7 weeks or 42 to 49 days, and / or the compound of formula (I) is preferably used in combination with temozolomide, and temozolomide is administered as follows:

[0057] i. Dosage ranges from 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days, or

[0058] ii. Dose of 75 mg / m 2 / day, daily administration for 6 weeks, daily administration for 7 weeks or daily administration for 42 to 49 days, and / or

[0059] The compound of formula (I) is preferably used in combination with temozolomide and radiotherapy, optionally wherein the compound of formula (I) is administered as described above and wherein temozolomide is administered at a dose of 50 to 300 mg / m 2 / day, preferably 75 mg / m 2 1-2 weeks, daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days; and / or optionally, wherein the radiation therapy is fractionated radiation therapy and is administered as follows:

[0060] i. a regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days,

[0061] ii. a regimen of 2 Gy per day, 5 consecutive days per week, for a total of 60 Gy, or

[0062] iii. 60 Gy total dose in 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days.

[0063] In some aspects of the uses or methods according to the invention, the glioma has progressed or recurred after initial or previous glioma treatment. In these aspects, the compound of formula (I) is preferably administered orally as follows:

[0064] i. On days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle,

[0065] ii. on Days 1 to 5, Days 8 to 12, and Days 15 to 19 of a 28-day cycle, or

[0066] iii. on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle,

[0067] wherein the compound of formula (I) can be administered in 1, 2, 3, 4, 5, 6 or more 28-day cycles; and / or the compound of formula (I) is used in combination with temozolomide, and temozolomide is administered as follows:

[0068] i. On days 1 to 5 of a 28-day cycle, the dose is 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably the dose is 50 to 200 mg / m 2 / sky,

[0069] ii. 150 mg / m2 on days 1 to 5 of a 28-day cycle 2 / day, or

[0070] iii. 200 mg / m2 on days 1 to 5 of a 28-day cycle 2 / sky.

[0071] In some aspects of the uses or methods according to the invention, the initial or previous glioma treatment comprises radiotherapy administration and / or TMZ administration.

[0072] In some aspects of the uses or methods according to the invention, the glioma is a glioblastoma.

[0073] In some aspects of the uses or methods according to the invention, the glioma is (IDH)-wild type according to WHO 2021.

[0074] In some aspects of the uses or methods according to the invention, the glioma is an astrocytoma.

[0075] In some aspects of the uses or methods according to the invention, the glioma is IDH mutant according to WHO 2021. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 A graph showing that the compound of formula (I) ( Figure 1 (A)), 30 mg / kg bid AZD1775 ( Figure 1 (B)) and 80 mg / kg qd of Zn-c3 ( Figure 1 (C)) Plasma and brain concentrations in healthy mice measured on day 4 after RT-PCR, as described in Example 1.

[0077] Figure 2 is a graph showing the total plasma concentration, total brain concentration, unbound CSF concentration and calculated unbound plasma concentration of the compound of Formula (I) over time following a single dose administration of 15 mg / kg of the compound of Formula (I) in healthy rats, as described in Example 2.

[0078] Figure 3 A diagram showing the following is shown: In T98G ( Figure 3 A), LN18( Figure 3 B) SNB-19( Figure 3 C) and U251( Figure 3 D) In ​​vitro efficacy of different doses of the compound of formula (I) [CoF(I)] in combination with radiotherapy (RT) in GBM cell lines, as described in Example 4.

[0079] Figure 4 Shown is a graph showing the in vivo efficacy of the compound of formula (I) [CoF(I)] as a monotherapy in mice implanted subcutaneously with the U87-MG-luc GBM cell line and treated with 30 mg / kg or 60 mg / kg of the compound of formula (I) ( Figure 4 A, tumor volume), or were implanted into the brain of mice and treated with 30 mg / kg of the compound of formula (I) ( Figure 4 B, relative BLI), as described in Example 5.

[0080] Figure 5 is a graph showing the in vivo efficacy of the compound of formula (I) [CoF(I)] in combination with TMZ in mice implanted intracranially with the U87-MG-luc GBM cell line as described in Example 6, showing relative BLI curves at doses of 3 mg / kg TMZ, 10 mg / kg CoF(I), and a combination of 3 mg / kg TMZ + 10 mg / kg CoF(I).

[0081] Figure 6 is a graph showing the survival probability of mice bearing GL261 intracranial tumors when treated with TMZ (3 mg / kg) as monotherapy, compound of formula (I) (30 mg / kg) [CoF(I)] as monotherapy, or a combination of both, as described in Example 7.

[0082] Figure 7The in vitro efficacy of the compound of formula (I) as a monotherapy in the ATRX-deficient SF188 GBM cell line is shown as described in Example 8: Cell viability assay ( Figure 7 A and 7B) and colony formation assay ( Figure 7 C).

[0083] Figure 8 is a graph of the Phase 1 arm (Arm) A clinical study as described in Example 9.

[0084] Figure 9 is a graph of the Phase 1 Group B clinical study as described in Example 9.

[0085] Figure 10 This is a clinical study diagram of the Phase 2 experimental group as described in Example 9. DETAILED DESCRIPTION

[0086] The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating glioma in a patient in need thereof. The compound of formula (I) is a WEE1 inhibitor. In some embodiments, an N-oxide or N-oxide derivative of the compound of formula (I) may be used.

[0087] In healthy mice, rats, and monkeys, the compound of formula (I) has been found to exhibit good ability to cross the blood-brain barrier. Furthermore, in a mouse GBM xenograft model, the compound of formula (I) has been found to exhibit antitumor activity and good tolerability as a single agent or in combination with TMZ. Furthermore, the compound of formula (I) has been found to exhibit radiosensitization effects on various cell lines, including GBM cell lines.

[0088] definition

[0089] In order to make the present invention more easily understood, certain terms are specifically defined below. Unless explicitly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the relevant art.

[0090] As used herein, including in the appended claims, singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0091] It should be understood that wherever herein the language "comprising" is used to describe an embodiment, similar embodiments are also provided in other instances described in terms of "consisting of" and / or "consisting essentially of."

[0092] As used herein, the term "and / or" in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" and "B." Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; 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).

[0093] As used herein, "WEE1 inhibitor" refers to a compound that inhibits WEE1 kinase activity, for example with an IC50 < 10 nm in an ADP-GLO kinase assay or an IC50 < 100 nm in a zymography assay. The compound of formula (I) herein is an example of a WEE1 inhibitor.

[0094] In some respects, " brain penetration " WEE1 inhibitor refers to the WEE1 inhibitor that can pass through the blood-brain barrier (no matter whether damaged) and be distributed to the brain. In some respects, the ability that compound passes through the blood-brain barrier and is distributed to the brain is reflected by the brain concentration of compound and plasma concentration ratio exceeding a certain threshold value. For example, compared with AZD1775 and Zn-c3, formula (I) compound can show better ability of passing through the blood-brain barrier and being distributed to the brain, as demonstrated by its higher brain concentration and plasma concentration ratio. Therefore, formula (I) compound can be referred to as brain penetration WEE1 inhibitor.

[0095] When referring to a compound of formula (I), the expression "pharmaceutically acceptable salt" as used herein refers to a salt prepared from a pharmaceutically acceptable non-toxic acid, including an inorganic acid or an organic acid. For example, acceptable salts derived from an acid, such as a quaternary salt, acetate, carbonate, carbamate, sulfonate, strong inorganic acid, etc., are included. Typically, a pharmaceutically acceptable salt can be used to alter the solubility or hydrolysis characteristics of a compound, or to be used in a sustained release formulation. It should be understood that, unless otherwise indicated, references to a compound of formula (I) as used herein are also intended to include pharmaceutically acceptable salts.

[0096] As used herein, the term "subject" refers to any animal (e.g., mammal) that is to be the recipient of a particular treatment, including but not limited to humans, non-human primates, rodents, etc. Generally speaking, the terms "subject" and "patient" are used interchangeably herein when referring to a human subject.

[0097] As used herein, administration "in combination with" one or more additional therapeutic agents includes simultaneous (concurrent) and sequential (separate) administration in any order.

[0098] As used herein, terms such as "treat" and variations thereof or "alleviate" and variations thereof refer to therapeutic measures that cure, alleviate, lessen the symptoms of, and / or halt or reverse the progression or severity of a diagnosed pathological condition, disorder, or disease. Thus, those in need of treatment include those already diagnosed with or suspected of having the condition. In certain embodiments, a subject's cancer is successfully "treated" according to the methods of the present invention if the patient exhibits one or more of the following: a decrease in the number of cancer cells or the complete absence of cancer cells; a decrease in tumor size or burden; inhibition or absence of cancer cell infiltration into peripheral organs; inhibition or absence of tumor metastasis; inhibition or absence of tumor growth; relief of one or more symptoms associated with a particular cancer; a reduction in corticosteroid dosage requirements; reduced morbidity and mortality; improved quality of life; a decrease in the tumorigenicity, tumorigenic frequency, or tumorigenic capacity of the tumor; a decrease in the number or frequency of cancer stem cells in the tumor; differentiation of tumorigenic cells to a non-tumorigenic state; and an increased chance of having an overall response (OR), including a complete response (CR) or a partial response (PR), an increased chance of having disease under control (e.g., CR, PR, stable disease (SD)) to survive longer without progression and an increased chance of living disease-free and thus longer, a reduced risk of having progressive disease (PD) and an increased time until progression. In general, for a group or population of patients, successful treatment can result in an endpoint, such as improved Overall Response Rate (ORR), Best Overall Response (BOR), Duration of Response (DOR), Disease Control Rate (DCR), progression-free survival (PFS), overall survival (OS), time to progression (TTP), or any combination thereof.

[0099] The term "glioma" as used herein refers to a class of primary brain tumors derived from glial cells. It includes, for example, glioblastoma, astrocytoma and oligodendroglioma. For example, glioma can be classified according to the 5th edition of the World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification 2021 (hereinafter referred to as WHO 2021) (Louis DN, et al. 2021. 'The 2021WHO Classification of Tumors of the Central Nervous System: Asummary ', Neuro Oncol, 23: 1231-51). In some embodiments, WHO classification may develop in the future, and (one or more) new versions may be issued and considered.

[0100] In some aspects, when referring to gliomas, WHO 2021 refers to the integrated histological and molecular grade of tumors. Grades 1 and 2 are generally considered "low grade", while grades 3 and 4 are generally considered "high grade".

[0101] As used herein, the term "glioma treatment" refers to any treatment or therapy for treating a glioma that is approved by at least one health authority, such as the FDA or EMA, or is under investigation in a clinical trial. "Initial glioma treatment" refers to the first glioma treatment for a given patient diagnosed with a glioma, including but not limited to surgical resection, radiation therapy (RT), and / or temozolomide (TMZ). "Prior" or "previous glioma treatment" refers to one or more glioma treatments for a given patient diagnosed with a glioma prior to the methods of the present invention.

[0102] According to WHO 2021, the terms "glioblastoma," "glioblastoma multiforme," or "GBM" used in this article may refer to isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic grade 4 tumors.

[0103] As used herein, the term "diffuse glioma" is used to encompass a variety of poorly marginated, central nervous system infiltrating tumors that histologically resemble glial cells, particularly astrocytes and oligodendrocytes. These range in biological behavior from very indolent to extremely aggressive, and this is reflected in the grading, which ranges from grade 1 to grade 4. For clarity, the term diffuse glioma does not include circumscribed astrocytic tumors.

[0104] The term "astrocytoma" as used herein may refer to an IDH-mutant glioma. For example, according to WHO 2021, IDH-mutant astrocytomas are divided 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 previous term "glioblastoma, IDH-mutant, WHO grade 4").

[0105] In some aspects, when referring to gliomas, the term "ATRX deficiency" or "ATRX deficiency" means that there is an alteration in the alpha-thalassemia / mental retardation syndrome X-linked (ATRX) gene in gliomas, such as a nonsense mutation or a frameshift mutation, resulting in protein truncation and / or reduced or lost protein expression (usually as a result of 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 blotting for protein levels, and / or by measuring mRNA expression levels using whole transcriptome sequencing or microarray technology.

[0106] In some aspects, when referring to glioma, "isocitrate dehydrogenase (IDH) status" or "IDH status" or "IDH mutation status" refers to whether the isocitrate dehydrogenase enzyme (IDH) gene in the glioma contains a mutation. In humans, the IDH1, IDH2 and IDH3 genes express three subtypes of the IDH enzyme, all of which have important functions in metabolic reactions. IDH1 is present in the cytoplasm and peroxisomes, while IDH2 and IDH3 are present in the mitochondrial matrix. The mutations observed in the IDH enzyme in glioma are mainly in cytoplasmic IDH1 and mitochondrial IDH2, most commonly at codons R132 and R172, respectively. "IDH status" in glioma generally refers to IDH1 or IDH2, sometimes also referred to as "IDH1 / 2 status". In the absence of a mutation that changes enzyme activity, the IDH state is referred to as "wild type". If there is one or more mutations that change enzyme activity, the IDH state is referred to as "IDH mutation" or "IDH mutant type". Mutations in the IDH gene can be detected by known methods, including, for example, polymerase chain reaction (PCR) on formalin-fixed, paraffin-embedded (FFPE) glioma tissue. In some cases, in addition to PCR, negative immunohistochemistry for IDH1 R132H can also be used to classify IDH wild-type glioblastomas.

[0107] In some aspects, when referring to glioma, "MGMT status" refers to the methylation status of the promoter of the gene encoding the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), i.e., whether such a 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).

[0108] In some aspects, 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. The complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) (1p / 19q co-deletion or co-deleted) is typically a molecular genetic feature of oligodendrogliomas, a subtype of primary brain tumors that accounts for approximately 10% to 15% of all diffuse gliomas in adults. In the absence of 1p / 19q co-deletion, the status is generally considered to be "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 single glioma cells from FFPE glioma tissue sections transcribed onto unstained slides; 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 allows detection of loss of heterozygosity (LOH) at selected loci, and next-generation sequencing-based NGS methods can also be used to assess 1p / 19q status.

[0109] In some aspects, when referring to gliomas, "CDKN2A / B status" refers to whether the cyclin-dependent kinase inhibitors 2A and / or 2B (CDKN2A / B) genes are altered, in particular whether there is a homozygous deletion of CDKN2A and CDKN2B. CDKN2A / B is a driver tumor suppressor gene that regulates cell cycle progression. Loss of CDKN2A is believed to promote the formation of gliomas 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 can be considered to retain CDKN2A / B. Potential changes in CDKN2A / B can be detected using known methods, such as FISH, qPCR, or NGS-based methods.

[0110] In some aspects, when referring to gliomas, "TERT promoter mutation status" or TERTp mutation status refers to the presence or absence of certain mutations in the promoter of the TERT gene. TERTp mutations occur in 51% of all glioma grades. TERTp mutations can be identified using known methods based on molecular characteristics of tumor DNA, such as Sanger sequencing based on tumor DNA sequencing, droplet digital PCR (ddPCR), mass spectrometry-based testing, or next-generation sequencing (NGS).

[0111] In some aspects, when referring to 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 by fluorescence in situ hybridization (FISH), chromosomal microarray, or real-time quantitative PCR.

[0112] In some aspects, when referring to a glioma, "chromosome 7 / 10 status" refers to whether the glioma has a combination of a gain of chromosome 7 (including the EGFR gene) and 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).

[0113] In the absence of microvascular proliferation and / or necrosis in diffuse gliomas, EGFR amplification, a combination of chromosome 7 gain and chromosome 10 loss (7+ / 10-), and TERT promoter mutation (pTERTmut) are frequently observed alterations in adults and are defined as molecular features of IDH-wild-type glioblastoma in the WHO 2021.

[0114] In some aspects, when referring to a glioma, "H3.3 G34 status" or "H3 K27M status" refers to whether the glioma has a histone H3.3 G34 mutation or a loss of nuclear K27-trimethylated histone H3 (H3K27me3), for example due to an H3K27 mutation. Thus, a glioma can be H3.3 G34 wild-type, H3.3 G34 mutant, such as H3.3 G34R / V mutant or H3K27M mutant, or can have a loss of H3K27me3. The presence of an H3.3 G34 mutation (e.g., H3.3G34R / V) or an H3 K27M mutation can be assessed by known methods, such as immunohistochemistry or DNA sequencing, to identify H3.3 G34-mutant diffuse hemispheric glioma or diffuse midline glioma, H3 K27M-mutant WHO grade 4, respectively. In glioblastoma or GBM, the H3.3G34 status is wild-type.

[0115] As used herein, the term "relapse" and variations thereof when referring to glioma or patients having glioma means worsening of the disease and / or signs and symptoms of the disease after a period of improvement, stabilization, or disease absence.

[0116] As used herein, the term "progression" and variations thereof when referring to glioma or patients with glioma refers to a condition in which the cancer worsens due to existing lesions growing and / or due to the appearance of new lesions.

[0117] As used herein, the term "WEEl inhibitor treatment day" refers to the day on which a compound of formula (I) is administered according to the methods of the present invention.

[0118] When used for monotherapy, the term "therapeutically effective amount" of a given drug as used herein, for example, "WEE1 therapeutically effective amount" or "TMZ therapeutically effective amount", refers to the amount of the drug that effectively "treats" a disease or disorder in a subject or patient while maintaining an acceptable safety profile. In some aspects, when WEE1 and TMZ (optionally further combined with radiotherapy) are administered in combination, their respective therapeutically effective amounts may be referred to as "WEE1 combined therapeutic effective amount" and "TMZ combined therapeutic effective amount". When administered as a monotherapy, the "WEE1 therapeutic effective amount" of a compound of formula (I) may be different from the "WEE1 combined therapeutic effective amount" of a compound of formula (I) when used in combination with TMZ and / or radiotherapy. In the case of cancer, a therapeutically effective amount of a given drug can reduce the number of cancer cells; reduce tumor size or burden; inhibit (i.e., slow to some extent, and in some embodiments, stop) the infiltration of cancer cells into peripheral organs; inhibit (i.e., slow to some extent, and in some embodiments, stop) tumor metastasis; inhibit tumor growth to some extent; alleviate one or more symptoms associated with cancer to some extent; reduce the dose requirement of corticosteroids; and / or result in a favorable response, such as an improved overall response (OR), objective 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, disease stabilization (SD) rate, reduction in progressive disease (PD), increase in time to tumor progression (TTP), or any combination thereof. See the definition of "treat" herein.

[0119] As used herein, "RANO criteria" refers to the response assessment in neuro-oncology recommendations set forth 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 some embodiments, the RANO guidelines may evolve in the future, and new versions (one or more) may be published and considered.

[0120] As used herein, "mRANO criteria" refers to the modified response assessment in neuro-oncology recommendations set forth in "Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials" by Ellington BM, et al. 2017, Neurotherapeutics, 14(2): 307-20 ("mRANO 2017"). In some embodiments, the mRANO guidelines may evolve in the future, and new versions (one or more) may be published and considered.

[0121] "Progression-free survival" (PFS) in clinical trials used herein refers to the time from registration, first administration or randomization until disease progression or death from any cause (whichever occurs first). In the field of glioma, PFS is typically measured using the RANO criteria, such as according to the RANO 2010 or mRANO 2017 criteria, and is typically summarized using the Kaplan-Meier method.

[0122] "Time before tumor progression" (TTP) in clinical trials used herein refers to the time from enrollment, first administration or randomization to disease progression. In the field of glioma, TTP is typically measured using the RANO criteria, for example, according to the RANO 2010 or mRANO 2017 criteria.

[0123] "Complete response" or "complete remission" or "CR" in clinical trials used herein means that there is no detectable evidence of tumor response to treatment. This does not always mean that cancer has been cured. The complete response of brain tumors such as gliomas is usually measured using the RANO criteria. For example, according to the RANO 2010 or mRANO 2017 criteria, a complete response requires all of the following: complete disappearance of all measurable and unmeasurable enhancing diseases for at least 4 weeks; no new lesions; stable or improved non-enhancing (T2 / FLAIR) lesions; and the patient must stop corticosteroids or only use physiological replacement doses, and be clinically stable or improved. In the absence of a confirmed scan after 4 weeks, this response will only be considered as disease stabilization. Fluid-attenuated inversion recovery (FLAIR) is a magnetic resonance imaging (MRI) sequence that produces a strong T2 weight, suppresses CSF signals, and minimizes the contrast between gray matter and white matter.

[0124] "Partial response" or "PR" in clinical trials used herein refers to a decrease in the size or volume of one or more tumors or lesions, or a decrease in the degree of cancer in the body, when responding to treatment according to the RANO criteria. For example, according to the RANO 2010 or mRANO 2017 criteria, a partial response requires all of the following: compared to baseline, the sum of the products of the perpendicular diameters of all measurable enhancing lesions for at least 4 weeks is reduced by >= 50%; there is no progression of unmeasurable disease; there are no new lesions; compared to baseline scans, stable or improved non-enhanced (T2 / FLAIR) lesions with the same or lower doses of corticosteroids; and the patient's corticosteroid dose must not exceed the dose at the baseline scan, and clinically stable or improved. In the absence of a confirmed scan after 4 weeks, this response will only be considered to be disease stabilization.

[0125] As used herein, "stable disease" or "SD" in clinical trials refers to the absence of disease progression or recurrence. In stable disease, there is neither sufficient tumor shrinkage to qualify as a partial response nor sufficient tumor increase to qualify as progressive disease, with the smallest sum diameter on study as a reference. This can typically be measured using the RANO criteria, for example, according to the RANO 2010 or mRANO 2017 criteria.

[0126] As used herein, "progression," "progressive disease," or "PD" in a clinical trial or study refers to the appearance of one or more new lesions or tumors and / or clear progression of existing target and / or non-target lesions and / or an increase of at least 25% in the sum of the products of the perpendicular diameters of target lesions, with the minimum sum in the study as a reference (note: the appearance of one or more new lesions is also considered progression). RANO criteria are typically used for measurement. For example, according to the RANO 2010 criteria, progression is defined as any of the following: a 25% increase in the sum of the products of the perpendicular diameters of enhancing lesions (compared to baseline, if not decreased) with a stable or increased dose of corticosteroids; a significant increase in T2 / FLAIR non-enhancing lesions with a stable or increased dose of corticosteroids compared to the baseline scan or the best response after initial treatment, not due to comorbid events; the appearance of any new lesions; significant progression of unmeasurable lesions; or clear clinical worsening that is not due to reasons other than tumors or a reduction in corticosteroid doses. Failure to return for evaluation due to death or worsening of the condition should also be considered progression.

[0127] As used herein, "objective response rate" or "ORR" refers to the percentage of subjects in a study, clinical trial, or treatment group who have a partial or complete response to treatment. It is typically measured using the RANO criteria, for example, according to the RANO 2010 or mRANO 2017 criteria.

[0128] As used herein, "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 assessment point. It is typically measured using the RANO criteria, for example, according to the RANO 2010 or mRANO 2017 criteria.

[0129] "Best overall response" or "BOR" as used herein refers to the best response recorded for a given patient in a study, clinical trial, or treatment group from baseline assessment (enrollment, start of treatment, or randomization) until disease progression / recurrence (using the smallest measurement recorded since the start of treatment as a reference for progressive disease) or death from any cause. Typically measured using the RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria.

[0130] As used herein, "Disease Control Rate" or "DCR" refers to the percentage of patients in a study, clinical trial, or treatment group who achieve a complete response, partial response, or stable disease to a therapeutic intervention. Typically, DCR is measured using the RANO criteria, e.g., according to the RANO 2010 or mRANO 2017 criteria.

[0131] " Duration of response " (DoR) used herein refers to the time from early response (PR or better) to disease progression or death due to any reason. RANO criteria are usually used to measure, for example, according to RANO 2010 or mRANO 2017 criteria.

[0132] "Overall survival" (OS) in clinical trials used herein refers to the time from patient registration, first treatment administration or randomization to death due to any cause or censoring at the date of last known survival. Improvements in OS include an extension of life expectancy compared to initial (naive) or untreated individuals or patients. Overall survival refers to a situation in which a patient remains alive within a specified time period (e.g., one year, five years, etc.), for example, from the time of randomization or first treatment.

[0133] As used herein, the term "pharmaceutical formulation" or "pharmaceutical composition" refers to a preparation in such form that the biological activity of the active ingredient is effective and that contains no additional components that are unacceptably toxic to a subject to which the formulation would be administered.

[0134] The expression "oral dosage form" as used herein refers to any form of pharmaceutical composition suitable for oral administration.

[0135] About the administration plan of given medicine, the expression " intermittent " or " intermittent plan " used in this article refers to the administration plan comprising regularly repeated phase, wherein each regularly repeated phase includes one or more predetermined drug administration days and one or more predetermined non-administration drug days.The expression " regularly repeated phase " should be understood as the time period with predetermined administration plan, which is repeated once or more times during the treatment of glioma.The regularly repeated phase can be a 28-day treatment cycle, or a week in a 6 or 7-week treatment. For example, if the duration of the regularly repeated phase has n days, the number of predetermined drug administration days can be selected from 1 to n-1 days, and the remaining number of days is predetermined non-administration drug day. If the number of predetermined administration drug days is 2 days or more, these predetermined number of days can be continuous or discontinuous. In the context of the present application, "n" can preferably be 28 days or 7 days (one week). An intermittent schedule of a compound of formula (I) can be administered, for example, on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle; on days 1 to 5, 8 to 12, and 15 to 19 of a 28-day cycle; on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle; on days 1 to 3 of each week for 6 or 7 weeks; on days 1 to 5 of each week for 6 or 7 weeks; or on days 1 to 4 of each week for 6 or 7 weeks.

[0136] As used herein, the expression "continuously" or "continuous schedule" with respect to a given drug administration schedule refers to a schedule in which the drug is administered every day during regularly repeating periods. A continuous schedule can be, for example, daily administration over one or more 28-day cycles; daily administration over 6 or 7 weeks of treatment; or daily administration over 42 to 49 days.

[0137] Treatment methods and uses

[0138] In one embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof

[0139]

[0140] For use as monotherapy in the treatment of glioma in patients in need thereof.

[0141] In another embodiment of the present invention, the 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.

[0142] In yet another embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with radiation therapy for the treatment of glioma in a patient in need thereof.

[0143] In yet another embodiment of the present invention, the 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.

[0144] In some embodiments of the uses and methods of the present invention, the treatment of glioma is independent of its WHO grade.

[0145] In some embodiments of the uses and methods of the present invention, the glioma is grade 1 according to WHO 2021. In other embodiments of the uses and methods of the present invention, the glioma is grade 2 according to WHO 2021. In other embodiments of the uses and methods of the present invention, the glioma is grade 3 according to WHO 2021. In other embodiments of the uses and methods of the present invention, the glioma is grade 4 according to WHO 2021.

[0146] In some embodiments of the uses or methods of the present invention, the treatment of glioma is independent of its isocitrate dehydrogenase (IDH) status (eg, wild type or mutant).

[0147] In some embodiments of the uses or methods of the invention, the glioma is (IDH)-wild type. In some alternative embodiments of the uses or methods of the invention, the glioma is (IDH)-mutant.

[0148] In some embodiments of the uses or methods of the present invention, the glioma is treated independent of its MGMT status.

[0149] In some embodiments of the uses or methods of the invention, the glioma presents a methylated MGMT promoter. In some alternative embodiments of the uses or methods of the invention, the glioma presents an unmethylated MGMT promoter.

[0150] In some embodiments of the uses or methods of the present invention, the treatment of the glioma is independent of its 1p / 19q status.

[0151] In some embodiments of the uses or methods of the invention, the glioma is 1p / 19q co-deleted. In some alternative embodiments of the uses or methods of the invention, the glioma is 1p / 19q intact.

[0152] In some embodiments of the uses or methods of the present invention, the treatment of the glioma is independent of its CDKN2A / B status.

[0153] In some embodiments of the uses or methods of the invention, the glioma carries a homozygous deletion of CDKN2A / B. In some alternative embodiments of the uses or methods of the invention, the glioma retains CDKN2A / B.

[0154] In some embodiments of the uses or methods of the present invention, the treatment of the glioma is independent of its ATRX status.

[0155] In some specific aspects of the invention, the glioma is ATRX-deficient. In some alternative aspects, the glioma retains ATRX. For example, the improved efficacy of treating gliomas with the uses or methods of the invention may be more pronounced in ATRX-deficient gliomas, for example when the compound of formula (I) is used as a monotherapy.

[0156] In some specific aspects, the glioma is IDH wild-type and has necrosis and / or microvascular proliferation.

[0157] In some specific aspects, the glioma is IDH wild-type without microvascular proliferation or necrosis. For example, an IDH wild-type glioma may have EGFR amplification, a combination of chromosome 7 gain and chromosome 10 loss (7+ / 10-), and / or a TERT promoter mutation (pTERTmut).

[0158] In some specific aspects of the uses and methods of the present invention, the treatment of glioma is independent of its H3.3G34 status.

[0159] In some specific aspects, the glioma is H3.3 G34 wild-type.

[0160] In some specific aspects of the uses and methods of the present invention, the treatment of glioma is independent of its H3K27M status.

[0161] In some specific aspects, the glioma is H3 K27M mutant or has loss of H3K27me3.

[0162] A variety of possible molecular states and alterations of gliomas in patients can be detected or determined independently of one another. The uses or methods of the present invention are applicable to gliomas with any molecular state or alteration, in particular gliomas with a single identified molecular alteration or a combination of 2, 3, 4, 5, 6 or more identified molecular alterations.

[0163] For example, in the uses or methods of the present invention, IDH status and MGMT status can be determined independently of each other, and the glioma can be IDH wild-type and MGMT methylated, IDH wild-type and MGMT unmethylated, IDH mutant and MGMT methylated, or IDH mutant and MGMT unmethylated.

[0164] In some embodiments of the uses or methods of the invention, the glioma has recurred or progressed after an initial glioma treatment. In some embodiments of the uses or methods of the invention, the glioma has recurred or progressed after a previous glioma treatment.

[0165] In some alternative embodiments, the patient has not received any prior treatment for glioma, or the glioma is newly diagnosed.

[0166] In some specific aspects of the present invention, the glioma is a glioblastoma. For example, the glioma can be a GBM, isocitrate dehydrogenase (IDH) wild type, grade 4 according to WHO 2021.

[0167] In other specific aspects of the present invention, the glioma is an astrocytoma. For example, the glioma can be an astrocytoma with IDH mutation, grade 2, 3 or 4 according to WHO 2021, preferably grade 3 according to WHO 2021.

[0168] In other specific aspects of the present invention, the glioma is an oligodendroglioma. For example, the glioma can be an oligodendroglioma with IDH mutation and 1p / 19q co-deletion, grade 2 or 3 according to WHO 2021.

[0169] In some embodiments, the use or method of treatment according to the present invention exhibits advantageous properties in improving the efficacy of treating gliomas, such as improved OS, PFS, OR, ORR, BOR, DOR, DC and / or DCR as assessed by RANO 2010 or mRANO 2017 criteria, with an acceptable safety profile and no adverse effect on the patient's quality of life compared to SOC. In the same or other embodiments, the use or method of treatment according to the present invention reduces the need for steroids in patients with gliomas.

[0170] Dosage, schedule, and route of administration

[0171] As used herein, the term "about" describes a deviation of ±10% from the stated value. Individual values ​​should be understood to describe a range between any stated values.

[0172] Compound of formula (I)

[0173] In purposes and methods of the present invention, formula (I) compound can be with the dosage of about 30 to about 1000mg free alkali / treatment day, preferably in the dosage of about 30 to about 720mg free alkali / treatment day.In some embodiments, formula (I) compound can preferably be with the dosage of about 90 to about 720mg free alkali / treatment day or about 150 to about 720mg free alkali / treatment day.

[0174] For example, the compound of formula (I) can 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 free base per treatment day.

[0175] In more specific embodiments, the compound of formula (I) can be administered at a dosage 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 alkali per treatment day. Preferably, the compound of formula (I) can be administered at a dosage 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 alkali per treatment day.

[0176] In some preferred embodiments, a therapeutically effective amount of WEE1 or a therapeutically effective amount of a combination of WEE1 may be administered.

[0177] In some embodiments of the present invention, the compound of formula (I) is administered orally.

[0178] In some embodiments of the invention, the compound of formula (I) is administered as a single dose per treatment day (QD), or as two doses per treatment day (BID).

[0179] In some embodiments, the compound of Formula (I) is administered on an intermittent schedule.

[0180] In some embodiments, formula (I) compound is used at the 1st day to the 5th day, the 8th day to the 10th day and the 15th day to the 17th day of 28 day cycles.In such embodiments, formula (I) compound can be used 1,2,3,5,4,5,6 or more cycles.In some respects, the treatment with formula (I) compound can continue for 2 years or until disease progression, unacceptable toxicity, patient decision to stop, according to the decision of the physician, start subsequent antitumor therapy, clinical study end or death.In some respects, the treatment with formula (I) compound can continue for up to 2 years.In some embodiments, formula (I) compound can be used at the 1st day to the 5th day, the 8th day to the 10th day and the 15th day to the 17th day of 28 day cycles with the dosage / treatment day of above-mentioned indication.

[0181] In some embodiments, formula (I) compound is used at the 1st day to the 5th day, the 8th day to the 12th day and the 15th day to the 19th day of 28 day cycles.In such embodiments, formula (I) compound can be used 1,2,3,5,4,5,6 or more cycles.In some respects, treatment with formula (I) compound can continue for 2 years or until disease progression, unacceptable toxicity, patient decision to stop, according to physician's decision to stop, start subsequent antitumor therapy, clinical study end or death.In some respects, treatment with formula (I) compound can continue for up to 2 years.In some embodiments, formula (I) compound can be used at the 1st day to the 5th day, the 8th day to the 12th day and the 15th day to the 19th day of 28 day cycles with the dosage / treatment day of above-mentioned indication.

[0182] In some embodiments, formula (I) compound is used at the 1st day to the 5th day, the 8th day to the 12th day, the 15th day to the 19th day and the 22nd day to the 26th day of 28 day cycles.In such embodiments, formula (I) compound can be used 1,2,3,5,4,5,6 or more cycles.In some respects, the treatment with formula (I) compound can continue for 2 years or until disease progression, unacceptable toxicity, patient decision to stop, according to the decision of the physician, start subsequent antitumor therapy, clinical study end or death.In some respects, the treatment with formula (I) compound can continue for up to 2 years.In some embodiments, formula (I) compound can be used at the 1st day to the 5th day, the 8th day to the 12th day, the 15th day to the 19th day and the 22nd day to the 26th day of 28 day cycles with the dosage / treatment day of above-mentioned indication.

[0183] In some embodiments, the compound of formula (I) is administered on day 1 to day 3 of each week for several weeks, particularly 6 or 7 weeks. In other embodiments, the compound of formula (I) may be administered on day 1 to day 3 of each week 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 at the above indicated doses / treatment days for 6 weeks, for 7 weeks or for 42 to 49 days.

[0184] In some embodiments, the compound of formula (I) is administered on day 1 to day 5 of each week for several weeks, particularly 6 or 7 weeks. In other embodiments, the compound of formula (I) may be administered on day 1 to day 5 of each week 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 at the above indicated doses / treatment days for 6 weeks, for 7 weeks or for 42 to 49 days.

[0185] In some embodiments, the compound of formula (I) is administered on day 1 to day 4 of each week for several weeks, particularly 6 or 7 weeks. In other embodiments, the compound of formula (I) may be administered on day 1 to day 4 of each week 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 at the above indicated doses / treatment days for 6 weeks, for 7 weeks or for 42 to 49 days.

[0186] In some embodiments, the 6-week plan of formula (I) compound includes one or more holiday periods, such as one or more holiday periods each for a week. The holiday period should be understood as a period during which the compound of formula (I) is not administered. The holiday period does not affect the administration of TMZ and / or radiotherapy, which will continue according to the dosage and plan specified above or below. The 6-week plan of formula (I) compound can be any 6-week plan described above or below for the compound of formula (I). For example, the compound of formula (I) can be administered from day 1 to day 3 of week 1, week 2, week 4, and week 5, wherein week 3 and week 6 are holiday periods (without administration of formula (I) compound). Or the compound of formula (I) can be administered from day 1 to day 3 of week 1, week 2, week 3, week 5, and week 6, wherein week 4 is a holiday period (without administration of formula (I) compound). In such embodiments involving one or more rest periods, the compounds of formula (I) may be administered at the dosages indicated above per treatment day.

[0187] In other embodiments of the present invention, formula (I) compound is used with a continuity plan. For example, formula (I) compound is used every day for several weeks, particularly 6 or 7 weeks. In some embodiments, formula (I) compound can be used every day for 42 to 49 days, for example, for 42, 43, 44, 45, 46, 47, 48 or 49 days. In some embodiments, formula (I) compound can be used every day for 6 weeks, for 7 weeks or for 42 to 49 days with the dosage / treatment day indicated above. If the glioma to be treated has relapsed after an initial or previous glioma treatment (second (or higher) line treatment), it may be preferred that the compound of formula (I) (optionally in combination with TMZ in a schedule defined herein) is administered on days 1 to 5, 8 to 10 and 15 to 17 of a 28-day cycle, or on days 1 to 5, 8 to 12 and 15 to 19 of a 28-day cycle, or on days 1 to 5, 8 to 12, 15 to 19 and 22 to 26 of a 28-day cycle. If the glioma to be treated is newly diagnosed (first-line treatment), it may be preferred that the compound of formula (I) (optionally in combination with TMZ and / or radiotherapy in a schedule defined herein) is administered daily for 6 weeks, daily for 7 weeks or for 42 to 49 days. It may be more preferred that if the glioma to be treated is newly diagnosed (first-line treatment) the compound of formula (I) (optionally in combination with TMZ and / or radiotherapy in a schedule defined herein) is administered from day 1 to day 3 of each week for 6 or 7 weeks, or from day 1 to day 5 of each week for 6 or 7 weeks, or from day 1 to day 4 of each week for 6 or 7 weeks.

[0188] In some embodiments of the invention, the compound of formula (I) is administered at approximately the same time on each treatment day, e.g., at the same time ± about 60 minutes, preferably ± 60 minutes, on each treatment day, e.g., in a given cycle. In more specific embodiments, the compound of formula (I) is administered in the morning, e.g., between 5 a.m. and noon.

[0189] In some aspects 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 some of the same or other aspects, administration of the compound of formula (I) may be followed by fasting, preferably by a 2-hour fasting period.

[0190] In some alternative aspects of the uses and methods according to the invention, the compound of formula (I) is administered in a fed state.

[0191] In further alternative aspects of the uses or methods according to the invention, the compound of formula (I) is administered independently of the patient's food status.

[0192] Temozolomide (TMZ)

[0193] In some embodiments 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 may be 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 / day dosage administration.

[0194] In some preferred embodiments, a therapeutically effective amount of TMZ or a therapeutically effective amount of a combination of TMZs may be administered.

[0195] In some embodiments, TMZ may be administered at a dose of about 75 mg / m 2 / day, about 150mg / m 2 / day or about 200 mg / m 2 Preferably, TMZ can be administered at a dose of 75 mg / m 2 / day, 150mg / m 2 / day or 200 mg / m 2 / day dosage administration.

[0196] In some embodiments, TMZ can be administered on days 1 to 5 of a 28-day cycle. In other embodiments, TMZ can be administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle. The 28-day cycle can be the same as the 28-day cycle of the compound of formula (I).

[0197] TMZ can be administered in 1, 2, 3, 4, 5, 6 or more cycles. In some aspects, treatment with TMZ can last for 2 years. In some aspects, treatment with TMZ can last for up to 2 years.

[0198] In yet other embodiments, TMZ may be administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days.

[0199] In some specific preferred embodiments, TMZ may be administered at a dose of 50 to 300 mg / m2 on days 1 to 5 of a 28-day cycle. 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 Preferably, TMZ can be administered at a dose of 150 mg / m2 on days 1 to 5 of a 28-day cycle. 2 / day or 200 mg / m 2In some embodiments, TMZ may be administered at a dosage of 1, 2, 3, 4, 5, 6, or more per cycle. In some aspects, TMZ may be administered for 2 years. In some aspects, TMZ may be administered for up to 2 years. If the glioma to be treated recurs after initial or previous glioma treatment, the TMZ plan may be preferred, wherein the compound of formula (I) is administered on the administration day defined above, particularly on the 1st to 5th day of a 28-day cycle.

[0200] In other specific preferred embodiments, TMZ can be administered at a dose of 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 The dosage of TMZ may be administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days. 2 The dosage of TMZ is administered daily for 6 weeks, daily for 7 weeks or daily for 42 to 49 days. If the glioma to be treated is newly diagnosed, the TMZ schedule may be preferred, wherein the compound of formula (I) is administered on the administration days defined above, in particular daily for 6 weeks, daily for 7 weeks or daily for 42 to 49 days. For the treatment of newly diagnosed gliomas, radiation therapy may be administered in addition, as further defined below.

[0201] In other embodiments, TMZ may be administered at a dose of 50 to 300 mg / m2 on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle. 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 Preferably, TMZ can be administered at a dose of 75 mg / m2 on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle. 2 / day, 150mg / m 2 / day or 200 mg / m 2 If the glioma to be treated relapses after initial or previous glioma treatment, the TMZ schedule may be used wherein the compound of formula (I) is administered on the same administration days, i.e., both the compound of formula (I) and TMZ are administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle.

[0202] TMZ may be administered on the same day as the compound of formula (I), or on a different schedule, as defined below.

[0203] In some embodiments, TMZ is administered on a different schedule than the compound of formula (I).

[0204] In one 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 be administered on days 1 to 5 of a 28-day cycle. In another example, if the compound of formula (I) is administered on days 1 to 5, 8 to 12, and 15 to 19 of a 28-day cycle, TMZ may be administered on days 1 to 5 of a 28-day cycle. In yet another example, if the compound of formula (I) is administered on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle, TMZ may be administered on days 1 to 5 of a 28-day cycle. The dosage of the compound of formula (I) and the dosage of TMZ on each corresponding administration day may be defined as above. If the glioma to be treated recurs after initial or previous glioma treatment, this plan may be preferred.

[0205] In some other examples: if the compound of formula (I) is administered on days 1 to 3 of each week for 6 or 7 weeks or 42 to 49 days, TMZ can be administered daily for the 6 weeks, 7 weeks or 42 to 49 days; if the compound of formula (I) is administered on days 1 to 5 of each week for 6 or 7 weeks or 42 to 49 days, TMZ can be administered daily for the 6 weeks, 7 weeks or 42 to 49 days; if the compound of formula (I) is administered on days 1 to 4 of each week for 6 or 7 weeks or 42 to 49 days, TMZ can be administered daily for the 6 weeks, 7 weeks or 42 to 49 days. The dosages of the compound of formula (I) and TMZ on the administration day may be as defined above. If the glioma to be treated is newly diagnosed, these plans of 6 or 7 weeks or 42 to 49 days may be preferred.

[0206] In other embodiments, TMZ is administered on the same schedule as the compound of formula (I). In one example, if the compound of formula (I) is administered daily for 6 weeks, daily for 7 weeks, or daily for 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 day of administration may be as defined above. If the glioma to be treated is newly diagnosed, this schedule may be preferred.

[0207] 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 a 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 preferred if the glioma to be treated has recurred after an initial or previous glioma treatment.

[0208] Specific TMZ regimens that may be combined with the compounds of formula (I) in the uses and methods according to the invention include:

[0209] a) 75 mg TMZ / m 2 / day, daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days,

[0210] b) 150 mg TMZ / m on days 1 to 5 of each 28-day cycle 2 / sky,

[0211] c) 200 mg TMZ / m on days 1 to 5 of each 28-day cycle 2 / sky,

[0212] d) 50 mg TMZ / m 2 / day, daily until progression,

[0213] e) TMZ for 1 week (e.g., 120 mg / m 2 / day, every day, for 7 days) / stop for 1 week (no TMZ for 7 days),

[0214] f) TMZ for 3 weeks in a 28-day cycle (e.g., 80 mg / m 2 / day, daily for 21 days) / 1 week off (7 days without TMZ), or

[0215] g) 75 mg TMZ / m on days 1 to 5 of each week 2 / day for 6 or 7 weeks, or for 42 to 49 days.

[0216] In some embodiments, it may be desirable to express the amount of TMZ to be administered in mg / treatment day. In such embodiments, the indicated mg / m 2 The daily dose is calculated based on the body surface area (BSA) of the patient. The BSA can be determined by a skilled person by methods known to him, for example by the Du Bois method (see, for example, 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, for example, Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987; 317: 1098).

[0217] Table 1 below provides information on how to convert 75 mg / m2 to 100 mg / m2 based on BSA. 2 / day, 150mg / m 2 / day or 200 mg / m 2 An overview of the conversion of a daily dose to mg / treatment day. For example, for a patient with a BSA of 2.0, 75 mg / m 2 A dose of 150 mg / day would mean that a total of 150 mg of TMZ could be administered.

[0218] Table 1: Calculation of daily TMZ dose based on body surface area (BSA)

[0219]

[0220] In some embodiments of the invention, TMZ is administered orally. In some alternative embodiments of the 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 the oral formulation.

[0221] Of course, in some embodiments, TMZ can be used in the form of a pharmaceutically acceptable salt. In such embodiments, the dosage, amount or concentration of TMZ indicated herein, i.e., the free base, can be appropriately adjusted according to the molecular weight of the corresponding salt.

[0222] Radiation therapy

[0223] In some embodiments of the methods of the 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 to be treated is newly diagnosed, the use of radiation therapy is generally preferred (first-line treatment).

[0224] 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 radiotherapy, or fractionated radiation therapy.

[0225] In some embodiments, radiation therapy is fractionated radiation therapy.

[0226] In some preferred embodiments, radiation therapy is administered for 5 consecutive days per week until the total radiation dose has been administered. In another preferred embodiment, radiation therapy is administered in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days. It will be appreciated that radiation therapy need not be administered every day.

[0227] In one example, if the compound of formula (I) is administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, the radiation therapy can be administered in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days. In another example, if the compound of formula (I) and TMZ are administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, the radiation therapy can be administered in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days. The dose of the compound of formula (I) and / or the dose of TMZ per respective administration day may be as defined above.

[0228] Alternatively, if the compound of formula (I) is administered on days 1 to 3 of each week for 6 or 7 weeks or 42 to 49 days, the radiation therapy can be administered in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days. In another example, if the compound of formula (I) is administered on days 1 to 3 of each week for 6 or 7 weeks or 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 can be administered in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days. The dose of the compound of formula (I) and / or the dose of TMZ per respective administration day may be as defined above.

[0229] Alternatively, if the compound of formula (I) is administered on days 1 to 5 of each week for 6 or 7 weeks or 42 to 49 days, the radiation therapy can be administered in equal doses over a period of 6 weeks, 7 weeks, or 42 to 49 days. In another example, if the compound of formula (I) is administered on days 1 to 5 of each week for 6 or 7 weeks or 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 can be administered in equal doses over a period of 6 weeks, 7 weeks, or 42 to 49 days. The dose of the compound of formula (I) and / or the dose of TMZ per respective administration day may be as defined above.

[0230] Alternatively, if the compound of formula (I) is administered on days 1 to 4 of each week for 6 or 7 weeks or 42 to 49 days, the radiation therapy can be administered in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days. In another example, if the compound of formula (I) is administered on days 1 to 4 of each week for 6 or 7 weeks or 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 can be administered in equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days. The dose of the compound of formula (I) and / or the dose of TMZ per respective administration day may be as defined above.

[0231] 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, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days.

[0232] In some specific preferred embodiments, radiation therapy is administered as follows: 2 Gy fractions per day for 5 consecutive days per week for a total of 60 Gy, and / or 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days for a total dose of 60 Gy.

[0233] In some aspects, the administration plan described herein, such as when relating to radiotherapy, can be understood as covering an administration plan that has been interrupted for one or several days (continuous or discontinuous).For example, the reason for the interruption can be a damaged radiotherapy machine. On such an interruption day, RT, formula (I) compound and TMZ (if the plan is to be used on the day) are interrupted. The day of the administration interruption can be added at the end of the treatment period. For example, administration can be interrupted on one day of a 6-week (42-day) treatment period, and then the missed administration day can be added on the first day of the 7th week (after the 42nd day), preferably on the 43rd day, during the 7th week. In the case of several missed administration days, the total treatment period can be extended according to the number of missed administration days, up to a maximum of 7 weeks (49 days). The specific treatment of the missed administration day is determined by the physician team or treating physician around the glioma patient according to their professional knowledge and the patient's condition.

[0234] Combination therapy involving compounds of formula (I)

[0235] In some embodiments of the invention wherein a compound of formula (I) is used in combination with TMZ and / or radiation therapy, if TMZ and / or radiation therapy is administered on said WEE1 inhibitor treatment day, the compound of formula (I) is administered prior to TMZ and / or radiation therapy on the WEE1 inhibitor treatment day.

[0236] In some embodiments, on a WEE1 inhibitor treatment day, if TMZ is administered on the WEE1 inhibitor treatment day, TMZ administration is initiated about 30 minutes to 4 hours, preferably about 30 minutes to 1 hour after administration of a compound of formula (I). In some alternative embodiments, on a WEE1 inhibitor treatment day, if TMZ is administered on the WEE1 inhibitor treatment day, TMZ is administered at bedtime, e.g., between 9 pm and midnight.

[0237] In some embodiments of the invention wherein a compound of formula (I) is used in combination with both TMZ and radiation therapy, on a WEE1 inhibitor treatment day, if TMZ and / or radiation therapy is 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.

[0238] In some embodiments of the invention wherein a compound of formula (I) is used only in combination with radiation therapy, if radiation therapy is administered on the WEE1 inhibitor treatment day, 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).

[0239] Glioma patients may need steroid support. In some embodiments of the present invention, in the context of glioma treatment of patients in need thereof, for example, in the context of the first or previous glioma treatment, steroids are administered to patients in need thereof. In some embodiments of the present invention, in addition to the combination therapy of formula (I) compound and TMZ, formula (I) compound and TMZ and RT or formula (I) compound and RT, steroids are administered to patients in need thereof. In some specific embodiments, steroid is a corticosteroid, such as but not limited to dexamethasone (dexamethasone) or prednisone (prednisone). In some specific embodiments, 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.

[0240] Glioma patients may also require anticonvulsant support, for example, in the event of epileptic seizures. In some embodiments of the present invention, in addition to the combination therapy of a compound of formula (I) with TMZ, a compound of formula (I) with TMZ and RT, or a compound of formula (I) with RT, an anticonvulsant is administered to a glioma patient in need thereof. In some specific embodiments, the anticonvulsant lacks enzyme inhibition or induction properties, such as, but not limited to, lacosamide, gabapentin, or pregabalin.

[0241] In some embodiments of the invention, for example, when the patient is receiving concomitant TMZ and RT therapy, the patient is administered Pneumocystis jiroveciipneumonia (PCP) prophylaxis in addition to the combination therapy of a compound of Formula (I) with TMZ and RT.

[0242] In some aspects of the uses or methods according to the invention, such as (but not limited to) where the glioma is newly diagnosed, the combined treatment plan or regimen may be defined as the following alternatives or additions:

[0243] a) daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of a compound of formula (I) in combination with daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of TMZ, and concomitant radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days;

[0244] b) daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of a compound of formula (I) in combination with daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of TMZ, and concomitant radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein the compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base 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 free base per treatment day;

[0245] c) daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of a compound of formula (I) in combination with daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of TMZ, and concomitant radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein

[0246] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0247] oTMZ at 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day dosage administration;

[0248] d) daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of a compound of formula (I) in combination with daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of TMZ, and concomitant radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein

[0249] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base 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 of free base per treatment day,

[0250] oTMZ at 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day dose administration, and

[0251] o Radiation therapy is administered in a fractionation schedule of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days; most preferably administered in a fractionation schedule of 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, for a total dose of 60 Gy, or, for example, 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, for a total dose of 60 Gy;

[0252] e) daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of a compound of formula (I) in combination with daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of TMZ, and concomitant radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days of radiation therapy, wherein

[0253] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base 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 of free base per treatment day,

[0254] oTMZ at 75 mg / m 2 / day dose administration, and

[0255] o Radiation therapy is administered with the following fractionation schedule: 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, 60 Gy total dose, or 30 fractions, 60 Gy total dose, e.g., over a period of 6, 7 weeks, or 42 to 49 days;

[0256] f) daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days of a compound of formula (I) in combination with radiation therapy for 6 weeks, 7 weeks, or 42 to 49 days, wherein the compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base 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 free base per treatment day;

[0257] g) daily administration for 6 weeks, daily administration for 7 weeks or daily administration for 42 to 49 days of a compound of formula (I) in combination with radiation therapy for 6 weeks, 7 weeks or 42 to 49 days, wherein

[0258] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0259] o Radiation therapy is administered in a fractionation schedule of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days; most preferably administered in a fractionation schedule of 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, for a total dose of 60 Gy, or, for example, 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, for a total dose of 60 Gy;

[0260] h) daily administration for 6 weeks, daily administration for 7 weeks or daily administration for 42 to 49 days of a compound of formula (I) in combination with radiation therapy for 6 weeks, 7 weeks or 42 to 49 days, wherein

[0261] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0262] o Radiation therapy is administered in the following fractionation schedule: 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, 60 Gy total dose, or 30 fractions, 60 Gy total dose, e.g., over a period of 6, 7 weeks, or 42 to 49 days.

[0263] In some aspects, an intermittent schedule may be used in cases where unacceptable toxicity is observed following continuous (ie, daily) administration.

[0264] In some aspects of the uses or methods according to the invention, such as (but not limited to) where the glioma is newly diagnosed, the combined treatment plan or regimen may be defined as the following alternatives or additions:

[0265] 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 in combination with TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days;

[0266] bb) administration of a compound of formula (I) on days 1 to 3 of each week for 6 or 7 weeks or for 42 to 49 days in combination with daily administration of TMZ for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days, and concomitant radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein the compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base 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 free base per treatment day;

[0267] cc) 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 TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein

[0268] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0269] oTMZ at 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day dosage administration;

[0270] dd) 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 TMZ administered daily for 6 weeks, daily for 7 weeks or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks or for 42 to 49 days, wherein

[0271] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base 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 of free base per treatment day,

[0272] oTMZ at 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day dose administration, and

[0273] o Radiation therapy is administered in a fractionation schedule of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days; most preferably administered in a fractionation schedule of 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, for a total dose of 60 Gy, or, for example, 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, for a total dose of 60 Gy;

[0274] ee) 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 TMZ administered daily for 6 weeks, daily for 7 weeks or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks or for 42 to 49 days, wherein

[0275] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base 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 of free base per treatment day,

[0276] oTMZ at 75 mg / m 2 / day dose administration, and

[0277] o Radiation therapy is administered with the following fractionation schedule: 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, 60 Gy total dose, or 30 fractions, 60 Gy total dose, e.g., over a period of 6, 7 weeks, or 42 to 49 days;

[0278] ff) administration of a compound of formula (I) 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 the compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base 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 free base per treatment day;

[0279] gg) administration of a compound of formula (I) 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

[0280] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0281] o Radiation therapy is administered in a fractionation schedule of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days; most preferably administered in a fractionation schedule of 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, for a total dose of 60 Gy, or, for example, 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, for a total dose of 60 Gy;

[0282] hh) administration of a compound of formula (I) 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

[0283] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0284] o Radiation therapy is administered in the following fractionation schedule: 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, 60 Gy total dose, or 30 fractions, 60 Gy total dose, e.g., over a period of 6, 7 weeks, or 42 to 49 days.

[0285] In some aspects of the uses or methods according to the invention, such as (but not limited to) where the glioma is newly diagnosed, the combined treatment plan or regimen may be defined as the following alternatives or additions:

[0286] 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 in combination with TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days;

[0287] bbb) administration of a compound of formula (I) on days 1 to 5 of each week for 6 or 7 weeks or 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 concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein the compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base 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 free base per treatment day;

[0288] ccc) 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 TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein

[0289] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0290] oTMZ at 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day dosage administration;

[0291] ddd) 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 TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein

[0292] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base 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 of free base per treatment day,

[0293] oTMZ at 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day dose administration, and

[0294] o Radiation therapy is administered in a fractionation schedule of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, most preferably in a fractionation schedule of 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, for a total dose of 60 Gy, or, for example, 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, for a total dose of 60 Gy;

[0295] eee) 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 TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein

[0296] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base 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 of free base per treatment day,

[0297] oTMZ at 75 mg / m 2 / day dose administration, and

[0298] o Radiation therapy is administered with the following fractionation schedule: 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, 60 Gy total dose, or 30 fractions, 60 Gy total dose, e.g., over a period of 6, 7 weeks, or 42 to 49 days;

[0299] fff) administration of a compound of formula (I) 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 compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base per treatment day, and most preferably 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 free base per treatment day;

[0300] ggg) administration of a compound of formula (I) 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

[0301] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0302] o Radiation therapy is administered in a fractionation schedule of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, most preferably in a fractionation schedule of 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, for a total dose of 60 Gy, or, for example, 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, for a total dose of 60 Gy;

[0303] hhh) administration of a compound of formula (I) 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

[0304] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0305] o Radiation therapy is administered in the following fractionation schedule: 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, 60 Gy total dose, or 30 fractions, 60 Gy total dose, e.g., over a period of 6, 7 weeks, or 42 to 49 days.

[0306] In some aspects of the uses or methods according to the invention, such as (but not limited to) where the glioma is newly diagnosed, the combined treatment plan or regimen may be defined as the following alternatives or additions:

[0307] 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 in combination with TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days;

[0308] bbbb) administration of a compound of formula (I) on days 1 to 4 of each week for 6 or 7 weeks or 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 concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein the compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base 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 free base per treatment day;

[0309] cccc) 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 TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein

[0310] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0311] oTMZ at 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day dosage administration;

[0312] dddd) 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 TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein

[0313] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base 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 of free base per treatment day,

[0314] oTMZ at 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, most preferably 75 mg / m 2 / day dose administration, and

[0315] o Radiation therapy is administered in a fractionation schedule of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days; most preferably administered in a fractionation schedule of 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, for a total dose of 60 Gy, or, for example, 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, for a total dose of 60 Gy;

[0316] eeee) 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 TMZ administered daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, and concomitantly with radiation therapy for 6 weeks, 7 weeks, or for 42 to 49 days, wherein

[0317] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base 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 of free base per treatment day,

[0318] oTMZ at 75 mg / m 2 / day dose administration, and

[0319] o Radiation therapy is administered with the following fractionation schedule: 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, 60 Gy total dose, or 30 fractions, 60 Gy total dose, e.g., over a period of 6, 7 weeks, or 42 to 49 days;

[0320] ffff) administration of a compound of formula (I) 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 compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base 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 free base per treatment day;

[0321] gggg) administration of a compound of formula (I) 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

[0322] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0323] o Radiation therapy is administered in a fractionation schedule of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, most preferably in a fractionation schedule of 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, for a total dose of 60 Gy, or, for example, 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, for a total dose of 60 Gy;

[0324] hhhh) administration of a compound of formula (I) 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

[0325] o The compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg of free base per treatment day, most preferably 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, and

[0326] o Radiation therapy is administered in the following fractionation schedule: 2 Gy fractions per day, 5 consecutive days per week, 30 fractions, 60 Gy total dose, or 30 fractions, 60 Gy total dose, e.g., over a period of 6, 7 weeks, or 42 to 49 days.

[0327] In some alternative embodiments of any of the above-mentioned combination therapies (e.g., items a) to h), aa) to hh), aaa) to hhh), and aaaa) to hhhh)) involving a compound of formula (I), one or more holiday periods are included in the 6-week schedule for the compound of formula (I), for example, one or more holiday periods of one week each. A holiday period is understood to be a time period during which the compound of formula (I) is not administered. The holiday period does not affect the administration of TMZ and / or radiation therapy, which will continue according to the plan and at the doses specified above or below. For example, in alternatives to items aa) to hh), the compound of formula (I) can be administered on days 1 to 3 of weeks 1, 2, 4, and 5, with weeks 3 and 6 being a holiday period (without administration of the compound of formula (I)). Alternatively, the compound of formula (I) can be administered on days 1 to 3 of weeks 1, 2, 3, 5, and 6, with week 4 being a holiday period (without administration of the compound of formula (I)).

[0328] In some embodiments of any of the above items a) to h), aa) to hh), aaa) to hhh), and aaaa) to hhhh), or some embodiments of some alternative embodiments that include a rest period, the compound of formula (I) may be preferably administered at a dose of about 90 to about 720 mg of the free base.

[0329] In further embodiments of any of the above items a) to h), aa) to hh), aaa) to hhh), and aaaa) to hhhh), or in further embodiments of some alternative embodiments that include a rest period, the compound of formula (I) may be administered preferably at a dose of about 30 to about 200 mg of the free base or 60 to 200 mg of the free base.

[0330] In other alternative embodiments of any of the above combination therapies involving a compound of formula (I) (e.g., items a) to h), aa) to hh), aaa) to hhh), and aaaa) to hhhh)), TMZ may be administered not every day but on days 1 to 5 of each week for 6 or 7 weeks, or on days 1 to 5 of each week for 42 to 49 days, preferably at a dose of 75 mg TMZ / m on days 1 to 5 of each week. 2 / day for 6 or 7 weeks, or 75 mg TMZ / m on days 1 to 5 of each week 2 / day administration continues for 42 to 49 days.

[0331] In any of items a) to h), aa) to hh), aaa) to hhh), and aaaa) to hhhh) above, or in some alternative embodiments that include a rest period, the 6-week, 7-week, or 42-49-day combination treatment regimen involving a compound of Formula (I) may be followed by maintenance treatment with TMZ, optionally with the addition of an alternating electric tumor treating field (TTField). In some more specific aspects, the 6-week, 7-week, or 42-49-day combination treatment regimen involving a compound of Formula (I) may be followed by one or more 28-day cycles of maintenance treatment with TMZ, wherein TMZ is administered on days 1 to 5 of each 28-day cycle. For example, maintenance treatment with TMZ comprises 6 cycles (e.g., 28-day cycles). Optionally, an alternating electric tumor treating field (TTField) may be added to the TMZ maintenance treatment. Optionally, a 4-6 week rest period is observed before starting TMZ maintenance treatment.

[0332] In some specific embodiments of any of the above combination therapies (e.g., items a) to h), aa) to hh), aaa) to hhh), and aaaa) to hhhh)) involving a compound of Formula (I), optionally followed by TMZ maintenance therapy, the glioma is newly diagnosed. In some more specific embodiments, the newly diagnosed glioma is grade 4 according to WHO 2021. In the same or other specific embodiments, the newly diagnosed glioma is IDH wild-type.

[0333] In some aspects of the uses or methods according to the invention, such as (but not limited to) where the glioma has recurred after an initial or previous glioma treatment, the combination therapy may be defined as an alternative or additional treatment to:

[0334] k) a compound of formula (I) in combination with TMZ administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle;

[0335] l) a compound of formula (I) in combination with TMZ 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 of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base 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 free base per treatment day;

[0336] m) a compound of formula (I) administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle in combination with TMZ, wherein the compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base per treatment day, 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 free base per treatment day, and wherein TMZ is administered at:

[0337] o 50 to 300 mg / m on days 1 to 5 of each 28-day cycle 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, even more preferably 150 to 200 mg / m 2 / day dose, or

[0338] ο 50 mg / m 2 / day dose daily until progression, or

[0339] o On days 1 to 7 of each 28-day cycle, for example, 120 mg / m 2 / day, or

[0340] o On days 1 to 21 of each 28-day cycle, for example, at 80 mg / m 2 / sky;

[0341] n) a compound of formula (I) administered on days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle in combination with TMZ, wherein the compound of formula (I) is administered at a dose of about 30 to about 1000 mg, preferably about 30 to about 720 mg free base per treatment day, 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 free base per treatment day, and wherein TMZ is administered at:

[0342] o 150 to 200 mg / m2 on days 1 to 5 of each 28-day cycle 2 / day dose, or

[0343] ο 50 mg / m 2 / day dose daily until progression, or

[0344] o On days 1 to 7 of each 28-day cycle, for example, 120 mg / m 2 / day, or

[0345] o On days 1 to 21 of each 28-day cycle, for example, at 80 mg / m 2 / sky.

[0346] In some alternative embodiments derived from any one of items k) to n) above, the compound of formula (I) may be additionally administered on days 11 to 12 and 18 to 19 of a 28-day cycle, i.e., the compound of formula (I) may be administered on days 1 to 5, 8 to 12, and 15 to 19 of a 28-day cycle (additional WEE1 inhibitor treatment days).

[0347] In further alternative embodiments derived from any one of items k) to n) above, the compound of formula (I) may be additionally 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 (additional WEE1 inhibitor treatment days).

[0348] In some embodiments of any of items k) to n) above, or any of the embodiments with an additional WEE1 inhibitor treatment day, the compound of formula (I) can be preferably administered at a dose of about 150 to about 720 mg of free base or about 200 to about 720 mg of free base.

[0349] In any of items k) to n) above, or in any of some embodiments with an additional WEE1 inhibitor treatment day, the compound of formula (I) can be administered for 1, 2, 3, 4, 5, 6 or more 28-day cycles. For example, the compound of formula (I) can be administered for up to 2 years.

[0350] In some specific embodiments of any one of the above-mentioned combination treatments relating to formula (I) compound and TMZ, for example, in some specific embodiments of items k) to n) with any number of cycles or in some specific embodiments of any one of some embodiments with other WEE1 inhibitor treatment days with any number of cycles, glioma recurs after initial glioma treatment. In some aspects, initial glioma treatment is based on TMZ. Glioma may also recur after up to 2 previous glioma treatments, wherein one glioma treatment is based on TMZ.

[0351] In some more specific embodiments, the recurrent glioma is grade 4 according to WHO 2021. In the same or other specific embodiments, the recurrent glioma is IDH wild-type.

[0352] In some alternative more specific embodiments, the recurrent glioma is grade 3 according to WHO 2021. In the same or other specific embodiments, the recurrent glioma is IDH mutant.

[0353] As noted above, in some aspects, administration schedules described herein, for example when referring to radiation therapy, may be understood to encompass administration schedules that have been interrupted for one or more days (continuous or non-continuous).

[0354] In some embodiments of the present invention, the compound of formula (I) exhibits synergistic effects in treating gliomas in combination with TMZ or radiation therapy or both.

[0355] In particular, in some embodiments, the combination of a compound of formula (I) with TMZ or radiation therapy shows synergy in treating gliomas, as well as an acceptable safety profile. In addition, in some embodiments, the triple combination of a compound of formula (I) with TMZ and radiation therapy shows synergy in treating gliomas, as well as an acceptable safety profile.

[0356] Pharmaceutical composition

[0357] Pharmaceutical compositions of the present invention suitable for oral administration (oral dosage forms) can be present in solid or liquid form. Suitable solid oral dosage forms include capsules, tablets, powders or granules, etc., each containing a predetermined amount of active ingredient. Suitable liquid oral dosage forms include solutions, emulsions or suspensions. The pharmaceutical compositions of the present invention can also be in the form of sustained-release formulations.

[0358] In the solid oral preparation of the present invention, any inert component commonly used as a carrier or diluent can be used as a pharmaceutically acceptable excipient, such as gum, starch, sugar, cellulose material, acrylate / salt or its mixture.Preferred diluents include, for example, microcrystalline cellulose, anhydrous lactose.Compositions can also include disintegrants (such as cross-linked sodium carboxymethyl cellulose, sodium starch glycolate) and lubricants (such as magnesium stearate), and can additionally include one or more additives selected from: binder (such as hydroxypropyl cellulose), glidant (such as silicon dioxide), buffer (such as citric acid), surfactant (such as Tween 80), solubilizer (such as cyclodextrin), plasticizer (such as triacetin), emulsifier (such as sodium lauryl sulfate), stabilizer (such as povidone, ascorbic acid), viscosity increasing agent (such as hydroxypropyl methylcellulose), sweetener (such as sucrose), film former (such as cellulose-based system, polymer), coloring agent (such as iron oxide), flavoring agent or its any combination.

[0359] The oral pharmaceutical compositions of the present invention can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier constituting one or more essential ingredients. Generally speaking, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired appearance. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules) optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0360] Compound of formula (I)

[0361] In some embodiments of the present invention, the compound of formula (I) is formulated into a pharmaceutical composition in an oral dosage form. In some more specific embodiments, the compound of formula (I) is in the form of a solid oral dosage form, such as a tablet or capsule (which may include a powder, granules, or microtablets). The capsule may be a soft capsule or a hard capsule.

[0362] For example, the compound of formula (I) is formulated into capsules, such as hard gelatin capsules comprising microtablets. Each microtablet can 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). Medium capsule strengths can be easily produced to cover alternative dosage levels.

[0363] In some embodiments, solid oral dosage forms are packaged in blisters and / or bottles. In some embodiments, one, two, three, four, five, or six unit dosage forms are administered each time a compound of formula (I) is taken. Preferably, one to four unit dosage forms are administered each time a compound of formula (I) is taken.

[0364] For example, when formulated as a capsule containing microtablets, the excipients in each microtablet may include microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, sodium starch glycolate, anhydrous colloidal silicon dioxide, and / or magnesium stearate.Alternative excipients may be used in bioequivalent oral dosage forms.

[0365] Temozolomide

[0366] In some embodiments of the present invention, TMZ is formulated in a pharmaceutical composition that is an oral dosage form. In some more specific embodiments, the pharmaceutical composition containing TMZ is a capsule, such as a hard capsule.

[0367] TMZ capsules may contain: lactose, anhydrous lactose, colloidal silicon dioxide, sodium starch glycolate, tartaric acid and / or stearic acid. Alternative excipients may be used in bioequivalent oral dosage forms.

[0368] 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.

[0369] For example, the inactive ingredients of TMZ capsules may be as follows:

[0370] TMZ 5mg: anhydrous lactose (132.8mg), colloidal silicon dioxide (0.2mg), sodium starch glycolate (7.5mg), tartaric acid (1.5mg), and stearic acid (3mg).

[0371] TMZ 20 mg: anhydrous lactose (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).

[0372] TMZ 100 mg: anhydrous lactose (175.7 mg), colloidal silicon dioxide (0.3 mg), sodium starch glycolate (15 mg), tartaric acid (3 mg), and stearic acid (6 mg).

[0373] TMZ 140 mg: anhydrous lactose (246 mg), colloidal silicon dioxide (0.4 mg), sodium starch glycolate (21 mg), tartaric acid (4.2 mg), and stearic acid (8.4 mg).

[0374] TMZ 180 mg: anhydrous lactose (316.3 mg), colloidal silicon dioxide (0.5 mg), sodium starch glycolate (27 mg), tartaric acid (5.4 mg), and stearic acid (10.8 mg).

[0375] TMZ 250 mg: anhydrous lactose (154.3 mg), colloidal silicon dioxide (0.7 mg), sodium starch glycolate (22.5 mg), tartaric acid (9 mg), and stearic acid (13.5 mg).

[0376] For each dosage form and strength, alternative excipients may be used in a bioequivalent oral dosage form. For example, each of the above capsule strengths may contain lactose, sodium starch glycolate (Type B), tartaric acid, and stearic acid as excipients.

[0377] For example, the body of the capsule can be made of gelatin. The cap can also be made of gelatin, and the color of the capsule cap can vary based on the dosage strength. The capsule body and cap can be embossed with pharmaceutical branding ink, which can contain shellac, dehydrated alcohol, isopropyl alcohol, butanol, propylene glycol, purified water, concentrated ammonia solution, potassium hydroxide, and / or iron or iron oxide.

[0378] In some alternative embodiments of the present invention, TMZ is formulated as a pharmaceutical composition for injection. For example, TMZ is formulated as a powder for injection containing 5 to 250 mg of temozolomide, such as 100 mg of powder for injection.

[0379] As an example, a vial may contain 100 mg of sterile and 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 a bioequivalent IV dosage form.

[0380] In some embodiments of the 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.

[0381] Of course, in some embodiments, TMZ can be used in the form of a pharmaceutically acceptable salt. In such embodiments, the dosage, amount or concentration of etoposide indicated herein, i.e., the free base, can be appropriately adjusted according to the molecular weight of the corresponding salt.

[0382] ***

[0383] Some embodiments of the present disclosure may be further defined and illustrated by reference to the following non-limiting examples. It will be apparent to those skilled in the art that many modifications or variations, such as to the materials and methods, may be implemented without departing from the scope of the present disclosure.

[0384] Example

[0385] Example 1: Concentrations of compound of formula (I), AZD1775 and Zn-c3 in brain tissue of healthy mice after repeated administration Sure.

[0386] Healthy male Nu / Nu mice were orally treated with: (i) a single dose of 30 mg / kg compound of formula (I) (25 mice total, 3 mice per time point), (ii) 30 mg / kg compound of formula (I) once daily for four consecutive days (27 mice total, 3 mice per time point), (iii) 30 mg / kg AZD-1775 (adavosertib, available from Combi-Blocks, San Diego, USA) twice daily for three consecutive days and once on the fourth day (27 mice total, 3 mice per time point), (iv) or 80 mg / kg Zn-c3 (available from EOS Med Chem, Jina City, China) once daily for four 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 containing 0.5% methylcellulose and 1% Tween 80 and administered at a concentration of 3.0 mg / mL. AZD-1775 was formulated as a suspension in water containing 0.5% methylcellulose at a dose concentration of 3.0 mg / mL, and Zn-c3 was prepared in water containing 20% ​​HP-β-CD ((2-hydroxypropyl)-β-cyclodextrin) and administered as a solution at a dose concentration of 8 mg / mL. The dosing volume for all formulations was 10 mL / kg.

[0387] At the designated time point, mice were euthanized by carbon dioxide inhalation, and blood samples were collected by cardiac puncture into tubes containing K2EDTA. The tubes were inverted several times, placed on ice, and centrifuged (4°C, 6000rpm for 5 minutes) within 30 minutes of collection to obtain plasma. Plasma samples were snap frozen in dry ice and stored at -80°C until analyzed. Brains were collected, weighed, and snap frozen in dry ice until further analyzed. In order to obtain brain homogenates, water was first added to each brain (brain weight: water volume = 1: 4), and then the brain was homogenized with a high-speed disperser (H-speed dispersator) (time program: homogenization 10 seconds, and each interval of 10 seconds, a total of 3 to 5 times; cleaning program of disperser: water-methanol-ethanol-water, each 10 seconds). Brain homogenate samples were transferred to separate tubes and stored at -80°C, then analyzed.

[0388] 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 (with K2EDTA anticoagulant) and brain homogenate. An internal standard (internal standard for compounds of formula (I)) in methanol / acetonitrile (1:1, v / v) was added to each aliquot of standards, QC, control blanks, and study samples. 13 CD6 - compound of formula (I), terfenadine as internal standard for AZD-1775 and Zn-c3. The sample was mixed for 1 minute and centrifuged at 4000 rpm for 15 minutes at 4°C. The supernatant was removed and diluted in MeOH / water (1:1, v / v, with 0.1% FA) prior to LC-MS / MS injection.

[0389] Chromatographic separation was achieved based on Shimadzu LC-20AD, using a Kinetex 2.6μ C18 100A column (50 mm*3.00 mm) for the compound of formula (I) and AZD-1775 samples and an ACE 5C4 column (50 mm*2.1 mm) for the Zn-c3 sample, with gradient elution using the following conditions: flow rate: 0.7 mL / min; run time: 3.0 min; mobile phase: A: 5 mM NH4OAc (0.1% FA), B: acetonitrile (0.1% FA).

[0390] Detection was performed using an AB Sciex 5500 electrospray MS / MS in positive ion multiple reaction monitoring (MRM) mode. For the compound of formula (I), the MRM transitions were 511.29 / 98, for AZD-1775, 501.47 / 442.20, and for Zn-c3, 527.36 / 468.10. For the compound of formula (I), the MRM transitions for the internal standard were 518.17 / 102.10 ( 13 CD6 - compound of formula (I)), 472.40 / 436.40 for AZD-1775 and Zn-c (terfenadine).

[0391] The plasma and brain concentrations measured at each time point, the nominal sample collection time, and the expected dose were used for pharmacokinetic analysis. The PK parameters of all study compounds were determined by non-compartmental analysis using WinNonlin version 8.0 (Pharsight). The results are summarized in Table 2 below.

[0392] Table 2

[0393]

[0394] AUC = Area Under the Concentration-Time Curve, measures exposure of the test item (compound of formula (I), AZD-1775, Zn-c3) in plasma or brain.

[0395] Cmax = maximum concentration of the test item measured in plasma or brain.

[0396] AUClast = area under the concentration-time curve, based on the time from time 0 to the last measured concentration in brain or plasma. For example, for the compound of formula (I), the last measured time point in plasma is 48 hours, and AUClast reflects the area under the plasma concentration-time curve from 0 hours to 48 hours.

[0397] AUCinf = area under the concentration-time curve, based on time 0 and extrapolated to infinity (i.e., beyond the last measured time point). For example, for the compound of formula (I), the last measured time point in plasma is 48 hours, and AUCinf reflects exposure from time 0 hours to beyond 48 hours.

[0398] Figure 1 Three graphs are shown showing the following: Compound of formula (I) ( Figure 1 (A)), 30 mg / kg bid AZD1775 ( Figure 1 (B)) and 80 mg / kg qd of Zn-c3 ( Figure 1 (C)) Plasma and brain concentrations measured on day 4 thereafter.

[0399] The results of Example 1 indicate that the 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 the compound of formula (I) is favorable compared to AZD1775 and Zn-c3, as reflected by the higher brain to plasma exposure ratio of the compound of formula (I) (which is over 10 times higher than that of AZD11775 and over 7 times higher than that of Zn-c3).

[0400] Example 2: Determination of the concentration of the compound of formula (I) in brain tissue and cerebrospinal fluid of healthy rats after a single administration.

[0401] Healthy male Wistar Han rats were orally treated with a single dose of 15 mg / kg of the compound of formula (I) (24 rats total, 3 rats at each time point). The compound of formula (I) was formulated as a suspension containing 0.5% methylcellulose and 1% Tween 80 and administered at a concentration of 1.5 mg / mL and a dosing volume of 10 mL / kg.

[0402] At designated time points (0.5, 1, 2, 4, 8, 24, 32, 48 hours after administration), rats were euthanized by carbon dioxide inhalation. After this, blood, CSF and brain samples were collected as follows. Blood samples were collected into tubes containing K2EDTA by cardiac puncture. The tubes were inverted several times, placed on ice, and centrifuged (4°C, 6000rpm for 5 minutes) within 30 minutes of collection to obtain plasma. Plasma samples were quickly frozen in dry ice and stored at -80°C until analyzed. CSF samples were collected by puncturing the foramen magnum with a scalp needle. CSF samples were acidified with 10% formic acid (final sample concentration was 0.5% formic acid) and stored at -80°C until further analyzed. Brains were collected, weighed, and quickly frozen in dry ice until further analyzed. To obtain brain homogenates, water was first added to each brain (brain weight: water volume = 1:4), and then the brain was homogenized using a high-speed disperser (time program: homogenization for 10 seconds, with a 10-second interval each time, a total of 3 to 5 times; disperser cleaning program: water-methanol-ethanol-water, each 10 seconds). Brain homogenate samples were transferred to individual tubes and stored at -80°C before analysis.

[0403] Samples were analyzed as follows. For each analytical batch of plasma and brain samples, standards and quality control (QC) samples were freshly prepared from blank male Wistar Han plasma (with K2EDTA anticoagulant) and brain homogenate. Acidified (containing 0.5% formic acid) artificial CSF was used as a standard and quality control for the CSF samples. In addition, a set of blank male Wistar Han CSF was included as a QC sample.

[0404] An aliquot of each standard, QC, control blank, and study sample was spiked with an internal standard ( 13 CD6 - Compound of Formula (I). The sample was mixed for 1 minute and centrifuged at 4000 rpm for 15 minutes at 4° C. The supernatant was transferred and diluted in MeOH / water (1:1, v / v, with 0.1% FA) before LC-MS / MS injection.

[0405] Chromatographic separation was achieved using a Kinetex 2.6μ C18 100A column (50 mm * 3.00 mm; for plasma and brain samples) or an ACE 5C4 column (50 mm * 2.1 mm; for CSF samples) on a Shimadzu LC-20AD (for plasma and brain samples) or a Shimadzu LC-30AD (for CSF samples). The following conditions were used: flow rate: 0.7 mL / min; run time: 3.0 min; mobile phase: A: 5 mM NH4OAc (0.1% FA), B: acetonitrile (0.1% FA).

[0406] Detection was performed using an AB Sciex 5500 electrospray MS / MS in positive ion multiple reaction monitoring (MRM) mode. For the compound of formula (I), the MRM transition was 511.29 / 98, and for the internal standard 13 CD6-compound of formula (I) is 518.17 / 102.10.

[0407] The plasma, CSF and brain concentrations measured at each time point, the nominal sample collection time and the expected dose were used for pharmacokinetic analysis. The PK parameters of all study compounds were determined by non-compartmental analysis using WinNonlin version 8.0 (Pharsight). The results are summarized in Table 3 below.

[0408] Table 3

[0409]

[0410] * The concentration of the compound of formula (I) in CSF reflects the concentration of the unbound drug. Therefore, in order to determine the CSF to plasma ratio, the unbound plasma concentration is more relevant than the total concentration. The unbound compound of formula (I) plasma concentration is calculated based on the 7.8% free fraction determined in rat plasma in a separate experiment (not shown), as follows. For example, Cmax plasma (1138 ng / mL) × free fraction in rat plasma (0.078) = unbound plasma concentration (88.76 ng / mL). Therefore, the CSF to unbound plasma ratio is calculated as follows: CSF concentration (15.6 ng / mL) / unbound plasma concentration (88.76 ng / mL) = 0.18.

[0411] Figure 2 Shown graphically are total plasma concentrations, total brain concentrations, unbound CSF concentrations, and calculated unbound plasma concentrations of compounds of formula (I) over time.

[0412] The results of Example 2 show that the compound of formula (I) can cross the blood-brain barrier and distribute in the brain in rats. In addition, the results show that the compound of formula (I) can cross the blood-CSF barrier and distribute in the CSF.

[0413] Example 3: Determination of drug concentrations in monkey brain after daily oral administration for 91 days

[0414] The compound of formula (I) was orally administered to 3 female cynomolgus monkeys by gavage once a day for 91 days. The administration 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; based on general toxicological evaluation, this dose level was assessed as the lowest no adverse effect level (NOAEL) in this study. Animals were autopsied 24 hours after the last dose after an overnight period without food. Samples from brain tissue (left forebrain) were collected from each animal, quickly frozen in liquid nitrogen, and stored frozen at <-50°C. Blood samples were collected from the femoral vein into tubes containing K2EDTA, completely inverted about 10 times, and placed on crushed wet ice until centrifuged at 2300g for 10 minutes at about 4°C. The resulting plasma was separated, transferred to polypropylene tubes, and frozen at <-50°C. Tissue and plasma samples were shipped frozen on dry ice to the respective analytical sites.

[0415] The compound of formula (I) and N in monkey plasma samples were analyzed as follows: 32 -demethyl-compound of formula (I) was analyzed. Plasma samples were fortified in human K2-EDTA plasma (1:9 monkey:human volume ratio) and then extracted. All solution preparations and dilutions were performed under a sodium vapor lamp and in "low binding" quality polypropylene tubes and deep well plates. Analytes and internal standards ( 13 CD6-compound of formula (I) and D7-N 32 -demethyl-compound of formula (I)) and subsequently analyzed by LC-MS / MS. Chromatographic separation was achieved based on the following: on a SynergiPolar-RP, 4 μm 75 × 2.00 mm column (Phenomenex) using a gradient elution of 0.1% formic acid in water as eluent A and 0.1% formic acid in acetonitrile as eluent B (5% B from 0 to 0.50 minutes, 42% B at 4.5 minutes, 95% B from 4.60 minutes to 5.50 minutes, 5% B at 5.60 minutes, 100% B at 5.70 minutes, 5% B at 6.40 minutes, 100% B at 6.50 minutes, 5% B at 7.00 minutes; 800 μl / min, 70°C). Detection was performed using an AB Sciex 6500+ mass spectrometer using electrospray MS / MS in positive ion multiple reaction monitoring (MRM) mode. Compounds of formula (I) and N 32 The lower limits of quantification of the -desmethyl-compound of formula (I) were 5.00 ng / mL and 2.50 ng / mL, respectively.

[0416] The monkey brain tissue samples were analyzed for the compounds of formula (I) and N 32 -demethyl-compound of formula (I) was determined by homogenizing tissue samples in human plasma (10 μL plasma for 1 mg tissue) at +4°C using a Precelly Evolution system. 13 CD6-compound of formula (I) and D7-N 32 The analytes (compound of formula (I) and N-demethyl-compound of formula (I)) were extracted by protein precipitation with methanol / acetonitrile (9:1, v:v). 32 -demethyl-compound of formula (I)) and subsequently analyzed by UHPLC-MS / MS. Chromatographic separation was achieved on an HSS T3 1.8 μm, 2.1×100 mme column (Waters) using a gradient elution of 0.1% formic acid in water as eluent A and 0.1% formic acid in acetonitrile as eluent B (20% B from 0 to 0.50 minutes, 90% B from 1.80 minutes to 2.30 minutes, and 20% B at 2.60 minutes; 0.6 mL / min, room temperature). Detection was performed using a Xevo TQ-S mass spectrometer (Waters) using electrospray MS / MS in positive ion multiple reaction monitoring (MRM) mode. Compound of formula (I) and N 32 The lower limits of quantification of the -desmethyl-compound of formula (I) were 55.00 ng / g tissue and 22.00 ng / g tissue, respectively.

[0417] The results are shown in Table 4 below.

[0418] Table 4

[0419]

[0420] For compounds of formula (I) and N 32 For both -desmethyl metabolites, brain concentrations were non-negligible compared to plasma concentrations 24 hours after the last dose, indicating that both compounds have the ability to cross the blood-brain barrier.

[0421] Example 4: In vitro efficacy of the compound of formula (I) in combination with radiotherapy (RT) in GBM cell lines Effectiveness

[0422] GBM tumor cells (T98G, LN18, SNB-19 and U251) were cultured as adherent monolayers at 37°C in a humidified atmosphere (5% CO2, 95% air). For experimental use, tumor cells were isolated from culture flasks by treating with trypsin-versene for 5 minutes in Hanks medium without calcium or magnesium and neutralized by adding complete medium. Cells were counted and viability was assessed using a 0.25% trypan blue exclusion assay. All cell lines were appropriately seeded in 6-well plates (Ref#152795, Nunc, Dutscher) containing 1.9 ml of cell culture medium at 3 densities according to the conditions for monolayer colony formation to evaluate the colony-forming effect. The cell density was 500, 100 or 200 cells / well for GL261 and LN-18 cell lines, 1500, 2000 and 2500 cells / well for SNB-19 cell line, and 250, 500 and 1000 cells / well for T98G cell line.

[0423] Treatment was performed 24 hours after seeding (D1) by adding ×20 concentrated compound or vehicle solution to obtain a final concentration of 0.1 μM to 5.0 μM of the compound of formula (I) [ Figure 3 =Referred to as CoF(I) in the text]. 0.1% DMSO vehicle was added as a control. The plates were irradiated at 1, 2 and 4 Gy immediately after compound treatment. Irradiation was performed using a SARRP irradiation system (Xstrahllife science). Simulated irradiation was performed on plates corresponding to unirradiated controls. On day 2 (the day after treatment and irradiation) and day 7, the culture medium in all plates was replaced with fresh culture medium without the compound of formula (I). After incubation for 14 days, the colonies were counted after staining by incubating for 2 hours with 500 μl of an aqueous solution containing 0.05% (w / v) methylene blue (Ref. M4159, Sigma). Colonies were counted using a colony counting pen (Ref#045855, Dutscher, Brumath, France). The survival fraction for each condition was calculated using the following equation and plotted on a semi-logarithmic graph using a linear quadratic model. The survival fraction was calculated using 1 / y 2 The curves were weighted. Statistical testing was performed using the extra sum of squares F test with H0 = one curve accurately fits all the data. All analyses were performed using GraphPad Prism 7 (Graphpad Inc., LaJolla, CA).

[0424]

[0425] Linear Quadratic Model:

[0426] Experiments for each cell line were pooled together for further analysis using a linear quadratic model.

[0427] The results showed that the compound of formula (I) significantly enhanced the effect of radiotherapy in T98G, SNB19 and LN18 cell lines (p < 0.0001) ( Figure 3 In the case of the U251 cell line, this was not significant (p=0.6); however, based on simulations, running the same analysis using more replicates or by comparing only the control and the 5 μM condition alone would also be statistically significant for this cell line.

[0428] Example 5: In vivo efficacy of the compound of formula (I) as a monotherapy in the U87-MG-luc GBM cell line

[0429] Male athymic nude mice were injected with 1×10 5 U87-MG-luc cells. Throughout the study, once a week, animals implanted with ic were imaged using an in vivo imaging system (IVIS) to monitor tumor establishment and growth, detecting tumor bioluminescence (BLI) in photons. For animals implanted with sc, tumor growth was monitored by caliper measurement twice a week, and tumor volume was calculated using the equation 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 tumor establishment was confirmed, animals were randomly assigned to 3 (A, sc) or 2 (B, ic) treatment groups (n=8 animals / group) consisting of vehicle (0.5% methylcellulose, 1% Tween 80 P.O. and saline IV) or a compound of formula (I) [CoF(I)] formulated as a suspension containing 0.5% methylcellulose and 1% Tween 80. Treatments were administered over a 28-day cycle, and the compound of formula (I) was orally administered once daily (QD) at a dose of 30 mg / kg (for both A and B) or 60 mg / kg (for A only). During routine monitoring, animals were examined for tumor growth and any effects of treatment on behavior, such as activity, food and water consumption, weight gain / loss (3 times per week), eye / hair matting, and any other abnormalities. The mortality rate and observed clinical signs of individual animals were recorded in detail. Results are given in Table 1. Figure 4 Shown in.

[0430] Treatment of subcutaneously implanted U876-MG-luc tumors with 30 mg / kg or 60 mg / kg of compound of formula (I) resulted in tumors significantly smaller than vehicle controls at the end of the treatment period (p=0.0009 and p<0.0001 on day 28, respectively).

[0431] Treatment of brain-implanted U876-MG-luc tumors with 30 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=0.0023 at day 28).

[0432] No significant weight loss was observed throughout the study, indicating that treatment with the compound of formula (I) was well tolerated at all dose levels.

[0433] Thus, the compounds of formula (I) used in monotherapy were well tolerated for the treatment of subcutaneously or intracerebrally implanted GBM tumors and resulted in significant antitumor activity.

[0434] Example 6: In vivo efficacy of the compound of formula (I) in combination with temozolomide in the U87-MG-luc GBM cell line

[0435] 1×10 5 U87-MG-luc cells were injected into the cerebellum of male athymic nude mice. Throughout the study, animals were imaged weekly using an in vivo imaging system (IVIS) to monitor tumor establishment and growth, detecting tumor bioluminescence (BLI) in photons. Once tumor establishment was confirmed, animals were randomly assigned to eight treatment groups: vehicle (0.5% methylcellulose, 1% Tween 80 P.O. and saline IV), compound of formula (I) [CoF (I)] (formulated as a suspension containing 0.5% methylcellulose and 1% Tween 80) administered orally once daily (QD) at 3 mg / kg, 10 mg / kg, or 30 mg / kg as a monotherapy over a 28-day period, temozolomide [TMZ] administered orally once daily (QD) at 3 mg / kg as a monotherapy, and a combination of compound of formula (I) + TMZ at each dose (n = 6 animals / group for the monotherapy group and n = 8 animals / group for the combination group). In the combination group, the compound of formula (I) was administered 2 hours before TMZ. During routine monitoring, animals were examined for tumor growth and any effects of treatment on behavior, such as activity, food and water consumption, weight gain / loss (3 times per week), dull eyes / hair, and any other abnormalities. Detailed records were kept of individual animal mortality and observed clinical signs.

[0436] Treatment of brain-implanted U876-MG-luc tumors with 3 mg / kg or 10 mg / kg of the compound of formula (I) as a monotherapy did not produce any significant antitumor activity, as determined by mean relative BLI, however treatment with 30 mg / kg of the compound of formula (I) resulted in tumors significantly smaller than vehicle controls (p = 0.0133 on day 36), consistent with the results presented in Example 5 (Bi.c.). Since U876-MG-luc is a TMZ-sensitive tumor model, treatment with TMZ resulted in a significant antitumor response (p = 0.0066 compared to vehicle on day 36) that persisted throughout the monitoring period, with 3 of 6 treated animals experiencing a complete response.

[0437] Furthermore, treatment of U87MG-luc tumors with a compound of Formula (I) in combination with TMZ also resulted in significant antitumor activity compared to vehicle controls (p<0.001 at all doses of the compound of Formula (I) on day 28), which persisted for up to 160 days. Additionally, during the treatment period, treatment with a combination of the compound of Formula (I) at doses of 10 mg / kg and 30 mg / kg showed significant antitumor activity compared to standard of care TMZ treatment (p=0.0213 and p=0.0174, respectively, on day 28). Figure 5 (This demonstrates that a 10 mg / kg dose of the compound of formula (I) in combination with TMZ is sufficient to achieve a significant antitumor effect.) In each combination group, treatment resulted in durable responses throughout the monitoring period, with 3 of 8 animals (3 mg / kg compound of formula (I), 6 of 8 animals (10 mg / kg compound of formula (I),) and 5 of 7 animals (30 mg / kg compound of formula (I)) experiencing a complete response (defined as a BLI value = 0).

[0438] 3 mg / kg of TMZ, 3, 10 and 30 mg / kg of the compound of formula (I) as a monotherapy, and the combination of the compound of formula (I) and temozolomide at all tested doses were also well tolerated, with no significant changes in animal body weight compared to pre-treatment levels during the 28-day treatment period. All groups maintained their body weight after the treatment period and no post-treatment intolerance was observed.

[0439] Example 7: The compound of formula (I) as a single treatment or in combination with TMZ has an effect on the survival of mice bearing GL261 intracranial tumors. In vivo evaluation.

[0440] GL261 cells were harvested during the logarithmic growth phase and resuspended in phosphate buffered saline (PBS). 5Female C57 / BL6 mice were inoculated with 10 μL of GL261 cells (10 μL of cell suspension). According to the protocol, the injection site was determined based on the intersection of the midline suture and the caudal transverse suture. The tip of a 25-gauge needle was placed 1 mm cranial to the intersection and 1 mm to the right or left, and 10 μL of GL261 glioma cell suspension was injected into this space. Intracranial injections were performed five days before the start of treatment.

[0441] The compound of formula (I) [CoF (I)] and temozolomide were orally administered (po) in a dosing volume of 10 mL / kg, adjusted in proportion to the latest body weight (BW) of the individual animals. The compound of formula (I) was administered once daily for fourteen days (qd×14) or twenty-eight days (qd×28). Temozolomide was administered once daily for five days (qd×5). For the combined treatment group, the compound of formula (I) was administered 2 hours before temozolomide was administered. Five days after GL261 tumor cell implantation (designated as the first day of the study), mice were divided into eight groups (n=8) by BW. Dosing began on the first day, with group 1 mice receiving vehicle poqd×14 and used as a control for efficacy analysis. Group 2 received 30 mg / kg of the compound of formula (I) poqd×14, Group 3 received 3 mg / kg of temozolomide qd×5, and Group 4 mice received a combination of 30 mg / kg of the compound of formula (I) qd×14 and 3 mg / kg of temozolomide qd×5. The study endpoint was death or moribundity due to glioma progression or the last day of the study, whichever came first (i.e., event). The time to event (TTE) value before the median event of each group was calculated. The median TTE of the treated mice was expressed as a percentage of the median TTE of the control mice (%T / C), and the increase in life span (ILS) was calculated as: ILS=%T / C-100%, where T=median TTE treated and C=median TTE control. Therefore, if T=C, then ILS=0%. Based on the ratio between the study endpoint and the median TTE of the control group (22.5 days), the maximum %ILS in this study was 296% (Teicher, Beverly A. Tumor models in cancer research. New York: Humana Press Springer, 2011).

[0442] For the 30 mg / kg combination group of the compound of formula (I) and temozolomide, the median TTE was 30.0 days, corresponding to 33% ILS. The overall survival of the combination group was improved over the temozolomide single-agent regimen (p<0.01) ( Figure 6 ).

[0443] Example 8: In vitro efficacy of the compound of formula (I) as a monotherapy in ATRX-deficient GBM cell lines

[0444] SF188 cells were transfected with ATRX siRNA (siATRX_1 or siATRX_2) alone (A) or as a pool (B and C) or with control siRNA (siCon), and relative ATRX protein levels were determined by western blotting to assess ATRX deficiency. Control and ATRX-deficient SF188 cells were then treated with ATRX at concentrations ranging from 0 to 1.5 μM ( Figure 7 A) and 400 nM ( Figure 7 B) were treated with compounds of formula (I) and drug sensitivity was assessed by ATP-based cell viability assay or in colony formation assay.

[0445] For cell viability assessment, SF188 cells were seeded in 96-well culture plates at 100 to 500 cells / well in 100 μl culture medium. After overnight incubation, 100 μl of culture medium containing the compound of formula (I) was added to each well at the desired final concentration. After 72 hours, cell viability was assessed by CellTiter-Glo 2.0 according to the manufacturer's instructions. Each condition was tested in triplicate or quadruplicate, and the average viability was expressed as a percentage of vehicle-treated cells. For colony formation assessment ( Figure 7 C), SF188 cells were seeded on 6-well plates at 100 cells / well in 1 ml of culture medium. After overnight incubation, 1 ml of culture medium containing the compound of formula (I) was added to each well at the desired final concentration (up to 400 nM). Ten days after treatment, the 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 of a single cell). The colony formation efficiency was determined by normalizing the number of colonies relative to the cells treated with the vehicle.

[0446] In the colony formation assay ( Figure 7 C), treatment with the compound of formula (I) significantly reduced the surviving fraction of cells, indicating its anti-tumor activity. In the cell viability assay ( Figure 7 A and 7B), treatment with the compound of formula (I) significantly reduced the viability of SF188 cells, and ATRX siRNA significantly improved this response to the compound of formula (I), with an IC50 less than half that of the control siRNA ( Figure 7 A). After treatment with 400 nM of the compound of formula (I), the cell viability of ATRX-deficient SF188 cells was significantly reduced (p<0.01) ( Figure 7B). Western blot showed that treatment with siRNA ATRX pool 1 (ATRX_1) or pool 2 (ATRX_2) resulted in a significant decrease in the protein level of ATRX ( Figure 7 bottom of B).

[0447] Example 9: Phase 1 / 2 clinical trial involving the compound of formula (I) (referred to herein as study drug)

[0448] The clinical trial will be conducted as a Phase 1 / 2, multicenter, open-label, non-randomized, controlled study in adult participants with glioma, as described below.

[0449] Phase 1 (dose escalation) consists of 2 groups:

[0450] - Group A: The study population in this group consists of adult participants with confirmed (according to WHO 2021)

[0451] -GBM isocitrate dehydrogenase (IDH) - wild type, grade 4, or

[0452] - Astrocytoma, IDH-mutant, Grade 3,

[0453] They have progressed or experienced disease relapse after up to 2 previous lines of treatment. All participants must have received temozolomide (TMZ)-based chemoradiation therapy as first-line treatment. These participants will receive oral dosing once daily in 28-day cycles as follows: study drug (increasing dose) is administered on Days 1 to 5 (Day, D), D8 to 10, and D15 to 17 of each cycle, and TMZ (150 mg / m 2 100 mg of study drug was administered daily on Days 1 to 5 of each cycle. Treatment will continue for up to 2 years or until disease progression, unacceptable toxicity, participant withdrawal, discontinuation at the investigator's discretion, initiation of subsequent anti-cancer therapy, end of study, or death, whichever occurs first. The starting dose of study drug was 150 mg, based on a dose level determined to be safe in ongoing Phase 1 studies, Study 101, which involves the study drug in combination with carboplatin, and Study 102, which involves the study drug as a monotherapy.

[0454] - Arm B: This study population consists of adult participants with confirmed, newly diagnosed GBM IDH-wild-type grade 4 (WHO 2021). These participants will receive oral administration once daily for 6 weeks as follows: continuous daily administration of study drug (escalating doses) and TMZ (75 mg / m 2 / day) and concomitantly with radiation therapy (RT; conventional fractionation schedule of 2 Gy per day, 5 consecutive days per week, for a total dose of 60 Gy in 30 fractions). The starting dose of study drug is 90 mg, which is based on available data from dose levels determined to be safe in ongoing Phase 1 studies, namely Study 101 involving the study drug in combination with carboplatin and Study 102 involving the study drug as a monotherapy. Emerging data, including those from Group A of this clinical trial, will be evaluated to determine the proposed starting dose. After a 4- to 6-week cool-down period following the end of study treatment, alternating current tumor treating fields (TTField) may be administered with or without the addition of standard of care (SOC) at the discretion of the investigator. TMZ maintenance therapy, if available, will last for 5 days (D1 to 5) and will be repeated every 28 days. Group B will begin after at least 2 dose levels in Group A are found to be safe.

[0455] During the dose escalation phase, dose recommendations for study drug will be provided independently to Group A and Group B. The maximum tolerated dose (MTD) and / or recommended Phase 2 dose (RP2D) to be used in Part 2 will be determined based on the Safety Monitoring Committee (SMC) recommendation.

[0456] After the end of treatment (EOT) visit, participants in phase 1 will be followed for safety and antitumor activity until disease progression or, in the absence of disease progression, until initiation of subsequent antitumor therapy, withdrawal of consent, loss to follow-up, death, or end of study, whichever occurs first.

[0457] Once the RP2D for Phase 1 Group A is determined following the recommendations of the SMC, Phase 2 will begin. Phase 2 is a multicenter, open-label, externally controlled study that compares the efficacy and safety of the study drug in combination with TMZ relative to SOC in adult participants diagnosed with GBM IDH-wild type grade 4 (WHO 2021) who have received first-line TMZ-based chemoradiation and have progressed or experienced disease recurrence. A group sequential design will be used to compare participants assigned to treatment with study drug and TMZ with patients in the external control arm (ECA).

[0458] Phase 2 consists of 2 groups:

[0459] - Experimental Group: The study population consists of adult participants with confirmed GBM IDH-wild type grade 4 (WHO 2021) who have received first-line TMZ-based chemoradiation therapy and have progressed or experienced disease recurrence. Participants enrolled in this group will receive oral dosing once daily over a 28-day cycle as follows: study drug at RP2D on Days 1 to 5, Days 8 to 10, and Days 15 to 17, and TMZ (150 mg / m 2 / day) were administered on Days 1 to 5. Treatment will continue for a maximum of 2 years or until disease progression, unacceptable toxicity, participant withdrawal, discontinuation at the investigator's discretion, study end, or death, whichever occurs first.

[0460] -ECA: The study population consists of adult participants with confirmed GBM IDH-wild-type grade 4 (WHO 2021) who have progressed or experienced disease recurrence after first-line TMZ-based chemoradiation. The ECA includes only patient-level data from patients who have been treated with SOC therapy in a recently completed historical clinical trial (HCT). A propensity score approach will be used to balance baseline and disease-specific prognostic factors in ECA patients with study drug participants.

[0461] The safety and efficacy of participants assigned to treatment with study drug and TMZ in Phase 2 were compared with those in the ECA.

[0462] After the end-of-treatment (EOT) visit, participants in the experimental group will be followed for safety and antitumor activity until disease progression, or in the absence of disease progression, until the start of subsequent antitumor therapy, withdrawal of consent, loss to follow-up, death, or end of study, whichever occurs first. In addition, these participants will be followed for OS.

[0463] In Phase 1 Cohort A and Phase 2 experimental groups, one treatment cycle was defined as 28 days.

[0464] Abbreviations used in tables and text:

[0465] AE = adverse event;

[0466] AUC = area under the concentration-time curve;

[0467] AUC24 = area under the concentration-time curve over 24 hours;

[0468] AUClast = area under the concentration-time curve until the last measurable concentration;

[0469] BOR=best overall response;

[0470] CL / F = apparent clearance;

[0471] Cmax = maximum plasma concentration;

[0472] CSF = cerebrospinal fluid;

[0473] Ctrough = trough plasma concentration;

[0474] CV = coefficient of variation;

[0475] DC = disease control;

[0476] DCR = disease control rate;

[0477] DOR = duration of response;

[0478] DLT = dose-limiting toxicity;

[0479] DOR = duration of response;

[0480] ECG = electrocardiogram;

[0481] ECHO = echocardiogram.

[0482] EOT = end of treatment;

[0483] FACT-Br = Functional Assessment of Cancer Therapy-Brain;

[0484] GBM = glioblastoma;

[0485] Gd-based = gadolinium-based (a contrast agent used in MRI);

[0486] ka = absorption rate constant;

[0487] KPS = Karnofsky Performance Status; KPS is an assessment tool for functional impairment. It is a standard way to measure the ability of participants with cancer to perform common tasks. Scores range from 0 (death) to 100 (no evidence of disease). Higher scores mean that participants are better able to perform daily activities.

[0488] LVEF = left ventricular ejection fraction.

[0489] mRANO = Modified Response Assessment in Neuro-Oncology; i.e., the 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.

[0490] NCI-CTCAE 5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0;

[0491] OR = objective response;

[0492] ORR = objective response rate.

[0493] OS = overall survival;

[0494] PD = progressive disease;

[0495] PFS = progression-free survival;

[0496] PK = pharmacokinetics;

[0497] QoL = quality of life;

[0498] RANO = Response Assessment in Neuro-Oncology; i.e., the recommendations 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.

[0499] RP2D = recommended phase 2 dose;

[0500] RT = radiation therapy.

[0501] SOC = standard of care;

[0502] t1 / 2 = apparent terminal half-life;

[0503] TEAE = treatment-emergent adverse event;

[0504] tmax = time to reach Cmax;

[0505] TMZ = temozolomide;

[0506] Vd = volume of distribution;

[0507] Vd / F = Apparent Vd

[0508] The primary objectives and estimates (Estimands) of the clinical trial (including endpoints) include:

[0509]

[0510]

[0511] Secondary objectives and estimates (including endpoints) for clinical trials include:

[0512]

[0513]

[0514]

[0515] Exploratory objectives of the clinical trial include:

[0516]

[0517] The clinical trial Research group As follows: 1st issue:

[0518] - Group A: Adult participants (≥18 years) with confirmed (WHO 2021) GBM IDH-wildtype Grade 4 or astrocytoma IDH-mutant Grade 3 who received first-line TMZ-based chemoradiation and have progressed or relapsed on up to 2 lines of treatment.

[0519] - Group B: Adult participants (≥18 years) with confirmed, newly diagnosed GBM IDH-wildtype grade 4 (WHO 2021).

[0520] Phase 2:

[0521] - Experimental Group: Adult participants (≥18 years) with confirmed (WHO 2021) GBM-IDH wild-type grade 4 disease who have received first-line TMZ-based chemoradiation therapy and have progressed or experienced disease recurrence.

[0522] -ECA: Adult patients with confirmed (WHO 2021) GBM IDH-wildtype Grade 4 disease who have progressed or experienced disease recurrence after first-line TMZ-based chemoradiation. The ECA will consist of patients treated with standard of care from HCT.

[0523] Inclusion criteria :

[0524] For both Phase 1 (Arms A and B) and Phase 2, inclusion criteria included:

[0525] - (Both) Willingness to provide archived or fresh tumor samples (if available). Receipt of tumor samples is not required at the start of study treatment.

[0526] -(Both) Adequate bone marrow, liver, and kidney function:

[0527] 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 of study treatment.

[0528] 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 phosphatases (ALP) < 2.5 × ULN, or ≤ 5 × ULN for participants with liver metastases.

[0529] Calculated creatinine clearance ≥50 mL / minute (min) (as determined by the Chronic Kidney Disease–Epidemiology Collaboration (CKD EPI) formula).

[0530] Coagulation status: INR or prothrombin time ≤1.5×ULN; activated partial thromboplastin time (aPTT) ≤1.5×ULN.

[0531] - (Both) Life expectancy is at least 3 months based on the investigator's best judgment.

[0532] - (Both) Participants receiving corticosteroids must have maintained a stable or decreasing dose of ≤4 mg dexamethasone (or ≤25 mg prednisone) daily for 7 days prior to the start of study treatment.

[0533] - (Both) Participants with epileptic seizures must be adequately controlled on a stable anti-epileptic medication regimen.

[0534] Caution: Anticonvulsants with enzyme-inhibiting or -inducing properties are contraindicated.

[0535] - (Both) Measurable or non-measurable disease according to RANO criteria by Gd-based contrast-enhanced brain magnetic resonance imaging (MRI).

[0536] -(Both) Willingness to practice highly effective contraceptive methods.

[0537] Additional specific inclusion criteria for Phase 1, Group A:

[0538] -(A) Participants must have one of the following histopathologically confirmed diagnoses (WHO 2021):

[0539] GBM IDH-wildtype grade 4, which may include secondary GBMs (i.e., those that progress from low-grade gliomas)

[0540] Astrocytoma, IDH-mutant, grade 3

[0541] - (A) Up to 2 prior lines of treatment, of which the first line must have been treatment with TMZ-based chemoradiotherapy (TMZ concomitant with RT).

[0542] -(A) Disease recurrence or progression documented by diagnostic biopsy or Gd-based contrast-enhanced brain MRI according to RANO criteria. Progressive disease (PD) on the most recent treatment regimen is required. The subsequent brain MRI must be obtained within 10 days before the start of study treatment, unless study treatment is started within 28 days of the diagnostic brain MRI.

[0543] -(A) Surgery after the first disease progression will be permitted. Postoperative brain MRI must be available within 72 hours of surgery to avoid interpreting postoperative changes as residual enhancing disease. Subsequent brain MRIs documenting disease progression according to RANO criteria must be obtained within 10 days before the start of study treatment. Surgery must be performed at least 2 weeks before the start of study treatment, and the participant must have recovered.

[0544] -(A) Karnofsky performance status (KPS) ≥60.

[0545] Additional specific inclusion criteria for Phase 1, Group B:

[0546] -(B) Participants must have a new, histopathologically confirmed diagnosis of GBM IDH-wildtype grade 4 (WHO 2021), which may include secondary GBM (i.e., those that have progressed from low-grade gliomas) if previous treatment has consisted of surgery only. The histological diagnosis can be obtained from a brain biopsy or surgical resection.

[0547] - (B) Study treatment is planned to be initiated ≥2 weeks after diagnostic biopsy or within 3 to 7 weeks after maximum surgical resection (subtotal or wide total resection).

[0548] -(B) For participants who undergo tumor resection, a postoperative brain MRI is recommended within 72 hours. Subsequent brain MRIs must be obtained within 10 days prior to the start of study treatment.

[0549] -(B) For participants who undergo only a diagnostic biopsy, a subsequent brain MRI must be obtained 10 days prior to the start of study treatment unless study treatment is started within 28 days of the diagnostic brain MRI. -(B) KPS ≥ 70.

[0550] Additional specific inclusion criteria for Phase 2:

[0551] -(Phase 2) Participants must have a histopathologically confirmed diagnosis of GBM IDH-wildtype grade 4 (WHO2021).

[0552] - (Phase 2) Prior first-line treatment with TMZ-based chemoradiotherapy (TMZ concomitantly with RT), i.e., up to 1 prior line of treatment.

[0553] -(Period 2) First disease relapse or progression documented by diagnostic biopsy or Gd-based contrast-enhanced brain MRI according to RANO criteria. Subsequent brain MRI must be obtained within 10 days before the start of study treatment.

[0554] -(Phase 2) KPS ≥ 60.

[0555] Exclusion criteria:

[0556] For both Phase 1 (Groups A and B) and Phase 2, exclusion criteria included:

[0557] - (Both) History of other malignancies requiring active treatment within the past 2 years before the first dose of study treatment, excluding the following: superficial bladder cancer, low-risk prostate cancer adequately treated under active surveillance, ductal carcinoma in situ or other carcinoma in situ, and non-melanoma skin cancer (basal cell / squamous cell skin cancer) that has been treated with curative intent.

[0558] -(Both) Currently using investigational agents.

[0559] - (Both) known contraindications to undergoing Gd-based contrast-enhanced MRI.

[0560] - (Both) Major surgery for other diseases within 4 weeks prior to the first dose of study treatment.

[0561] - (Both) history of myocardial infarction or stroke within 6 months, congestive heart failure greater than New York Heart Association (NYHA) class II, unstable angina, recurrent syncope of unknown origin, arrhythmia requiring treatment, or a known family history of sudden death from cardiac-related causes before age 50 years, or any cardiotoxicity experienced after previous chemotherapy.

[0562] - (Both) LVEF less than 55%.

[0563] - (Both) baseline QTcF interval > 450 milliseconds, history of congenital long QT syndrome, or clinically significant conduction abnormalities, or any conduction abnormality that increases the risk of TdP or QTc interval prolongation. - (Both) concomitant use of medications with known risk of QTc prolongation / TdP. If participants have used such medications, a washout period of at least 5 half-lives of the drug must have occurred prior to the first administration of study treatment.

[0564] - (Both) concomitant use of drugs or herbal products that are inhibitors or inducers of CYP3A4, strong inhibitors of CYP2D6, or other drugs mentioned in the prohibited drugs section of the protocol (Section 6.3.3) (e.g., proton pump inhibitors, H2 receptor antagonists, etc.). If the participant has used such drugs, a washout period of at least 5 drug half-lives (4 weeks for irreversible CYP inhibitors and CYP inducers) must exist before the first administration of study treatment. - (Both) clinically significant gastrointestinal disorders that affect drug absorption (e.g., ulcerative disease, gastrointestinal dysfunction, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, subtotal or total gastrectomy of the small intestine, or inflammatory bowel disease).

[0565] - (Both) Any infection requiring systemic antibiotics or antivirals within 1 week prior to the start of study treatment.

[0566] - (Both) Immunization with a live or live-attenuated vaccine within 28 days prior to study entry.

[0567] -(Both) Inability or unwillingness to swallow oral medications.

[0568] - (Both) Exposure to high levels of UV light, such as occupational exposure to sunlight or tanning.

[0569] - (Both) Chemotherapy with curative intent, monoclonal antibodies / biologics, investigational therapy, or RT within 28 days prior to the start of study treatment.

[0570] - (Both) Unresolved AEs or toxicities > Grade 1 due to prior therapy, except for hemoglobin (≥9 g / dL or 5.6 mmol / L). Note: Participants with ≤ Grade 2 alopecia or endocrinopathies controlled by alternative therapy (e.g., hypothyroidism due to immune checkpoint inhibitors) are exceptions and may be eligible for this study.

[0571] - (Both) Hypersensitivity to study drug, TMZ, dacarbazine, or any excipients present in the study drug or TMZ formulation.

[0572] - (Both) known history of human immunodeficiency virus (HIV) infection or positive HIV 1 / 2 serology at screening.

[0573] - (Both) known active HCV or HBV infection or positive serology at screening, defined as:

[0574] o HBV screening test: both HBV sAg and anti-HepB core IgG.

[0575] NOTE: For participants with a positive anti-HepB core IgG and negative HBsAg test, a negative HBV DNA test is mandatory.

[0576] o HCV screening test: both HCV antibodies and positive viral load HCV ribonucleic acid (RNA) by polymerase chain reaction (PCR).

[0577] - (Both) Presence of extracranial metastases, leptomeningeal disease, infratentorial component, or primary spinal cord tumor.

[0578] - (Both) Evidence of intracranial or intratumoral hemorrhage by brain MRI. Participants with resolved postoperative changes, petechiae, or hemosiderin are eligible.

[0579] - (Both) Participants with clinical or imaging signs of herniation.

[0580] - (Both) Previous exposure to any WEE1 inhibitor.

[0581] Specific exclusion criteria for Phase 1 Group A:

[0582] - (A) With more than 2 lines of prior treatment for GBM IDH-wild-type Grade 4 or astrocytoma IDH-mutant Grade 3.

[0583] NOTE: Only 1 prior line of systemic therapy was allowed; combination therapy with TMZ and RT, with or without subsequent TMZ maintenance, was considered 1 line. Prior surgery, radiation, or locally delivered therapeutic agents (i.e., carmustine-containing wafers) for first recurrence was allowed. ).

[0584] - (A) Prior treatment with bevacizumab or other VEGF inhibitors or VEGF receptor signaling inhibitors.

[0585] - (A) Previous TMZ-related hematologic events leading to TMZ discontinuation during concurrent chemoradiotherapy.

[0586] Specific exclusion criteria for Phase 1 Group B:

[0587] - (B) Prior radiation, chemotherapy, biological therapy, interstitial brachytherapy, implantable chemotherapy, therapeutic agents delivered by local injection or convection-enhanced delivery for GBM.

[0588] - (B) Previous treatment resulting in radiation field overlap.

[0589] Specific exclusion criteria for Phase 2:

[0590] -(Phase 2) For GBM IDH-wild-type Grade 4 with more than 1 prior line of systemic therapy. Combination therapy with TMZ and RT, with or without subsequent TMZ maintenance therapy, is considered 1 line.

[0591] -(Phase 2) Prior treatment with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor signaling inhibitors.

[0592] - (Phase 2) Prior TMZ-related hematologic events leading to TMZ discontinuation during concurrent chemoradiation.

[0593] The investigational products used in this clinical trial are as follows:

[0594] The study drug was formulated as 20, 30, 60, 100, 130, and 150 mg hard gelatin capsules. The capsules contained 10 mg microtablets (excipients were as follows: microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, sodium starch glycolate, anhydrous colloidal silicon dioxide, and magnesium stearate). A medium capsule strength was produced to cover the alternative dose levels.

[0595] Study medication was taken orally on an empty stomach (ie, participants had to fast [only water allowed] for at least 4 hours before and 2 hours after ingestion).

[0596] Concomitant RT for Phase 1 Group B will be delivered using intensity modulated radiation therapy (IMRT) or three-dimensional (3D) conformal radiation therapy (conventional fractionation schedule: 2 Gy daily, 5 consecutive days per week, total dose of 60 Gy in 30 fractions) for 6 weeks. RT will be administered approximately 1 hour after TMZ ingestion.

[0597] TMZ is formulated as capsules with 5, 20, 100, 140, 180, and 250 mg for oral administration.

[0598] In Phase 1 (Group A), participants will receive TMZ (150 mg / m2) orally once daily starting on Days 1 to 5 of a 28-day cycle. 2 TMZ will be administered approximately 1 hour after study drug.

[0599] In period 1 (Group B), TMZ (75 mg / m2) was administered orally approximately 30 minutes to 1 hour after the study drug. 2 / day), once daily, along with RT (only on the first 5 days of each week) for 6 weeks.

[0600] In Phase 2, participants in the experimental arm will receive once-daily oral dosing over a 28-day cycle as follows: study drug at RP2D on Days 1 to 5, 8 to 10, and 15 to 17 and TMZ (150 mg / m 2 / day) will be administered on Days 1 to 5. TMZ will be administered approximately 1 hour after study drug.

[0601] Duration of treatment

[0602] Phase 1 (dose escalation):

[0603] The duration of study treatment for participants in Group A was up to 2 years, or until disease progression, unacceptable toxicity, participant withdrawal, discontinuation at the investigator's discretion, subsequent antineoplastic therapy, end of study, or death, whichever occurred first. For Group B, participants were considered to have completed the study treatment period if they had received 6 weeks (42 days) of daily dosing with study drug, along with TMZ and RT. After a 4- to 6-week break following the end of study treatment, the investigator continued the study with or without alternating electric fields (TTTFields) at the discretion of the SOC. Maintenance therapy with TMZ was initiated after the study treatment period and lasted for 5 days (D1 to 5), repeated every 28 days. Maintenance therapy with TMZ occurred after the study treatment period.

[0604] Phase 2:

[0605] Participants in phase 2 were treated for a maximum of 2 years or until disease progression, unacceptable toxicity, participant withdrawal, discontinuation at the investigator's discretion, end of study, or death, whichever occurred first.

[0606] It is estimated that this study will enroll up to 89 evaluable participants.

[0607] Figure 8 、 9and 10 provide study diagrams showing Phase 1 Group A, Phase 1 Group B, and Phase 2 experimental groups, respectively.

[0608] In the figures, the following abbreviations are used: AE = adverse event; C = cycle; D = day; DLT = dose-limiting toxicity; EOS = end of study; EOT = end of treatment; mRANO = modified response assessment in neuro-oncology; PO = oral; RANO = response assessment in neuro-oncology; SAE = serious adverse event; SFU = safety follow-up; TMZ = temozolomide; TT field = tumor treated field; W = week.

[0609] Specificity of Phase 1 Group A Figure 8 ):

[0610] EOT: 20 days after the last dose of study treatment.

[0611] SFU: Following the safety visit and until the participant's EOS, all SAEs (regardless of causality assessment) and non-serious AEs considered to be related to study treatment according to the investigator's assessment will be collected.

[0612] 1 Subsequent cycles will continue for a maximum of 2 years or until disease progression documented by RANO and determined by mRANO, unacceptable toxicity, participant withdrawal, discontinuation at the investigator's discretion, subsequent antineoplastic therapy, end of study, or death, whichever occurs first.

[0613] Limit one cycle to 28 days.

[0614] The specificity of Phase 1 Group B ( Figure 9 ):

[0615] EOT: 20 days after the last dose of study treatment.

[0616] SFU: Following the safety visit and until the participant's EOS, all SAEs (regardless of causality assessment) and non-serious AEs considered to be related to study treatment according to the investigator's assessment will be collected.

[0617] 1 After the completion of study treatment and a 4- to 6-week rest period, the investigator may administer standard of care with or without the addition of alternating current tumor treating fields (TTFields). TMZ maintenance therapy, in the absence of treatment, lasted for 5 days (D1 to 5) and was repeated every 28 days.

[0618] The specificity of the Phase 2 experimental group ( Figure 10 ):

[0619] EOT: 20 days after the last dose of study treatment.

[0620] SFU: Following the safety visit and until the participant's EOS, all SAEs (regardless of causality assessment) and non-serious AEs considered to be related to study treatment according to the investigator's assessment will be collected.

[0621] 1 Subsequent cycles will continue for a maximum of 2 years or until disease progression documented by RANO and determined by mRANO, unacceptable toxicity, participant withdrawal, discontinuation at the investigator's discretion, subsequent antineoplastic therapy, end of study, or death, whichever occurs first.

[0622] Limit one cycle to 28 days.

[0623] Example 10: Phase 1 / 2 clinical trial involving the compound of formula (I) (referred to herein as study drug)

[0624] A clinical trial as described above in Example 9 will be conducted, which is a Phase 1 / 2, multicenter, open-label, non-randomized, controlled study in adult participants with glioma, with a new Phase 1 Cohort C (dose escalation) as follows.

[0625] The study population for this Cohort C is adult participants with confirmed, newly diagnosed GBM IDH-wildtype grade 4 (WHO 2021). Participants will receive continuous daily doses of TMZ (75 mg / m 2 / day, oral, once daily administration) for 6 weeks, and concomitantly administered radiotherapy (RT; conventional fractionation schedule is 2 Gy fractions per day, 5 consecutive days per week, with a total dose of 60 Gy in 30 fractions).

[0626] Participants will also receive study medication (in ascending doses) administered orally once daily for 6 weeks according to a schedule selected from the following options:

[0627] Study drug (in ascending doses) is administered on days 1 to 3 of each week; or

[0628] • Study drug (in ascending doses) was administered on days 1 to 5 of each week.

[0629] The starting dose of study drug is based on available data from dose levels determined to be safe in ongoing Phase 1 studies, i.e., Study 101 involving study drug in combination with carboplatin, Study 102 involving study drug as monotherapy, and preliminary data from the studies described in Example 9. Such a starting dose may be 60 mg or 90 mg, and a dose reduction to 30 mg may be considered if necessary.

[0630] In the event that unacceptable toxicity is observed in the above study drug regimen of Group C, one or more holiday periods (one week each) may be introduced into the 6-week regimen, for study drug only.

[0631] After a 4- to 6-week cool-down period following the end of study treatment, the investigator may administer standard of care (SOC) with or without the addition of alternating current tumor treating fields (TTFields). TMZ maintenance therapy, in the absence of treatment, lasted for 5 days (D1 to 5) and was repeated every 28 days.

[0632] Example 11: The compound of formula (I) (study drug) is present in CSF, indicating that it effectively crosses the blood-brain barrier and distributes to the brain of glioma patients

[0633] In the clinical trial described in Example 9, cerebrospinal fluid (CSF) stabilized with 0.5% formic acid and matched plasma samples collected on K2 EDTA were collected from three patients in Group A on Day 11 of Cycle 1 (i.e., two patients who received 150 mg of study drug and one patient who received 200 mg of study drug) and from one patient in Group B on Day 1 of Week 3 (i.e., Day 15 after receiving a daily dose of 90 mg of study drug).

[0634] The LC-MS / MS method was used to characterize the drug (parent, active moiety) and its active metabolite N 32 -Demethyl-study drug was measured. Results are provided in ng / mL of plasma or CSF and are followed by the use of study drug (511.45 g / mol) and N 32 -Demethyl-The molecular weight of the study drug (497.42 g / mol) was converted to nmol / L.

[0635] In plasma, the active metabolite constituted approximately 10% of the parent study drug, and both compounds were moderately bound to plasma proteins: 91.7% for the parent study drug and 91.7% for N 32 - demethylation - study drug, was 87.1%. Therefore, the study drug and N 32 -Demethyl-unbound (or free portion) of study drug.

[0636] In CSF, total protein concentration varies between 0.2% and 0.5% of the total blood protein concentration (H. Reiber, Clinica Chimica Acta, 2001; Schilde LM et al., PLoS ONE, 2018), so the concentration measured in CSF essentially corresponds to the free fraction of the compound.

[0637] For each of the four patients, the CSF / plasma ratio of a given compound (study drug parent or metabolite) was calculated using the CSF concentration of the compound (in nmol / L) and the unbound or free fraction of the compound in plasma (in nmol / L). The raw data and results are shown in Tables 5 and 6.

[0638] Table 5

[0639]

[0640] Table 6

[0641]

[0642] Active moiety (study drug and N 32 The CSF / plasma ratio of the sum of the 2,3-desmethyl-study drug (drug) was approximately 1 / 3, indicating relatively high levels in the CSF and, therefore, good drug penetration in the patient's brain.

[0643] Although N 32 The CSF / plasma ratio of -desmethyl-study drug concentrations was approximately 5%, but that of the parent drug ranged from 33% to 42%, indicating a particularly high propensity for brain penetration of the study drug.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, For the treatment of glioma in patients in need.

2. The compound of formula (I) for use according to claim 1, wherein the compound of formula (I) is used in combination with temozolomide (TMZ) and / or radiotherapy.

3. The compound of formula (I) for use according to claim 1 or 2, wherein the glioma is a glioblastoma, an astrocytoma or an oligodendroglioma.

4. The compound of formula (I) for use 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) for use according to any one of claims 1 to 4, wherein the compound of formula (I) is orally administered as follows: Intermittent schedule, preferably selected from any one of (i) to (vi): i. On days 1 to 5, 8 to 10, and 15 to 17 of a 28-day cycle, ii. on days 1 to 5, 8 to 12, and 15 to 19 of a 28-day cycle, iii. on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle, iv. on days 1 to 3 of each week for 6 or 7 weeks, v. on days 1 through 5 of each week for 6 or 7 weeks, or vi. on days 1 to 4 of each week for 6 or 7 weeks, Or with a continuity plan, preferably vii. Daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days.

6. A compound of formula (I) for use according to any one of claims 1 to 5, wherein the compound of formula (I) is administered in 1, 2, 3, 4, 5, 6 or more 28-day cycles.

7. The compound of formula (I) for use according to any one of claims 1 to 6, wherein the compound of formula (I) is administered as follows: i. a dosage range of about 30 to about 1000 mg / treatment day, preferably about 30 to about 720 mg / treatment day, and / or ii. a single dose on treatment day, and / or iii. At approximately the same time on each treatment day.

8. The compound of formula (I) for use according to any one of claims 1 to 7, wherein the compound of formula (I) is used in combination with temozolomide, and temozolomide is administered as follows: i. On days 1 to 5 of a 28-day cycle, the dose is 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably the dose is 50 to 200 mg / m 2 / sky, ii. 150 mg / m2 on days 1 to 5 of a 28-day cycle 2 / sky, iii. 200 mg / m2 on days 1 to 5 of a 28-day cycle 2 / sky, iv. Dosage ranges from 50 to 300 mg / m 2 / day, preferably 50 to 250 mg / m 2 / day, more preferably 50 to 200 mg / m 2 / day, daily for 6 weeks, daily for 7 weeks, or daily for 42 to 49 days, or v.Dose is 75mg / m 2 / day, daily administration for 6 weeks, daily administration for 7 weeks, or daily administration for 42 to 49 days.

9. A compound of formula (I) for use according to any one of claims 1 to 8, wherein the compound of formula (I) is used in combination with temozolomide and, on a WEE1 inhibitor treatment day, if temozolomide is administered on the WEE1 inhibitor treatment day, the administration of the compound of formula (I) is carried out before the administration of temozolomide, optionally by a period of about 30 minutes to 4 hours before.

10. The compound of formula (I) for use according to any one of claims 1 to 8, wherein the compound of formula (I) is used in combination with temozolomide, and on a WEE1 inhibitor treatment day, if temozolomide is administered on the WEE1 inhibitor treatment day, the administration of temozolomide is concomitant with the administration of the compound of formula (I).

11. The compound of formula (I) for use according to any one of claims 1 to 10, wherein the compound of formula (I) is used in combination with temozolomide and radiotherapy.

12. The compound of formula (I) for use according to claim 11, wherein the compound of formula (I) is administered according to any one of embodiments (iv), (v), (vi) or (vii) of claim 5, and wherein temozolomide is administered at a dose of 50 to 300 mg / m 2 / day, preferably 75 mg / m 2 The dosage may be 240 mg / day, administered daily for 6 weeks, administered daily for 7 weeks, or administered daily for 42 to 49 days.

13. A compound of formula (I) for use according to claim 11 or 12, wherein the radiotherapy is fractionated radiotherapy and is administered as follows: i. a regimen of 1 Gy to 100 Gy, preferably 2 Gy to 80 Gy, further preferably 10 Gy to 60 Gy, and even more preferably 60 Gy, divided over 5 consecutive days per week until the total radiation dose has been administered, or divided into equal fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days, ii. a regimen of 2 Gy per day, 5 consecutive days per week, for a total of 60 Gy, or iii. 60 Gy total dose in 30 fractions over a period of 6 weeks, 7 weeks, or 42 to 49 days.

14. A compound of formula (I) for use according to any one of claims 1 to 13, wherein the glioma is newly diagnosed, wherein the use is preferably according to embodiment (iv), (v), (vi) or (vii) of claim 5, embodiment (iv) or (v) of claim 8 or any one of claims 11 to 13.

15. A compound of formula (I) for use according to any one of claims 1 to 13, wherein the glioma has progressed or recurred after an initial or previous glioma treatment, wherein the use is preferably according to any one of embodiments (i) to (iii) of claim 5, claim 6, or embodiments (i), (ii) or (iii) of claim 8.

16. A compound of formula (I) for use according to claim 15, wherein the initial or previous glioma treatment comprises administration of radiotherapy.

17. A compound of formula (I) for use according to claim 15 or 16, wherein the initial or previous glioma treatment comprises TMZ administration.

18. A compound of formula (I) for use according to any one of claims 1 to 17, wherein the glioma is a glioblastoma.

19. A compound of formula (I) for use according to any one of claims 1 to 17, wherein the glioma is (IDH)-wild type according to WHO 2021.

20. A compound of formula (I) for use according to any one of claims 1 to 17, wherein the glioma is an astrocytoma.

21. A compound of formula (I) for use according to any one of claims 1 to 17, wherein the glioma is an IDH mutant according to WHO 2021.

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