RAF inhibitors for treating low-grade gliomas

Abstract

Described herein are methods and compositions for treating glioma (e.g., pediatric low-grade glioma). In some embodiments, described herein are methods for treating pediatric low-grade glioma, the methods comprising administering to a subject in need thereof (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 mg / m per week. 2 ~about 600mg / m 2 of Compound A. In some embodiments, the subject is under 20 years of age.

Description

[Technical Field]

[0001] Statement regarding government-funded research This invention was developed with government support under grant number P50 CA 165962 as part of a SPORE grant for targeted therapy in gliomas from the National Cancer Institute of the National Institutes of Health, USA. The government reserves certain rights in this invention.

[0002] cross reference This application claims the benefits of U.S. Provisional Patent Application No. 63 / 110,724 filed on November 6, 2020, and U.S. Provisional Patent Application No. 63 / 138,285 filed on January 15, 2021 (the entire contents of each of these are incorporated herein by reference). [Background technology]

[0003] background In 2012, there were an estimated 14.1 million cancer cases worldwide. This number is projected to increase to 24 million by 2035. Cancer remains the second leading cause of death in the United States, accounting for nearly one in four deaths. In 2014, an estimated 1,665,540 new cancer cases were diagnosed in the United States, and there are believed to have been 585,720 cancer-related deaths. While medical advances have improved cancer survival rates, certain patient populations and specific types of cancer still require further research. In particular, the need for cancer treatment in pediatric patients remains.

[0004] Each year, approximately 15,500 children under the age of 18 in the United States and 300,000 children worldwide are diagnosed with cancer. Furthermore, cancer remains the leading cause of death from childhood disease in the United States, accounting for over 1,700 deaths annually. Despite the need for safer and more effective treatments for childhood cancer, new drugs for pediatric patients are scarce. There are no approved or standard treatments for pediatric patients with recurrent or progressive low-grade gliomas, i.e., pLGG, the most common brain tumor diagnosed in children. Therefore, there is an unmet need for new and more effective treatments for pediatric cancer patients. [Overview of the project] [Means for solving the problem]

[0005] In one aspect, the present disclosure provides a method for treating low-grade glioma (LGG) in a subject requiring treatment of LGG, comprising the steps of administering to the subject (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide (compound A) or a pharmaceutically acceptable salt thereof, wherein the initial dose of compound A or a pharmaceutically acceptable salt thereof is approximately 400 mg / m² per week. 2 ~about 600mg / m 2 The present invention provides a method comprising a step equivalent to compound A, wherein the subject is under 20 years of age. In some embodiments, the initial dose of compound A or a pharmaceutically acceptable salt thereof is approximately 500 mg / m² per week. 2 ~about 600mg / m 2 This is equivalent to compound A. In some embodiments, the initial dose of compound A or a pharmaceutically acceptable salt thereof is approximately 400 mg / m² per week. 2 ~about 500mg / m 2 It is equal to compound A. In some embodiments, the initial dose of compound A or a pharmaceutically acceptable salt thereof is approximately 410 mg / m² per week. 2 ~about 430mg / m 2equal to Compound A. In some embodiments, the initial dose of Compound A or a pharmaceutically acceptable salt thereof is about 420 mg / m per week 2 equal to Compound A. In some embodiments, the initial dose of Compound A or a pharmaceutically acceptable salt thereof is about 530 mg / m per week 2 equal to Compound A.

[0006] In one aspect, the present disclosure provides a method of treating low-grade glioma (LGG) in a subject who needs treatment for LGG, the method comprising administering to the subject (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve a maximum observed plasma concentration (Cmax) of Compound A of at least 2000 ng / mL in the subject, wherein the subject is under 20 years old. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to the subject in an amount sufficient to achieve a Cmax of Compound A of 2000 ng / mL to 8000 ng / mL.

[0007] In one aspect, the present disclosure provides a method of treating low-grade glioma (LGG) in a subject who needs treatment for LGG, the method comprising administering to the subject (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an area under the concentration curve (AUCss) of Compound A of at least about 400,000 ng*h / mL, wherein the subject is under 20 years old. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to the subject in an amount sufficient to achieve an (AUCss) of Compound A of 400,000 ng*h / ml to 1600,000 ng*h / ml.

[0008] A method for treating low-grade glioma (LGG) in a subject requiring treatment of LGG in one aspect is provided herein, comprising the steps of (i) administering to the subject (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide (compound A) or a pharmaceutically acceptable salt thereof, and (ii) in combination with one or more therapeutic agents for treating a skin-related condition or disorder, wherein the subject is under 20 years of age. In some embodiments, one or more therapeutic agents are administered to pigmented skin.

[0009] In one aspect, a method for treating low-grade glioma (LGG) in subjects requiring treatment of LGG by administering compound A or a pharmaceutically acceptable salt thereof is provided herein. In some embodiments, LGG is a recurrent or progressive disease on radiographic imaging. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered as a liquid suspension. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered as a tablet. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered as a single dose per week. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered in 2 to 4 doses per week. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered over a period of at least 24 months. In some embodiments, the subject is 20 years of age or younger. In some embodiments, the subject is 15 years of age or younger. In some embodiments, the subject is 0.5 m 2 ~about 2.0m 2The subject has a body surface area (BSA) of 0.5 m². In some embodiments, the subject has a body surface area (BSA) of 0.5 m². 2 ~about 1.5m 2 It has BSA. In some embodiments, LGG has one or more of the following mutations: RAS-positive mutations, RAF-positive mutations, MEK-positive mutations, and ERK-positive mutations. In some embodiments, LGG has a BRAF mutation. In some embodiments, the BRAF mutation is a non-V600 BRAF mutation. In some embodiments, subjects are identified to have one or more of the following wild-type fusions:KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:BRAF, SRGAP3:RAF1, QK1:RAF1, FYC·:RAF1, ATG7:RAF1, and NFIA:RAF1. In some embodiments, subjects are identified to have the KIAA1549:BRAF wild-type fusion.

[0010] In another aspect, the present disclosure provides a method for treating a subject requiring treatment for low-grade glioma (LGG) as described herein, the method further comprising the administration of compound A or a pharmaceutically acceptable salt thereof at a maximum dose. In some embodiments, the maximum dose of compound A or a pharmaceutically acceptable salt thereof is 600 mg. In some embodiments, the maximum dose of compound A or a pharmaceutically acceptable salt thereof is (PO) 600 mg orally once a week.

[0011] Supporting display All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference.

[0012] Brief explanation of the drawing Novel features of the present invention are shown in particular in the appended claims. A better understanding of the features and advantages of the present invention can be obtained by referring to the following detailed description illustrating illustrative embodiments, in which the principles of the present invention are utilized, and the accompanying drawings are as follows: [Brief explanation of the drawing]

[0013] [Figure 1] Figure 1 illustrates Phase 1 clinical trial data in pLGG patients who achieved a complete response (100% reduction) or partial response (>50% reduction in two-dimensional tumor measurement) to treatment with compound A. Of the eight patients with RAF fusion, five achieved either a complete response or a partial response (defined as ≥50% reduction) compared to baseline, according to the RANO criteria. Two of the eight patients with RAF fusion maintained long-term stable disease. One patient with RAF fusion did not respond to compound A. One patient with NF1-associated pLGG did not respond to compound A.

[0014] [Figure 2] Figure 2 illustrates Phase 1 clinical trial data for individual pLGG patient responses to compound A over time. A reduction in lesion size was observed in 6 out of 9 patients on the first radiographic image taken after the start of compound A administration. The median time to response was 10.5 weeks. Two patients achieved a complete response, which was maintained throughout the entire administration period up to 2 years. Three patients had a partial response, two achieved long-term stable disease, and two did not achieve a response.

[0015] [Figure 3]Figure 3 illustrates the Phase 2 clinical trial design for compound A in pLGG patients. The trial includes pediatric patients aged 6 months to 25 years with relapsed or progressive pLGG who have an activated BRAF mutation (e.g., KIAA1549-BRAF fusion) or a BRAF activating mutation (e.g., V600E). Compound A is administered orally once weekly at a dose of 420 mg / m2. [Modes for carrying out the invention]

[0016] Detailed description of the invention Protein kinases play a crucial role in the cell regeneration process. Specifically, the mitogen-activated protein kinase (MAPK) signaling pathway consists of a kinase cascade that relays extracellular signals to the nucleus, regulating gene expression and critical cellular functions. Gene expression regulated by the Ras / Raf / MEK / ERK signaling pathway regulates fundamental cellular processes, including proliferation, differentiation, apoptosis, and angiogenesis. These diverse roles of Ras / Raf / MEK / ERK signaling are abnormally activated in various types of cancer. Mutations in genes within this pathway can result in constitutively active proteins that lead to increased cell proliferation and resistance to apoptosis.

[0017] Raf (serine / threonine protein kinase) is encoded by a gene family consisting of three genes that give rise to three Raf isoform members (B-Raf, C-Raf (Raf-1), and A-Raf). Each of these proteins shares a highly conserved amino-terminal regulatory region and a catalytic domain at the carboxyl terminus. Each isoform plays a role in the Ras / Raf / MEK / ERK pathway, but B-Raf has been shown to be the major activator of MEK. B-Raf is recruited by Ras:GTP to the cell membrane within the cell where it is activated. Subsequently, B-Raf is responsible for the activation of MEK1 / 2, and MEK1 / 2 activates ERK1 / ERK2. Mutations in the B-Raf gene allow B-Raf to signal independently of upstream signals. As a result, mutated B-Raf proteins (e.g., V600E) cause excessive downstream signaling of MEK and ERK. This leads to excessive cell proliferation and survival, as well as tumorigenesis. Overactivation of the signaling cascade by mutated B-Raf is thought to be associated with numerous malignancies. B-Raf-specific inhibitors (e.g., vemurafenib) have shown promise in treating melanoma expressing the mutant B-Raf V600E.

[0018] Gliomas are histologically defined based on whether they primarily exhibit astrocytic or oligodendrocyte morphology and are graded by cellular solidity, nuclear atypicality, necrosis, mitotic figures, and microangiogenicity (all features associated with biologically invasive behavior). Astrocytomas are of two main types: high-grade and low-grade. High-grade tumors grow rapidly, are highly angiogenic, and can easily spread to the brain. Low-grade astrocytomas are usually localized and grow slowly over a long period. High-grade tumors are far more invasive, require very intensive treatment, and are associated with shorter survival times than low-grade tumors. The majority of astrocytomas in children are low-grade, while the majority in adults are high-grade. These tumors can occur anywhere in the brain and spinal cord. Some of the more common low-grade astrocytomas include: juvenile pilocytic astrocytoma (JPA), fibrous astrocytoma, pleomorphic xantroastrocytoma (PXA), and deembryoplastic neuroepithelial tumor (DNET). The two most common high-grade astrocytomas are undifferentiated astrocytoma (AA) and glioblastoma multiforme (GBM).

[0019] Pediatric low-grade gliomas (PLGGs) encompass a heterogeneous group of World Health Organization (WHO) grades I and II tumors, representing the most common pediatric brain tumors. They include tumors of various histologies (e.g., pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, and angiocentric glioma). Angiocentric gliomas are WHO grade I tumors with a slow clinical course. They occur in the cerebral cortex and share histological features with astrocytomas and ependymomas. Angiocentric gliomas cause medically intractable epileptic seizures in children.

[0020] The Ras pathway is associated with numerous tumors in adult patients. Low-grade gliomas (LGGs) are the most common brain tumors in children, and most have abnormal signaling via the RAS / RAF pathway. Complete resection is often not feasible in many patients, and incompletely resected LGGs have a high rate of progression and recurrence. The best available treatments currently have limited efficacy, and long-term disease burden and procedure-related morbidity are significant. Results from the largest randomized phase III trial to date in children with LGGs showed a 5-year event-free survival rate of only 47%.

[0021] This disclosure provides a method for treating gliomas (e.g., pediatric low-grade gliomas) by administering compound A, or a pharmaceutically acceptable salt or solvate thereof. The dosage regimen is based on the patient's body surface area (e.g., mg / m²). 2 ) was found to be suitable for the described method. In some embodiments, a dosage regimen based on the patient's body surface area (e.g., mg / m²) 2 ) is more suitable than a dosage regimen based on the patient's weight (e.g., mg / kg). Also, treatment at a specific dose (e.g., 400 mg / m² per week) is preferable. 2 It has been found that starting with a higher-grade compound (A) may be beneficial.

[0022] Unless otherwise specified, terms used herein shall have the same meaning as defined below.

[0023] definition In this application, the use of “or” means “and / or” unless otherwise stated. The terms “and / or” and “any combination thereof” and their grammatical equivalents may be used interchangeably as used herein. These terms may convey that any combination is specifically intended. For illustrative purposes only, the following phrases “A, B, and / or C” or “A, B, C, or any combination thereof” may mean “A individually; B individually; C individually; A and B; B and C; A and C; as well as A, B, and C.” The term “or” may be used conjunctively or disjunctively unless the context specifically refers to a disjunctive use.

[0024] As used herein, the term “Raf kinase” refers to any one of the serine / threonine protein kinase family, which consists of three isoform members (B-Raf, C-Raf (Raf-1), and A-Raf). Raf protein kinases are involved in the MAPK signaling pathway, a kinase cascade that relays extracellular signals to the nucleus and regulates gene expression and important cellular functions. Unless otherwise indicated by context, the term “Raf kinase” means any Raf kinase protein derived from any species (including, but not limited to, any species). In one aspect, the above Raf kinase refers to human Raf kinase.

[0025] The terms “Raf inhibitor” or “inhibitor of Raf” may be used to describe compounds that can interact with one or more isoform members (B-Raf, C-Raf (Raf-1), and / or A-Raf) of Raf (including variant forms), which is the serine / threonine protein kinase described above. Some examples of Raf variant forms include, but are not limited to, B-Raf V600E, B-Raf V600D, B-Raf V600K, B-Raf V600E + T5291, and / or B-Raf V600E + G468A.

[0026] In some embodiments, the Raf kinase is inhibited by at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In some embodiments, the concentration of the Raf kinase inhibitor required to reduce Raf kinase activity by 50% is less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM.

[0027] In some embodiments, such inhibition is selective for one or more Raf isoforms. That is, the Raf inhibitor is selective for one or more of B-Raf (wild-type), mutant B-Raf, A-Raf, and C-Raf kinases. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600E, A-Raf, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600E, A-Raf, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600D, A-Raf, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600K, and C-Raf. In some embodiments, the Raf inhibitor is not simply selective for B-Raf V600. In some embodiments, the Raf inhibitor is not simply selective for B-Raf V600E.

[0028] In some embodiments, the Raf inhibitor is selective for B-Raf and C-Raf kinases. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600E, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600D, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600K, and C-Raf. In some embodiments, the Raf inhibitor is selective for mutant B-Raf. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600E. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600D. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600K.

[0029] The term "pan-Raf inhibitor" refers to a Raf inhibitor that inhibits Raf protein isoforms other than the B-Raf V600 isoform.

[0030] The terms “about” or “approximately” may mean within an acceptable margin of error for a particular value, as determined by those skilled in the art, and this depends in part on how the value was measured or determined, i.e., the limits of the measuring system. For example, “about” may mean within 1 or a standard deviation greater than 1, according to the convention of the art. Alternatively, “about” may mean a range of up to 20%, 15%, 10%, 5%, or 1% of a given value. In some embodiments, “about” refers to a range of up to 10% of a given value. In some embodiments, “about” refers to a range of up to 5% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within one order of magnitude, five times, or twice the value.

[0031] When used in this specification and in the scope of the claims, the words “comprising” (and any form of “comprising” (e.g., “comprise” and “comprises”)), “having” (and any form of “having” (e.g., “have” and “has”)), “including” (and any form of “including” (e.g., “includes” and “include”)), or “containing” (and any form of “containing” (e.g., “contains” and “contain”)) are not exclusive or limiting and do not preclude further, undescribed elements or steps of methods. Any embodiment considered herein is intended to be performed with respect to any method or composition of this disclosure, and vice versa. Furthermore, the compositions of this disclosure may be used to achieve the methods of this disclosure.

[0032] References herein to “some embodiments,” “an embodiment,” “one embodiment,” or “other embodiments” mean that certain features, structures, or characteristics described in relation to that embodiment are included in at least some embodiments of this disclosure, but not necessarily in all embodiments. To facilitate understanding of this disclosure, many terms and phrases are defined below. As used herein, the terms “treatment,” “treat,” and “treating” mean the entire scope of interventions relating to the cancer in which the subject is affected (e.g., combination administrations to alleviate, delay, stop, or reverse one or more symptoms of the cancer, and to slow the progression of the cancer, even if the cancer is not actually eliminated). Treatments may include, for example, a reduction in the severity of symptoms, the number of symptoms, or the frequency of recurrence, e.g., inhibition of tumor growth, cessation of tumor growth, or regression of an existing tumor.

[0033] The term "therapeutably effective amount," as used herein, refers to an effective amount in terms of the dosage and duration required to achieve the desired therapeutic effect. The therapeutically effective amount of the composition may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the protein to induce the desired response in the individual. The therapeutically effective amount is also an amount that has a beneficial effect on the treatment and exceeds any toxic or harmful effects of the composition.

[0034] The term “subject” as used herein means a mammal, and “mammal” includes, but is not limited to, humans. In some embodiments, the subject has received treatment prior to the commencement of treatment according to the method of this disclosure. In some embodiments, the subject is at risk of developing or experiencing cancer recurrence.

[0035] "Pharmacologically acceptable excipients, carriers, or diluents" means excipients, carriers, or diluents that can be administered to a subject together with a drug, do not destroy its pharmacological activity, and are non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the drug.

[0036] A “pharmaceutically acceptable salt” as appropriate to this disclosure may be a salt of an acid or base that is generally considered in the art to be suitable for use in contact with human or animal tissue without excessive toxicity, irritation, allergic response, or other problems or complications. Such salts include inorganic and organic acid salts of basic residues (e.g., amines), as well as alkali salts or organic salts of acidic residues (e.g., carboxylic acids). Specific examples of pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanic acid (e.g., acetic acid), and HOOC-(CH2)n-COOH (where n is 0-4). Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Those skilled in the art will recognize from this disclosure and articulate knowledge that further pharmaceutically acceptable salts include those listed in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, p. 1418 (1985). In general, pharmaceutically acceptable salts of acids or bases can be synthesized from parent compounds containing the basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in a suitable solvent.

[0037] It is understood that the ranges provided herein are abbreviated notation for all values ​​within that range. For example, the range 1 to 50 is understood to include any digits, combinations of digits, or subranges of the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as any decimal values ​​that fall between all of the aforementioned integers (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9). With regard to subranges, the specific intention is to define "nested subranges" extending from any endpoint of the above range. For example, a nested subrange of the exemplary range 1 to 50 may include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0038] Unless otherwise stated, the structures shown herein are to be understood to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, compounds having the structure described herein are within the scope of this disclosure except that a hydrogen atom is substituted with deuterium or tritium, or that a carbon atom is substituted with carbon that is 13C-enriched or 14C-enriched.

[0039] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the above compounds are within the scope of this disclosure. Unless otherwise stated, structures shown herein also mean all stereochemical forms of that structure; i.e., R and S configurations with respect to each chiral center. Accordingly, single stereoisomers of the compounds of the present invention, as well as enantiomers and diastereomer mixtures, are within the scope of this disclosure.

[0040] RAF inhibitor Compounds capable of inhibiting the activity of Raf kinase can be used in the methods of the present disclosure. In some embodiments, the Raf inhibitor inhibits more Raf kinase isoforms than B-Raf V600. In some embodiments, the Raf inhibitor inhibits more Raf kinase protein isoforms than B-Raf V600E. In some embodiments, the Raf inhibitor inhibits B-Raf (wild-type), mutant B-Raf, A-Raf, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600E, A-Raf, and / or C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600K, A-Raf, and / or C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600D, A-Raf, and / or C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600K, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600E, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600D, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild-type), B-Raf V600K, and C-Raf. In some embodiments, the Raf inhibitor is selective for mutant B-Raf. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600E. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600D. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600K.

[0041] Raf inhibitors can be assayed in vitro or in vivo for their ability to bind to and / or inhibit Raf kinase. In vitro assays include a biochemical FRET assay to measure the phosphorylation of MEK by Raf kinase as a method for quantifying the ability of a compound to inhibit the enzymatic activity of Raf kinase. The above compounds can also be assayed for their ability to affect cellular or physiological functions mediated by Raf kinase activity. For example, an in vitro assay quantifies the amount of phosphor-ERK in cancer cells. Assays for each of these activities are known in the art.

[0042] In some embodiments, the above pharmaceutical composition also comprises: one or more fillers in a concentration of at least about 10% by weight of the composition (e.g., mannitol, cellulose, calcium carbonate, starch, sugar (e.g., dextrose, lactose, etc.)); a sweetener in a concentration of about 10% or less by weight of the composition (e.g., sucralose, sorbitol, saccharin, fructose, aspartame, or a combination thereof); and a disintegrant in a concentration of about 10% or less by weight of the composition (e.g., croscarmellose sodium). , sodium starch glycolate, or a combination thereof); optionally, a wetting agent (e.g., sodium lauryl sulfate, SLS) in a concentration of about 10% by weight or less by the weight of the composition; a flow promoter (glidant) (e.g., colloidal silicon dioxide, talc, or a combination thereof) in a concentration of about 2% by weight or less by the weight of the composition; and a lubricant (e.g., magnesium stearate, stearic acid, hydrogenated oil, sodium stearyl fumarate, or a combination thereof) in a concentration of about 5% by weight or less by the weight of the composition.

[0043] Such pharmaceutical compositions may, if necessary, contain one or more colorants, fragrances, and / or flavor and odor enhancers to enhance their visual appeal, taste, and aroma.

[0044] In other embodiments, the present invention provides pharmaceutical compositions in the form of powder compositions (as described above), which can also be formulated into solid-unit dosage forms for the treatment of various diseases. Accordingly, the present invention also aims to provide novel dosage forms (e.g., granules, pellets, mini-tablets, and other solid-unit dosage forms) that overcome the above-mentioned problems with respect to administration inaccuracies, particularly with respect to pediatric patients. These stable solid-unit dosage forms may have any shape (including, among others, oval, spherical, cylindrical, elliptical, cubic, square, or rectangular). Tablets or mini-tablets may have flat, shallow, standard, deep convex, or double deep convex surfaces or combinations thereof. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is formulated to have a strength of 10 to 500 mg per tablet. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is formulated to have a strength of 10-50 mg, 25-75 mg, 50-100 mg, 75-125 mg, 125-175 mg, or 150-250 mg per tablet. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is formulated to have a strength of 20 mg per tablet. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is formulated to have a strength of 100 mg per tablet. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is formulated to have a strength of 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg per tablet. In some embodiments, the dose strength of the above tablets is based on the free base of compound A.

[0045] In other embodiments, the present invention provides pharmaceutical compositions that can be formulated into tablets. In some embodiments, the tablets comprise compound A or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the tablets may further comprise an acceptable excipient. In some embodiments, the acceptable excipient may include, but is not limited to, one or more of microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, vinylpyrrolidone-vinyl acetate copolymer (copovidone), croscarmellose sodium, and Opradry®. In some embodiments, the tablets may be coated in different colors.

[0046] In one aspect, the pharmaceutical composition may be formulated into a unit dose form (e.g., capsule, sachet, etc.) containing at least one or more minitablets in order to simplify the administration of the pharmaceutical composition. In some embodiments, the unit dose may include a capsule or packet containing at least one minitablet, or a plurality of minitablets as provided above and below. In another embodiment, the unit dose may include a pouch, packet, or sachet in powder form containing a specific dose of substantially amorphous or amorphous compound A, or a pharmaceutically acceptable salt or solvate thereof.

[0047] In some embodiments, (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide (compound A), or a pharmaceutically acceptable salt or solvate thereof, is described herein as a Raf inhibitor. The structure of compound A is illustrated below: [ka] Compound A, or a pharmaceutically acceptable salt or solvate thereof, is described in US8293752B2. Compound A is also known as DAY101 (formerly TAK-580, BIIB024, or MLN2480). Compound A is also known as tovorafenib. In some embodiments, the Raf inhibitor is (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide. In some embodiments, the Raf inhibitor is Compound A, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the Raf inhibitor is a pharmaceutically acceptable salt of Compound A. In some embodiments, the Raf inhibitor is a solvate of Compound A. In some embodiments, the Raf inhibitor is the crystalline form of compound A. In some embodiments, the Raf inhibitor is the hydrate of compound A. In some embodiments, the Raf inhibitor is the crystalline form of compound A. In some embodiments, the Raf inhibitor is, [ka] That is the case.

[0048] In some embodiments, pharmaceutically acceptable salts of compound A are described. Suitable pharmaceutically acceptable salts include, for example, those described in SMBerge et al., d J. Pharmaceutical Sciences, 1977, 66, 1-19 (as incorporated herein by reference). Pharmaceutically acceptable salts of the compounds described herein include those obtained from suitable inorganic and organic acids, as well as inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or / or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include: adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptaneate, hexanoate, hydroiodide, and 2-H. Examples include droxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valersates, etc. Salts obtained from suitable bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4 alkyl) tetrasalts. This disclosure also assumes quaternization of any basic nitrogen-containing group. Water-soluble, oil-soluble, or dispersible products may be obtained by such quaternization.Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, which, where appropriate, are formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, quaternary alkyl sulfonates, and aryl sulfonates.

[0049] Administration The appropriate daily dose of a Raf kinase inhibitor can generally range from about 10% to about 100% of the maximum tolerated dose as a single agent, in single, divided, or multiple doses. In some embodiments, the appropriate dose is about 15% to about 100% of the maximum tolerated dose as a single agent. In some embodiments, the appropriate dose is about 25% to about 90% of the maximum tolerated dose as a single agent. In some other embodiments, the appropriate dose is about 30% to about 80% of the maximum tolerated dose as a single agent. In some other embodiments, the appropriate dose is about 40% to about 75% of the maximum tolerated dose as a single agent. In some other embodiments, the appropriate dose is about 45% to about 60% of the maximum tolerated dose as a single agent. In some embodiments, appropriate doses are about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, or 110% of the maximum tolerated dose as a single agent.

[0050] The appropriate dose of a Raf inhibitor can be taken at any time of day or night. In some embodiments, the appropriate dose of a selective inhibitor among the Raf inhibitors is taken in the morning. In some other embodiments, the appropriate dose of a Raf inhibitor is taken in the evening. In some other embodiments, the appropriate dose of a Raf inhibitor is taken both in the morning and evening. It is understood that the appropriate dose of a Raf inhibitor can be taken with or without food. In some embodiments, the appropriate dose of a Raf inhibitor is taken with a meal. In some embodiments, the appropriate dose of a Raf inhibitor is taken while fasting.

[0051] Methods for treating cancers such as gliomas (e.g., low-grade gliomas), comprising the step of administering a Raf inhibitor, are described herein. In some embodiments, the method comprises the step of administering compound A, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method comprises the step of administering compound A in crystalline form. In some embodiments, the method comprises the step of administering a salt of compound A. In some embodiments, the method comprises the step of administering compound A.

[0052] Based on the body surface area (BSA) of the subject, compound A, or its pharmaceutically acceptable salt or solvate (e.g., mg / m²) is used. 2 A method for treating cancer such as glioma (e.g., low-grade glioma), comprising the step of administering ), is described herein. BSA can be determined by any suitable calculation method. In some embodiments, the BSA is determined by the Mostler formula (√((height × weight) / 3600)). In some embodiments, the BSA is determined at the start of each cycle of administration.

[0053] In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered in amounts up to approximately 600 mg per dose. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered in amounts up to approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, or approximately 1000 mg per dose. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered in amounts up to approximately 600 mg of compound A per dose. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered in amounts up to approximately 800 mg of compound A per dose.

[0054] In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 1200 mg / m². 2 It is administered in amounts up to [amount]. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 1000 mg / m². 2 It is administered in amounts up to [amount]. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered at 800 mg / m² per dose. 2 It is administered in amounts up to [amount]. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 600 mg / m². 2 It is administered in amounts up to [amount]. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered at 500 mg / m² per dose. 2 It is administered in amounts up to [amount]. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered at 300 mg / m² per dose. 2 It is administered in amounts up to [amount]. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 200 mg / m². 2It is administered in amounts up to [amount]. The appropriate dose of a Raf inhibitor (e.g., compound A, or a pharmaceutically acceptable salt or solvate thereof) is generally 10 mg / m² per dose, in single, divided, or multiple doses. 2 ~about 1000mg / m 2 The range may extend to [a certain range]. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered as a single dose. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered as divided doses. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered as multiple doses. Other suitable doses of compound A, or a pharmaceutically acceptable salt or solvate thereof, are generally about 200 mg / m² per dose, in single, divided, or multiple doses. 2 ~about 800mg / m 2 This range may extend. Other suitable doses of compound A, or its pharmaceutically acceptable salt or solvate, are generally about 75 mg / m² per dose, in single, divided, or multiple doses. 2 ~about 200mg / m 2 It may extend to the range of. In some embodiments, the appropriate dose is about 100 mg / m² per dose. 2 ~about 200mg / m 2 In some other embodiments, the appropriate dose is approximately 150 mg / m² twice daily. 2 ~about 600mg / m 2 In some embodiments, the appropriate dose is approximately 20 mg / m² per dose. 2、 Approximately 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 55mg / m 2 , about 60mg, about 65mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2Approximately 85 mg / m 2 Approximately 90 mg / m 2 Approximately 95mg / m 2 Approximately 100 mg / m 2 Approximately 105 mg / m 2 Approximately 110 mg / m 2 Approximately 115 mg / m 2 Approximately 120 mg / m 2 Approximately 125 mg / m 2 Approximately 130 mg / m 2 Approximately 135 mg / m 2 Approximately 140 mg / m 2 Approximately 145 mg / m 2 Approximately 150 mg / m 2 Approximately 155 mg / m 2 Approximately 160 mg / m 2 Approximately 165 mg / m 2 Approximately 170 mg / m 2 Approximately 175 mg / m 2 Approximately 180 mg / m 2 Approximately 185 mg / m 2 Approximately 190 mg / m 2、 Approximately 195 mg / m 2 Approximately 200 mg / m 2、 Approximately 220 mg / m 2 、 Approximately 240 mg / m 2 Approximately 260 mg / m 2 Approximately 280 mg / m 2 Approximately 300 mg / m 2 Approximately 320 mg / m 2 Approximately 340 mg / m 2 Approximately 360 mg / m 2 Approximately 380 mg / m 2 Approximately 400 mg / m 2 Approximately 420 mg / m 2 Approximately 440 mg / m 2 Approximately 460 mg / m 2 Approximately 480 mg / m 2 Approximately 500 mg / m 2 Approximately 520 mg / m 2 、 Approximately 530 mg / m 2 Approximately 560 mg / m 2 Approximately 580 mg / m 2 Approximately 600 mg / m 2 Approximately 620 mg / m2 、 about 640 mg / m 2 、 about 660 mg / m 2 、 about 680 mg / m 2 、 about 700 mg / m 2 、 about 720 mg / m 2 、 about 740 mg / m 2 、 about 760 mg / m 2 、 about 780 mg / m 2 、 about 800 mg / m 2 、 about 825 mg / m 2 、 about 850 mg / m 2 、 about 900 mg / m 2 、 about 950 mg / m 2 about 1000 mg / m 2 、 about 1050 mg / m 2 、 or about 1100 mg / m 2 is. In some embodiments, a suitable dosage of compound A, or a pharmaceutically acceptable salt or solvate thereof, is about 100 mg to about 1000 mg of compound A per dose. In some embodiments, the suitable dosage is about 20 mg per d·se 、 about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg 、 about 195 mg, about 200 mg 、 about 220 mg 、 about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg 、The dosage is approximately 530 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered weekly. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week. In some embodiments, the administration is based on the free base form of compound A.

[0055] Compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to the subject at an initial dose. In some embodiments, the initial dose is approximately 100 to approximately 1000 mg / m² per week. 2 Compound A is used. In some embodiments, the starting dose is approximately 20 mg / m² per week. 2、 Approximately 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 55mg / m 2 , about 60mg, about 65mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 , about 100mg / m 2 , about 105mg / m 2 , about 110mg / m 2 , about 115mg / m 2 , about 120mg / m 2 , about 125mg / m 2 , about 130mg / m 2 , about 135mg / m 2 , about 140mg / m 2 , about 145mg / m 2 , about 150mg / m 2 , about 155mg / m2 Approximately 160 mg / m 2 Approximately 165 mg / m 2 Approximately 170 mg / m 2 Approximately 175 mg / m 2 Approximately 180 mg / m 2 Approximately 185 mg / m 2 Approximately 190 mg / m 2、 Approximately 195 mg / m 2 Approximately 200 mg / m 2、 Approximately 220 mg / m 2 、 Approximately 240 mg / m 2 Approximately 260 mg / m 2 Approximately 280 mg / m 2 Approximately 300 mg / m 2 Approximately 320 mg / m 2 Approximately 340 mg / m 2 Approximately 360 mg / m 2 Approximately 380 mg / m 2 Approximately 400 mg / m 2 Approximately 420 mg / m 2 Approximately 440 mg / m 2 Approximately 460 mg / m 2 Approximately 480 mg / m 2 Approximately 500 mg / m 2 Approximately 520 mg / m 2 、 Approximately 530 mg / m 2 Approximately 560 mg / m 2 Approximately 580 mg / m 2 Approximately 600 mg / m 2 Approximately 620 mg / m 2 Approximately 640 mg / m 2 Approximately 660 mg / m 2 Approximately 680 mg / m 2 Approximately 700 mg / m 2 Approximately 720 mg / m 2 Approximately 740 mg / m 2 Approximately 760 mg / m 2 Approximately 780 mg / m 2 Approximately 800 mg / m 2 Approximately 825 mg / m 2 Approximately 850 mg / m 2 Approximately 875 mg / m 2 Approximately 900 mg / m 2 Approximately 925 mg / m 2, about 950mg / m 2 , about 975mg / m 2 , or approximately 1000 mg / m² 2 In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered two, three, four, five, six, or seven times a week. In some embodiments, the starting dose is approximately 825 mg / m² per week. 2 In some embodiments, the starting dose is approximately 660 mg / m² per week. 2 A. In some embodiments, the starting dose is approximately 530 mg / m² per week. 2 In some embodiments, the starting dose is approximately 420 mg / m² per week. 2 In some embodiments, the starting dose is approximately 410 mg / m² per week. 2 ~about 430mg / m 2 In some embodiments, the starting dose is approximately 400 mg / m² per week. 2 ~about 450mg / m 2 In some embodiments, the starting dose is approximately 350 mg / m² per week. 2 ~about 450mg / m 2 In some embodiments, the starting dose is approximately 350 mg / m² per week. 2 In some embodiments, the starting dose is approximately 280 mg / m² per week. 2 In some embodiments, the initial dose is approximately 600 mg / m² per week. 2 ~about 700mg / m 2 In some embodiments, the initial dose is approximately 500 mg / m² per week. 2 ~about 550mg / m 2 In some embodiments, the initial dose is approximately 400 mg / m² per week. 2 ~about 450mg / m 2 In some embodiments, the initial dose is approximately 400 mg / m² per week. 2~about 500mg / m 2 In some embodiments, the initial dose is approximately 200 mg / m² per week. 2 ~about 300mg / m 2 In some embodiments, the initial dose is approximately 250 mg / m² per week. 2 ~about 300mg / m 2 In some embodiments, the above administration is based on the free base form of compound A. In some embodiments, the above administration is administered once a week.

[0056] Compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to the subject at a maintenance dose. In some embodiments, the maintenance dose is approximately 100 to 1000 mg / m². 2 It is equal to compound A. In some embodiments, the maintenance dose is about 100 to about 800 mg / m² per week. 2 In some embodiments, the maintenance dose is approximately 20 mg / m² per week. 2、 Approximately 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 55mg / m 2 , about 60mg, about 65mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 , about 100mg / m 2 , about 105mg / m 2 , about 110mg / m 2 , about 115mg / m 2 , about 120mg / m 2 , about 125mg / m 2 , about 130mg / m 2 , about 135mg / m 2 , about 140mg / m 2 , about 145mg / m2 Approximately 150 mg / m 2 Approximately 155 mg / m 2 Approximately 160 mg / m 2 Approximately 165 mg / m 2 Approximately 170 mg / m 2 Approximately 175 mg / m 2 Approximately 180 mg / m 2 Approximately 185 mg / m 2 Approximately 190 mg / m 2、 Approximately 195 mg / m 2 Approximately 200 mg / m 2、 Approximately 220 mg / m 2 、 Approximately 240 mg / m 2 Approximately 260 mg / m 2 Approximately 280 mg / m 2 Approximately 300 mg / m 2 Approximately 320 mg / m 2 Approximately 340 mg / m 2 Approximately 360 mg / m 2 Approximately 380 mg / m 2 Approximately 400 mg / m 2 Approximately 420 mg / m 2 Approximately 440 mg / m 2 Approximately 460 mg / m 2 Approximately 480 mg / m 2 Approximately 500 mg / m 2 Approximately 520 mg / m 2 、 Approximately 530 mg / m 2 Approximately 560 mg / m 2 Approximately 580 mg / m 2 Approximately 600 mg / m 2 Approximately 620 mg / m 2 Approximately 640 mg / m 2 Approximately 660 mg / m 2 Approximately 680 mg / m 2 Approximately 700 mg / m 2 Approximately 720 mg / m 2 Approximately 740 mg / m 2 Approximately 760 mg / m 2 Approximately 780 mg / m 2 Approximately 800 mg / m 2 Approximately 825 mg / m 2 Approximately 850 mg / m 2 Approximately 875 mg / m 2, about 900mg / m 2 , about 925mg / m 2 , about 950mg / m 2 , about 975mg / m 2 , or approximately 1000 mg / m² 2 In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered two, three, four, five, six, or seven times a week. In some embodiments, the maintenance dose is approximately 825 mg / m² per week. 2 In some embodiments, the maintenance dose is approximately 660 mg / m² per week. 2 In some embodiments, the maintenance dose is approximately 530 mg / m² per week. 2 In some embodiments, the maintenance dose is approximately 420 mg / m² per week. 2 In some embodiments, the maintenance dose is approximately 350 mg / m² per week. 2 In some embodiments, the maintenance dose is approximately 280 mg / m² per week. 2 In some embodiments, the maintenance dose is approximately 600 mg / m² per week. 2 ~about 700mg / m 2 In some embodiments, the maintenance dose is approximately 500 mg / m² per week. 2 ~about 550mg / m 2 In some embodiments, the maintenance dose is approximately 400 mg / m² per week. 2 ~about 450mg / m 2 In some embodiments, the maintenance dose is approximately 420 mg / m² per week. 2 In some embodiments, the maintenance dose is approximately 410 mg / m² per week. 2 ~about 430mg / m 2 In some embodiments, the maintenance dose is approximately 350 mg / m² per week. 2 ~about 450mg / m 2 In some embodiments, the maintenance dose is approximately 400 mg / m² per week.2 ~about 500mg / m 2 In some embodiments, the maintenance dose is approximately 200 mg / m² per week. 2 ~about 300mg / m 2 In some embodiments, the maintenance dose is approximately 250 mg / m² per week. 2 ~about 300mg / m 2 In some embodiments, the maintenance dose is the same as the initial dose. In some embodiments, the maintenance dose is higher than the initial dose. In some embodiments, the maintenance dose is lower than the initial dose. In some embodiments, the above dosage is based on the free base form of compound A. In some embodiments, the above dosage is administered once a week.

[0057] Compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject at the maximum tolerated dose. In some embodiments, the maximum tolerated dose is approximately 100 to 1200 mg / m² per week. 2 It is equal to compound A. In some embodiments, the maximum tolerated dose is about 100 to about 800 mg / m² per week. 2 In some embodiments, the maximum tolerated dose is approximately 20 mg / m² per week. 2、 Approximately 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 55mg / m 2 , about 60mg, about 65mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 , about 100mg / m 2 , about 105mg / m 2 , about 110mg / m 2 , about 115mg / m 2 , about 120mg / m2 Approximately 125 mg / m 2 Approximately 130 mg / m 2 Approximately 135 mg / m 2 Approximately 140 mg / m 2 Approximately 145 mg / m 2 Approximately 150 mg / m 2 Approximately 155 mg / m 2 Approximately 160 mg / m 2 Approximately 165 mg / m 2 Approximately 170 mg / m 2 Approximately 175 mg / m 2 Approximately 180 mg / m 2 Approximately 185 mg / m 2 Approximately 190 mg / m 2、 Approximately 195 mg / m 2 Approximately 200 mg / m 2、 Approximately 220 mg / m 2 、 Approximately 240 mg / m 2 Approximately 260 mg / m 2 Approximately 280 mg / m 2 Approximately 300 mg / m 2 Approximately 320 mg / m 2 Approximately 340 mg / m 2 Approximately 360 mg / m 2 Approximately 380 mg / m 2 Approximately 400 mg / m 2 Approximately 420 mg / m 2 Approximately 440 mg / m 2 Approximately 460 mg / m 2 Approximately 480 mg / m 2 Approximately 500 mg / m 2 Approximately 520 mg / m 2 、 Approximately 530 mg / m 2 Approximately 560 mg / m 2 Approximately 580 mg / m 2 Approximately 600 mg / m 2 Approximately 620 mg / m 2 Approximately 640 mg / m 2 Approximately 660 mg / m 2 Approximately 680 mg / m 2 Approximately 700 mg / m 2 Approximately 720 mg / m 2 Approximately 740 mg / m 2 Approximately 760 mg / m 2, about 780mg / m 2 , about 800mg / m 2 , about 825mg / m 2 , about 850mg / m 2 , about 875mg / m 2 , about 900mg / m 2 , about 925mg / m 2 , about 950mg / m 2 , about 975mg / m 2 , or approximately 1000 mg / m² 2 In some embodiments, the maximum tolerated dose is approximately 500 mg / m² per dose. 2 , about 520mg / m 2 、 Approximately 530mg / m 2 , about 560mg / m 2 , about 580mg / m 2 , or approximately 600 mg / m² 2 In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered two, three, four, five, six, or seven times a week. In some embodiments, the maximum tolerated dose is approximately 825 mg / m² per week. 2 In some embodiments, the maximum tolerated dose is approximately 660 mg / m² per week. 2 In some embodiments, the maximum tolerated dose is approximately 530 mg / m² per week. 2 In some embodiments, the maximum tolerated dose is approximately 420 mg / m² per week. 2 In some embodiments, the maximum tolerated dose is approximately 280 mg / m² per week. 2 In some embodiments, the maximum tolerated dose is approximately 800 mg / m² per week. 2 ~about 1000mg / m 2 In some embodiments, the maximum tolerated dose is approximately 600 mg / m² per week. 2 ~about 800mg / m 2 In some embodiments, the maximum tolerated dose is approximately 500 mg / m² per week. 2 ~about 550mg / m2 In some embodiments, the maximum tolerated dose is approximately 400 mg / m² per week. 2 ~about 450mg / m 2 In some embodiments, the maximum tolerated dose is approximately 400 mg / m² per week. 2 ~about 500mg / m 2 In some embodiments, the maximum tolerated dose is approximately 200 mg / m² per week. 2 ~about 300mg / m 2 In some embodiments, the maximum tolerated dose is approximately 250 mg / m² per week. 2 ~about 300mg / m 2 In some embodiments, the above administration is based on the free base form of compound A.

[0058] In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject over a long period of time. In some embodiments, the above long-term administration of compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week. In some embodiments, the above long-term administration of compound A, or a pharmaceutically acceptable salt or solvate thereof, is once a day, once every two days, once every three days, or once a week. In some embodiments, the above long-term administration of compound A, or a pharmaceutically acceptable salt or solvate thereof, is at least once a day, at least once every two days, at least once every three days, or at least once a week. The above long-term administration of compound A, or a pharmaceutically acceptable salt or solvate thereof, is at most once a day, at most once every two days, at most once every three days, or at most once a week. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered over a long period of time using the amounts disclosed herein.

[0059] In some embodiments, approximately 280 mg / m² 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week for an extended period. In some embodiments, the dose is approximately 350 mg / m².2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week for an extended period. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week for an extended period. In some embodiments, the dose is approximately 530 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week for an extended period.

[0060] In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject over a long period of time, once, twice, three, four, five, six times, or more times per month. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject over a long period of time, at least once, twice, three, four, five, or six times per month. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject over a long period of time, at most once, twice, three, four, five, or six times per month. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered over a long period of time, at most once, twice, three, four, five, or six times per month.

[0061] In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject over a course of 30, 60, 120, 180, 240, 300, 360, 720, 1440, 1880, or 3600 days. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject over a long-term course of up to 30 days, up to 60 days, up to 120 days, up to 180 days, up to 240 days, up to 300 days, up to 360 days, up to 720 days, up to 1440 days, up to 1800 days, or up to 3600 days. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered over a long-term course of up to 300 days, up to 60 days, up to 120 days, up to 180 days, up to 240 days, up to 300 days, up to 720 days, up to 1440 days, up to 1800 days, or up to 3600 days.

[0062] In some embodiments, approximately 280 mg / m² 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week, over a 360-day cycle. In some embodiments, the dose is approximately 350 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week, over a 360-day cycle. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week, over a 360-day cycle. In some embodiments, the dose is approximately 530 mg / m². 2Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week, over a 360-day cycle. In some embodiments, the dose is approximately 280 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least one year. In some embodiments, the dose is approximately 350 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least one year. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least one year. In some embodiments, the dose is approximately 530 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least one year.

[0063] In some embodiments, approximately 280 mg / m² 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week, over a period of 720 days. In some embodiments, the dose is approximately 350 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week, over a period of 720 days. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week, over a period of 720 days. In some embodiments, the dose is approximately 530 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week, over a period of 720 days. In some embodiments, the dose is approximately 280 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least two years. In some embodiments, the dose is approximately 350 mg / m². 2Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least two years. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least two years. In some embodiments, the dose is about 400 to 450 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least two years. In some embodiments, the dose is approximately 410 and 430 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least two years. In some embodiments, the dose is about 500 to 550 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least two years. In some embodiments, the dose is approximately 530 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least two years. In some embodiments, at least 530 mg / m² 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term, once a week for at least two years.

[0064] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered over a long-term period of 28-day treatment cycles over courses of 30, 60, 120, 180, 240, 300, 360, 720, 1440, 1880, or 3600 days. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered over a long-term period of 28-day treatment cycles over courses of at least 30, at least 60, at least 120, at least 180, at least 240, at least 300, at least 360, at least 720, at least 1440, at least 1880, or at least 3600 days. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered over a long period in 28-day treatment cycles over cycles of up to 30 days, up to 60 days, up to 120 days, up to 180 days, up to 240 days, up to 300 days, up to 360 days, up to 720 days, up to 1440 days, up to 1800 days, or up to 3600 days. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered over a long period using the amounts disclosed herein.

[0065] In some embodiments, approximately 280 mg / m² 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of 360 days. In some embodiments, the dose is approximately 350 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of 360 days. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of 360 days. In some embodiments, the dose is approximately 530 mg / m². 2Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of 360 days. In some embodiments, the dose is approximately 280 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of one year. In some embodiments, the dose is approximately 350 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of one year. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of one year. In some embodiments, the dose is approximately 530 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of one year.

[0066] In some embodiments, approximately 280 mg / m² 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of 720 days. In some embodiments, the dose is approximately 350 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of 720 days. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of 720 days. In some embodiments, the dose is approximately 530 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of 720 days. In some embodiments, the dose is approximately 280 mg / m². 2Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles for a period of at least two years. In some embodiments, the dose is approximately 350 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles over a period of at least two years. In some embodiments, the dose is approximately 420 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles for a period of at least two years. In some embodiments, the dose is approximately 400–450 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles for a period of at least two years. In some embodiments, the dose is approximately 410–430 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles for a period of at least two years. In some embodiments, the dose is approximately 530 mg / m². 2 Compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered long-term in 28-day treatment cycles for a period of at least two years.

[0067] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered once weekly (QW) up to the maximum dose. In some embodiments, the maximum once weekly (QW) dose of compound A or a pharmaceutically acceptable salt or solvate thereof is greater than 600 mg. In some embodiments, the maximum once weekly (QW) dose of compound A or a pharmaceutically acceptable salt or solvate thereof is at most 600 mg. In some embodiments, the maximum once weekly (QW) dose of compound A or a pharmaceutically acceptable salt or solvate thereof is at most 530 mg. In some embodiments, the maximum once weekly (QW) dose of compound A or a pharmaceutically acceptable salt or solvate thereof is at most 420 mg. In some embodiments, the maximum once weekly (QW) dose is at most 350 mg. In some embodiments, the maximum once weekly (QW) dose of compound A or a pharmaceutically acceptable salt or solvate thereof is at most 280 mg. In some embodiments, the maximum once-weekly (QW) dose of compound A or its pharmaceutically acceptable salt or solvate is 600 mg. In some embodiments, the maximum once-weekly (QW) dose of compound A or its pharmaceutically acceptable salt or solvate is 530 mg. In some embodiments, the maximum once-weekly (QW) dose of compound A or its pharmaceutically acceptable salt or solvate is 420 mg. In some embodiments, the maximum once-weekly (QW) dose is 350 mg. In some embodiments, the maximum once-weekly (QW) dose of compound A or its pharmaceutically acceptable salt or solvate is 280 mg. In some embodiments, compound A or its pharmaceutically acceptable salt or solvate is compound A.

[0068] In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered orally (PO) once weekly (QW) up to the maximum dose. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or a pharmaceutically acceptable salt or solvate thereof, is greater than 600 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or a pharmaceutically acceptable salt or solvate thereof, is up to 600 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or a pharmaceutically acceptable salt or solvate thereof, is up to 530 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or a pharmaceutically acceptable salt or solvate thereof, is up to 420 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) is up to 350 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or its pharmaceutically acceptable salt or solvate, is up to 280 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or its pharmaceutically acceptable salt or solvate, is 600 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or its pharmaceutically acceptable salt or solvate, is 530 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or its pharmaceutically acceptable salt or solvate, is 420 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or its pharmaceutically acceptable salt or solvate, is 350 mg. In some embodiments, the maximum once-weekly (QW) oral dose (PO) of compound A, or its pharmaceutically acceptable salt or solvate, is 280 mg. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is compound A.

[0069] Compound A, or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject in a dose-increase / decrease scheme. In some embodiments, the dose-increase / decrease scheme includes one or more cycles of dose increases, one or more cycles of dose decreases, or both. In some embodiments, the initial dose is approximately 200 to approximately 600 mg / m² per week. 2 It is equal to compound A. In some embodiments, the initial dose is about 400 to 500 mg / m² per week. 2 Equivalent to compound A (for example, 420 mg / m² once a week) 2 Compound A). In some embodiments, the initial dose is approximately 500 to 600 mg / m² per week. 2 It is equal to compound A. Exemplary dose increase / decrease schemes are illustrated in Tables 1-A, 1-B, and 1-C. As shown in Tables 1A-1C, the subject may be administered at its initial dose. If the subject does not tolerate the initial dose, a reduced dose may be administered. If the subject does not tolerate the reduced dose, a further reduced dose may be administered. If the subject tolerates the initial dose, the subject may be administered at an increased dose (see Table 1-A or Table 1-C) or continue at the initial dose (see Table 1-B).

[0070] [Table 1-A]

[0071] [Table 1-B]

[0072] [Table 1-C]

[0073] Compound A is a Raf kinase inhibitor with a long half-life that supports once-weekly (QW) administration. In some embodiments, compound A is administered once weekly with a 6-day rest period between each administration. Appropriate weekly doses of a Raf inhibitor (e.g., compound A, or a pharmaceutically acceptable salt or solvate thereof) can generally range from up to approximately 1500 mg once weekly (QW) in single, divided, or multiple doses. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof is administered once weekly (QW) at up to 1500 mg in single, divided, or multiple doses. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof is administered once weekly at up to approximately 1000 mg. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof is administered once weekly at up to 1000 mg. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered as a single dose. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered quarterly (QW) in amounts up to 600 mg per dose. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered orally once a week in amounts up to 600 mg. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered on days 2, 9, 16, and 23 of a 28-day cycle in amounts up to 600 mg per dose. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered as divided doses. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered as divided doses on the same day. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered in multiple doses. An appropriate weekly dose is up to approximately 1000 mg per dose, administered once a week with a 6-day rest period between doses.In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once a week with a 6-day rest period between doses, up to 1000 mg per dose. Other suitable weekly doses of compound A, or a pharmaceutically acceptable salt or solvate thereof, may generally range from about 200 mg to about 1000 mg per dose, once a week, in single, divided, or multiple doses. Other suitable weekly doses of compound A, or a pharmaceutically acceptable salt or solvate thereof, may generally range from about 400 mg to about 1000 mg, in single, divided, or multiple doses. In some embodiments, the above suitable weekly dose is about 400 mg to about 900 mg per dose, once a week. In some embodiments, the above suitable weekly dose is about 500 mg to about 900 mg per dose, once a week. In some other embodiments, the appropriate weekly dose is approximately 400 mg to approximately 600 mg per dose, once per week. In some other embodiments, the appropriate weekly dose is approximately 200 mg to approximately 500 mg per dose, once per week. In some other embodiments, the appropriate weekly dose is approximately 200 mg to approximately 300 mg per dose, once per week. In some embodiments, the appropriate weekly dose is approximately 200 mg, 300 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, or approximately 900 mg per dose, once per week. In some embodiments, the above QW dosing schedule distinguishes compound A, or a pharmaceutically acceptable salt or solvate thereof, and a combination of taxanes from other available treatments based on superior safety. In some embodiments, the above QW dosing schedule distinguishes a combination of compound A, or a pharmaceutically acceptable salt or solvate thereof, and a taxane from other available treatments based on superior efficacy.

[0074] Compound A may also be administered once a week in a 28-day treatment cycle. In some embodiments, the starting dose is 400 mg, then 600 mg, then 800 mg. In some embodiments, the maximum tolerated dose is reached with a treatment schedule of 200 mg every two days. In some embodiments, the maximum tolerated dose is reached with a treatment schedule of 600 mg once a week.

[0075] The dose of the Raf inhibitor administered to the subject also depends on the frequency of administration. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered once weekly (QW) with a 6-day rest period between each administration. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered daily. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered every two days. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered in a 22-day cycle. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered in a 28-day cycle. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered over a 28-day cycle, where compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 of the 28-day cycle. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered over a 28-day cycle, where compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered on days 2, 9, 16, and 23 of the 28-day cycle. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered over at least 26 cycles. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered over at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 cycles.In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered over a period of at least 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 40 cycles. In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered over a period of at least 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 48 months. In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of at least 8 weeks. In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject over a period of at least 10 weeks. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 10.5 weeks. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 12 weeks. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 15 weeks. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 20 weeks. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 28 weeks. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 2 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 3 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 4 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject for a period of at least 5 months.In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 6 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 7 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 8 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 9 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 10 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 11 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 12 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 13 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 14 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 15 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 16 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 17 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 18 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 19 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 20 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 21 months.In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 22 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 23 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 24 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 25 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 26 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 27 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 28 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 29 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 30 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 36 months. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 5 years. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a period of at least 10 years. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered to the subject over a long period. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered at a dose of 400 mg / m² per week. 2 ~about 600mg / m 2 (For example, 420 mg / m²) 2 Compound A of ) is administered to the subject. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is compound A.

[0076] A method for treating gliomas (e.g., pediatric low-grade gliomas) by administering compound A, or a pharmaceutically acceptable salt or solvate thereof, in a single phase to achieve a prescribed pharmacokinetic profile is disclosed herein. During or after administration of compound A, or a pharmaceutically acceptable salt or solvate thereof, the plasma concentration of compound A, or a pharmaceutically acceptable salt or solvate thereof may be determined by a validated bioanalytical assay. For example, the following pharmacokinetic (PK) parameters may be calculated, where appropriate: the maximum observed plasma concentration (Cmax), the area under the concentration-time curve from 0 to t (AUC0-t), and the apparent oral clearance of the drug (CL / F).

[0077] In some embodiments, methods for treating gliomas (e.g., pediatric low-grade gliomas) by administering compound A, or a pharmaceutically acceptable salt or solvate thereof, to achieve a prescribed Cmax level are disclosed herein. When compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered, Cmax can be measured. In some embodiments, the method comprises administering to the subject an amount of compound A or a pharmaceutically acceptable salt or solvate sufficient to achieve a Cmax of compound A of at least 2000 ng / mL. In some embodiments, the method includes administering to a subject an amount of compound A, or a pharmaceutically acceptable salt or solvate thereof, sufficient to achieve a Cmax of compound A of at least 2500 ng / mL, at least 3000 ng / mL, at least 3500 ng / mL, at least 4000 ng / mL, at least 4500 ng / mL, at least 5000 ng / mL, at least 5500 ng / mL, at least 6000 ng / mL, at least 6500 ng / mL, at least 7000 ng / mL, at least 7500 ng / mL, or at least 8000 ng / mL.

[0078] In some embodiments, the described method provides a method comprising the step of administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve a Cmax of compound A within a suitable range. In some embodiments, the Cmax is about 2,000 ng / mL to about 8,000 ng / mL. In some embodiments, the Cmax is at least about 2,000 ng / mL. In some embodiments, the Cmax is at most about 8,000 ng / mL. In some embodiments, the method involves administering approximately 2,000 ng / mL to approximately 2,500 ng / mL, approximately 2,000 ng / mL to approximately 3,000 ng / mL, approximately 2,000 ng / mL to approximately 3,500 ng / mL, approximately 2,000 ng / mL to approximately 4,000 ng / mL, approximately 2,000 ng / mL to approximately 4,500 ng / mL, approximately 2,000 ng / mL to approximately 5,000 ng / mL, and approximately 2,000 ng / mL to approximately 5,500 ng in the subject. / mL, approximately 2,000ng / mL to approximately 6,000ng / mL, approximately 2,000ng / mL to approximately 6,500ng / mL, approximately 2,000ng / mL to approximately 7,000ng / mL, approximately 2,000ng / mL to approximately 8,000n g / mL, approximately 2,500ng / mL to approximately 3,000ng / mL, approximately 2,500ng / mL to approximately 3,500ng / mL, approximately 2,500ng / mL to approximately 4,000ng / mL, approximately 2,500ng / mL to approximately 4,500 ng / mL, approximately 2,500ng / mL to approximately 5,000ng / mL, approximately 2,500ng / mL to approximately 5,500ng / mL, approximately 2,500ng / mL to approximately 6,000ng / mL, approximately 2,500ng / mL to approximately 6,50 0ng / mL, approximately 2,500ng / mL to approximately 7,000ng / mL, approximately 2,500ng / mL to approximately 8,000ng / mL, approximately 3,000ng / mL to approximately 3,500ng / mL, approximately 3,000ng / mL to approximately 4,0 00ng / mL, approximately 3,000ng / mL to approximately 4,500ng / mL, approximately 3,000ng / mL to approximately 5,000ng / mL, approximately 3,000ng / mL to approximately 5,500ng / mL, approximately 3,000ng / mL to approximately 6, 000ng / mL, approximately 3,000ng / mL to approximately 6,500ng / mL, approximately 3,000ng / mL to approximately 7,000ng / mL, approximately 3,000ng / mL to approximately 8,000ng / mL, approximately 3,500ng / mL to approximately 4,000ng / mL, about 3,500ng / mL to about 4,500ng / mL, about 3,500ng / mL to about 5,000ng / mL, about 3,500ng / mL to about 5,500ng / mL, about 3,500ng / mL to about 6,000ng / mL, about 3,500ng / mL mL ~ approx. 6,500ng / mL, approx. 3,500ng / mL ~ approx. 7,000ng / mL, approx. 3,500ng / mL ~ approx. 8,000ng / mL, approx. 4,000ng / mL ~ approx. 4,500ng / mL, approx. 4,000ng / mL ~ approx. 5,000ng / mL, approx. 000ng / mL ~ approx. 5,500ng / mL, approx. 4,000ng / mL ~ approx. 6,000ng / mL, approx. 4,000ng / mL ~ approx. 6,500ng / mL, approx. 4,000ng / mL ~ approx. 7,000ng / mL, approx. 4,000ng / mL ~ approx. 8,000ng / mL, approximately 4,500ng / mL to approximately 5,000ng / mL, approximately 4,500ng / mL to approximately 5,500ng / mL, approximately 4,500ng / mL to approximately 6,000ng / mL, approximately 4,500ng / mL to approximately 6,500ng / mL, approximately 4,500ng / mL to approximately 7,0 00ng / mL, approximately 4,500ng / mL to approximately 8,000ng / mL, approximately 5,000ng / mL to approximately 5,500ng / mL, approximately 5,000ng / mL to approximately 6,000ng / mL, approximately 5,000ng / mL to approximately 6,500ng / mL, approximately 5,000ng / m L ~ about 7,000ng / mL, about 5,000ng / mL - about 8,000ng / mL, about 5,500ng / mL - about 6,000ng / mL, about 5,500ng / mL - about 6,500ng / mL, about 5,500ng / mL - about 7,000ng / mL, about 5,50 The process includes administering a sufficient amount of compound A, or a pharmaceutically acceptable salt or solvate thereof, to achieve the Cmax of compound A, which is approximately 0 ng / mL to 8,000 ng / mL, approximately 6,000 ng / mL to 6,500 ng / mL, approximately 6,000 ng / mL to 7,000 ng / mL, approximately 6,500 ng / mL to 7,000 ng / mL, approximately 6,500 ng / mL to 8,000 ng / mL, or approximately 7,000 ng / mL to 8,000 ng / mL.

[0079] In some embodiments, a method for treating gliomas (e.g., pediatric low-grade gliomas) is disclosed herein by administering compound A, or a pharmaceutically acceptable salt or solvate thereof, to achieve a prescribed AUC level of compound A. In some embodiments, the area under the concentration-to-time curve (AUC0-t) or AUCss (steady-state AUC) from time 0 to t is measured in subjects administered compound A, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, AUC0-t is AUC0-12 (or AUC0-12hr), AUC0-24 (or AUC0-24hr), or AUC0-48 (or AUC0-48hr). In some embodiments, the above AUC0-t is AUC0-24. In some embodiments, the above AUC is AUCss.

[0080] In some embodiments, the methods described herein include administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve a prescribed steady-state AUC (AUCss). In some embodiments, the method includes administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve an AUCss of compound A of at least about 100,000 ng*h / mL. In some embodiments, the AUCss is at least about 200,000 ng*h / mL. In some embodiments, the AUCss is at least about 300,000 ng*h / mL. In some embodiments, the method includes administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve an AUCss of compound A of at least about 400,000 ng*h / mL. In some embodiments, the AUCss is at least about 500,000 ng*h / mL. In some embodiments, the AUCss is at least about 600,000 ng*h / mL. In some embodiments, the AUCss is at least about 400,000 ng*h / mL to at least about 800,000 ng*h / mL. In some embodiments, the AUCss is at least about 500,000 ng*h / mL to at least about 700,000 ng*h / mL. In some embodiments, the AUCss is at least about 300,000 ng*h / mL to at least about 800,000 ng*h / mL. In some embodiments, the AUCss is at least about 200,000 ng*h / mL to at least about 800,000 ng*h / mL. In some embodiments, the AUCss is about 100,000 ng*h / mL to about 800,000 ng*h / mL. In some embodiments, the AUCss is up to about 600,000 ng*h / mL. In some embodiments, the AUCss is up to about 800,000 ng*h / mL. In some embodiments, the AUCss is up to about 1,000,000 ng*h / mL.In some embodiments, the AUCss is up to about 1,200,000 ng*h / mL. In some embodiments, the AUCss is up to about 1,600,000 ng*h / mL. In some embodiments, the method involves the following ranges in the subject: approximately 100,000 ng*h / mL to approximately 1,600,000 ng*h / mL, approximately 100,000 ng*h / mL to approximately 1,000,000 ng*h / mL, approximately 100,000 ng*h / mL to approximately 800,000 ng*h / mL, approximately 100,000 ng*h / mL to approximately 600,000 ng*h / mL, 200,000 ng*h / mL to approximately 1,600,000 ng*h / mL, and approximately 200,000 ng*h / mL to approximately 1,000 0,000ng*h / mL, about 200,000ng*h / mL~about 800,000ng*h / mL, about 200,000ng*h / mL~about 600,000ng*h / mL, 300,000ng*h / mL~about 1,600,000ng*h / mL, about 300,000ng*h / mL~about 1,000,000ng*h / mL, about 300,000ng*h / mL~about 800,000ng*h / mL, about 300,000ng*h / mL~about 600,000ng*h / mL,400, 000ng*h / mL ~ approx. 1,600,000ng*h / mL, approx. 400,000ng*h / mL ~ approx. 1,000,000ng*h / mL, approx. 400,000ng*h / mL ~ approx. 800,000ng*h / mL, approx. 400,000ng* h / mL ~ approx. 600,000ng*h / mL, 500,000ng*h / mL ~ approx. 1,600,000ng*h / mL, approx. 500,000ng*h / mL ~ approx. 1,000,000ng*h / mL, approx. 500,000ng*h / mL ~ approx. 8 The process includes administering a sufficient amount of compound A, or a pharmaceutically acceptable salt or solvate thereof, to achieve an AUCss of compound A of approximately 00,000 ng*h / mL, approximately 500,000 ng*h / mL to approximately 600,000 ng*h / mL, approximately 600,000 ng*h / mL to approximately 1,600,000 ng*h / mL, approximately 600,000 ng*h / mL to approximately 1,000,000 ng*h / mL, or approximately 600,000 ng*h / mL to approximately 800,000 ng*h / mL.In some embodiments, the method involves the following concentrations in the subject: approximately 300,000 ng*h / mL to approximately 450,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 500,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 550,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 650,000 ng*h / mL, approximately 350,000 ng*h / mL to approximately 750,000 ng*h / mL, approximately 400,000 ng*h / mL to approximately 650, The process includes administering a sufficient amount of compound A, or a pharmaceutically acceptable salt or solvate thereof, to achieve an AUCss of compound A of approximately 000 ng*h / mL, approximately 400,000 ng*h / mL to approximately 750,000 ng*h / mL, approximately 400,000 ng*h / mL to approximately 850,000 ng*h / mL, approximately 400,000 ng*h / mL to approximately 950,000 ng*h / mL, or approximately 400,000 ng*h / mL to approximately 1,000,000 ng*h / mL.

[0081] In some embodiments, the method described herein comprises the step of administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve a prescribed AUC0-t. In some embodiments, the AUC0-t is AUC0-24. In some embodiments, the method comprises the step of administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve an AUC0-24 of compound A that is at least about 10,000 ng*h / mL. In some embodiments, the method comprises the step of administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve an AUC0-24 of compound A that is at least about 50,000 ng*h / mL. In some embodiments, the method comprises the step of administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve an AUC0-24 of compound A that is at least about 100,000 ng*h / mL. In some embodiments, AUC0-24 is at least about 100,000 ng*h / mL to at least about 600,000 ng*h / mL. In some embodiments, AUC0-24 is at least about 100,000 ng*h / mL to about 600,000 ng*h / mL. In some embodiments, AUC0-24 is at least about 100,000 ng*h / mL. In some embodiments, AUC0-24 is at most about 600,000 ng*h / mL. In some embodiments, the method involves injecting the subject with approximately 100,000 ng*h / mL to approximately 150,000 ng*h / mL, approximately 100,000 ng*h / mL to approximately 200,000 ng*h / mL, approximately 100,000 ng*h / mL to approximately 250,000 ng*h / mL, and approximately 100,000 ng*h / mL to approximately 300,000 ng*h / mL, about 100,000ng*h / mL~about 350,000ng*h / mL, about 100,000ng*h / mL~about 400,000ng*h / mL, about 100,000n g*h / mL ~ approx. 450,000ng*h / mL, approx. 100,000ng*h / mL ~ approx. 500,000ng*h / mL, approx. 100,000ng*h / mL ~ approx. 550,000 ng*h / mL, approximately 100,000 ng*h / mL to approximately 600,000 ng*h / mL, approximately 150,000 ng*h / mL to approximately 200,000 ng*h / mL, approximately 150,000 ng*h / mL to approximately 250,000 ng*h / mL, approximately 150,000 ng*h / mL to approximately 300,000 ng*h / mL, approximately 150,000 ng*h / mL to approximately 350,000 ng*h / mL, approximately 150,000 ng*h / mL to approximately 400,000 ng*h / mL, approximately 150,000 ng*h / mL to approximately 450,000 ng*h / mL, approximately 150,000 ng*h / mL mL ~ approx. 500,000 ng*h / mL, approx. 150,000 ng*h / mL ~ approx. 550,000 ng*h / mL, approx. 150,000 ng*h / mL ~ approx. 600,000 ng*h / mL, approx. 200,000 ng*h / mL ~ approx. 250,000 ng*h / mL, approx. 200,000 ng*h / mL ~ approx. 300,000 ng*h / mL, approx. 200,000 ng*h / mL ~ approx. 350,000 ng*h / mL, approx. 200,000 ng*h / mL ~ approx. 400,000 ng*h / mL, approx. 200,000 ng*h / mL ~ approx. 450,000 ng*h / mL, approx. 200, 000 ng*h / mL ~ approx. 500,000 ng*h / mL, approx. 200,000 ng*h / mL ~ approx. 550,000 ng*h / mL, approx. 200,000 ng*h / mL ~ approx. 600,000 ng*h / mL, approx. 250,000 ng*h / mL ~ approx. 300,000 ng*h / mL, approx. 250,000 ng*h / mL ~ approx. 350,000 ng*h / mL, approx. 250,000 ng*h / mL ~ approx. 400,000 ng*h / mL, approx. 250,000 ng*h / mL ~ approx. 450,000 ng*h / mL, approx. 250,000 ng*h / mL ~ approx. 500,000 ng*h / mL mL, approximately 250,000 ng*h / mL to approximately 550,000 ng*h / mL, approximately 250,000 ng*h / mL to approximately 600,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 350,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 400,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 450,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 500,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 550,000 ng*h / mL, approximately 300,000 ng*h / mL to approximately 600,000ng*h / mL, about 350,000ng*h / mL~about 400,000ng*h / mL, about 350,000ng*h / mL~about 450,000ng* h / mL, approx. 350,000ng*h / mL ~ approx. 500,000ng*h / mL, approx. 350,000ng*h / mL ~ approx. 550,000ng*h / mL, approx. 350,000ng*h / mL ~ approx. 600,000ng*h / mL, approx. 400,000ng*h / mL ~ approx. 450,000ng*h / mL, approx. 400,00 0ng*h / mL ~ approx. 500,000ng*h / mL, approx. 400,000ng*h / mL ~ approx. 550,000ng*h / mL, approx. 400,000ng*h / The process includes administering a sufficient amount of compound A, or a pharmaceutically acceptable salt or solvate thereof, to achieve an AUC0-24 of compound A in the following ranges: mL to approximately 600,000 ng*h / mL, approximately 450,000 ng*h / mL to approximately 500,000 ng*h / mL, approximately 450,000 ng*h / mL to approximately 550,000 ng*h / mL, approximately 450,000 ng*h / mL to approximately 600,000 ng*h / mL, approximately 500,000 ng*h / mL to approximately 550,000 ng*h / mL, or approximately 550,000 ng*h / mL to approximately 600,000 ng*h / mL.

[0082] In some embodiments, the methods described herein include administering to the subject a sufficient amount of compound A or a pharmaceutically acceptable salt or solvate thereof to achieve the prescribed AUC0-∞. In some embodiments, the AUC0-∞ of compound A includes about 250 μg·hr / L to about 1,600 μg·hr / L. In some embodiments, the AUC0-∞ of compound A includes at least about 250 μg·hr / L. In some embodiments, the AUC0-∞ of compound A includes up to about 1,600 μg·hr / L. In some embodiments, the AUC0-∞ of compound A is approximately 250 μg·hr / L to approximately 350 μg·hr / L, approximately 250 μg·hr / L to approximately 450 μg·hr / L, approximately 250 μg·hr / L to approximately 550 μg·hr / L, approximately 250 μg·hr / L to approximately 650 μg·hr / L, approximately 250 μg·hr / L to approximately 750 μg·hr / L, approximately 250 μg·hr / L to approximately 850 μg·hr / L, and approximately 250 μg·hr / L to Approximately 950μg·hr / L, approximately 250μg·hr / L to approximately 1,000μg·hr / L, approximately 250μg·hr / L to approximately 1,250μg·hr / L, approximately 250μg·hr / L to approximately 1,500μg·hr / L, approximately 2 50μg·hr / L~approx. 1,600μg·hr / L, approx. 350μg·hr / L~approx. 450μg·hr / L, approx. 350μg·hr / L~approx. 550μg·hr / L, approx. 350μg·hr / L~approx. 650μg·hr r / L, approximately 350μg·hr / L to approximately 750μg·hr / L, approximately 350μg·hr / L to approximately 850μg·hr / L, approximately 350μg·hr / L to approximately 950μg·hr / L, approximately 350μg·hr / L to approximately 1, 000μg·hr / L, approximately 350μg·hr / L to approximately 1,250μg·hr / L, approximately 350μg·hr / L to approximately 1,500μg·hr / L, approximately 350μg·hr / L to approximately 1,600μg·hr / L, approximately 45 0μg·hr / L~approx. 550μg·hr / L, approx. 450μg·hr / L~approx. 650μg·hr / L, approx. 450μg·hr / L~approx. 750μg·hr / L, approx. 450μg·hr / L~approx. 850μg·hr / L , about 450 μg hr / L to about 950 μg hr / L, about 450 μg hr / L to about 1,000 μg hr / L, about 450 μg hr / L to about 1,250 μg hr / L, about 450 μg hr / L to about 1,500µg·hr / L, 450µg·hr / L~1,600µg·hr / L, 550µg·hr / L~650µg·hr / L 550µg·hr / L~750µg·hr / L 550µg·hr / L~850µg·hr / L~550µg·hr / L~ 950µg·hr / L, 550µg·hr / L~1,000µg·hr / L, 550µg·hr / L~1,250µg·hr / L = 550µg·hr / L~ 1,500µg·hr / L 550µg·hr / L~1,600µg·hr / L 650µg ·hr / L~Volume 750µg·hr / L,Volume 650µg·hr / L~Volume 850µg·hr / L,Volume 650µg·hr / L~Volume 950µg ·hr / L, 650µg·hr / L~1,000µg·hr / L, 650µg·hr / L~1,250µg·hr / L, 65 0μg·hr / L~1,500μg·hr / L~650μg·hr / L~1,600μg·hr / L~750μg·hr / L~ 850µg·hr / L, 750µg·hr / L~950µg·hr / L, 750µg·hr / L~1,000µg·hr / L 750µg·hr / L~1,250µg·hr / L 750µg·hr / L~1,500µg·hr / L 750µg· hr / L~weight1,600µg·hr / L weight 850µg·hr / L~weight950µg·hr / L weight 850µg·hr / L~weight1,000 µg·hr / L, 850µg·hr / L~1,250µg·hr / L, 850µg·hr / L~1,500µg·hr / L 850µg·hr / L~Value 1,600µg·hr / L L~1,250µg·hr / L, 950µg·hr / L~1,500µg·hr / L, 950µg·hr / L~1,600 µg·hr / L, 1,000µg·hr / L~1,250µg·hr / L, 1,000µg·hr / L~1,500µg·hr / L ..1,000µg·hr / L(1,600µg·hr / L 、 1.250µg·hr / L(1,500µg·hr / L 、1 ,250µg·hr / L~value1,600µg·hr / L.

[0083] Administration of the second drug In some embodiments, compound A, or a pharmaceutically acceptable salt or solvate thereof, is administered together with a second therapeutic agent. In some embodiments, the second therapeutic agent is administered to treat skin-related conditions or disorders (e.g., acneiform rash, maculopapular rash, dry skin, or HFSR (rash, hand-foot skin reaction)). In some embodiments, treatment of low-grade glioma is administered with 1) compound A and 2) 1 or more therapeutic agents to treat skin-related conditions or disorders. In some embodiments, the second therapeutic agent is an agent for treating one or more of follicular reactions, eczematous reactions, paronychia, and hand-foot syndrome. In some embodiments, the second therapeutic agent is ketoconazole, steroid creams / ointments, topical clindamycin, oral antibiotics, and topical keratolytic agents. Subject

[0084] In some embodiments, the subject is approximately 0.5 m 2 ~about 2.0m 2 The subject has a body surface area (BSA) of approximately 0.5 m². In some embodiments, the subject has a body surface area (BSA) of approximately 0.5 m². 2 ~about 1.5m 2 It has a BSA. In some embodiments, the subject is about 0.5 m 2 , 0.75m 2 , 1.0m 2 , 1.25m 2 , 1.5m 2 , or 1.75m 2 It has a BSA. In some embodiments, the subject is about 0.5 m 2 ~about 1.5m 2 It has a BSA. In some embodiments, the subject is at least about 0.5 m 2 It has a BSA. In some embodiments, the subject is up to about 2.0 m 2It has a BSA. In some embodiments, the subject is up to about 1.9 m 2 It has a BSA. In some embodiments, the subject is up to about 1.8 m 2 It has a BSA. In some embodiments, the subject is up to about 1.7 m 2 It has a BSA. In some embodiments, the subject is up to about 1.6 m 2 It has a BSA. In some embodiments, the subject is up to about 1.5 m 2 It has a BSA. In some embodiments, the subject is up to about 1.4 m 2 It has a BSA. In some embodiments, the subject is up to about 1.3m 2 It has a BSA. In some embodiments, the subject is up to about 1.2 m 2 It has a BSA. In some embodiments, the subject is up to about 1.1m 2 It has a BSA. In some embodiments, the subject is up to about 1.0 m 2 It has a BSA. In some embodiments, the subject is up to about 0.9 m 2 It has a BSA. In some embodiments, the subject is up to about 0.8 m 2 It has a BSA. In some embodiments, the subject is up to about 0.7 m 2 It has a BSA. In some embodiments, the subject is up to about 0.6 m 2 It has a BSA. In some embodiments, the subject is up to about 0.5 m 2 It has a BSA. In some embodiments, the subject is at least about 0.4 m 2 It has a BSA. In some embodiments, the subject is at least about 0.5 m 2 It has a BSA. In some embodiments, the subject is at least about 0.6 m 2 It has a BSA. In some embodiments, the subject is at least about 0.7 m 2 It has a BSA. In some embodiments, the subject is at least about 0.8 m 2It has a BSA. In some embodiments, the subject is at least about 0.9 m 2 It has a BSA. In some embodiments, the subject is at least about 1.0 m 2 It has a BSA. In some embodiments, the subject is at least about 1.1 m 2 It has a BSA. In some embodiments, the subject is at least about 1.2 m 2 It has a BSA. In some embodiments, the subject is at least about 1.3 m 2 It has a BSA. In some embodiments, the subject is at least about 1.4 m 2 It has a BSA. In some embodiments, the subject is at least about 1.5 m 2 It has a BSA. In some embodiments, the subject is about 0.5 m 2 ~about 0.75m 2 , about 0.5m 2 ~approximately 1m 2 , about 0.5m 2 ~about 1.25m 2 , about 0.5m 2 ~about 1.5m 2 , about 0.75m 2 ~approximately 1m 2 , about 0.75m 2 ~about 1.25m 2 , about 0.75m 2 ~about 1.5m 2 Approximately 1 meter 2 ~about 1.25m 2 Approximately 1 meter 2 ~about 1.5m 2 , or approximately 1.25m 2 ~about 1.5m 2 It has a BSA. In some embodiments, the subject is about 1.5 m 2 ~about 2.0m 2 It has a BSA. In some embodiments, the subject is about 2m 2 ~about 2.5m 2 It has a BSA. In some embodiments, the subject is at least 1.5 m 2 It has a BSA.

[0085] A method for treating low-grade glioma (LGG) in a subject requiring treatment for LGG in a single context is described herein, the method comprising the step of administering compound A, or a pharmaceutically acceptable salt or solvate thereof, to the subject. In some embodiments, the LGG has one or more of the following mutations: RAS-positive mutation, RAF-positive mutation, MEK-positive mutation, and ERK-positive mutation. In embodiments, the patient is included to have progressive metastatic or respectable melanoma with a MAPK mutation. In some embodiments, the LGG has a BRAF mutation. In some embodiments, the LGG has a V600E mutation. In some embodiments, the LGG has a V600D mutation. In some embodiments, the LGG has a V600K mutation. In some embodiments, the LGG has a non-V600E mutation. In some embodiments, the BRAF mutation is a non-V600 BRAF mutation. In some embodiments, the subject is identified as having one or more of the following wild-type fusions: KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, and NFIA:RAF1. In some embodiments, the subject is identified as having the SRGAP3:RAF1 fusion. In some embodiments, the subject is identified as having a KIAA1549:BRAF fusion. In some embodiments, the subject has a KIAA1549:BRAF fusion. In some embodiments, the subject has a STARD3NL:BRAF fusion.In some embodiments, the subject has a BCAS1:BRAF fusion. In some embodiments, the subject has a KHDRBS2:BRAF fusion. In some embodiments, the subject has a CCDC6:BRAF fusion. In some embodiments, the subject has a FAM131B:BRAF fusion. In some embodiments, the subject has an SRGAP:BRAF fusion. In some embodiments, the subject has a CLCN6:BRAF fusion. In some embodiments, the subject has a GNAI1:BRAF fusion. In some embodiments, the subject has an MRKN1:BRAF fusion. In some embodiments, the subject has a GIT2:BRAF fusion. In some embodiments, the subject has a GTF21:BRAF fusion. In some embodiments, the subject has an FXR1:BRAF fusion. In some embodiments, the subject has an RNF130:BRAF fusion. In some embodiments, the subject has a GTF21:BRAF fusion. In some embodiments, the subject has a BRAF:MACF1 fusion. In some embodiments, the subject has a TMEM106B:BRAF fusion. In some embodiments, the subject has a PPC1CC:BRAF fusion. In some embodiments, the subject has a CUX1:BRAF fusion. In some embodiments, the subject has an SRGAP3:RAF1 fusion. In some embodiments, the subject has a QK1:RAF1 fusion. In some embodiments, the subject has a FYCO:RAF1 fusion. In some embodiments, the subject has an ATG7:RAF1 fusion. In some embodiments, the subject has an NFIA:RAF1 fusion. In some embodiments, the subject has a BRAF gene fusion. In some embodiments, the subject has a CRAF gene fusion.

[0086] Criteria for inclusion of a subject may be required while administering Compound A. In some embodiments, the subject has a recurrent non-blood malignancy or a progressive non-blood malignancy on radiographic imaging. In some embodiments, the blood malignancy is derived from the CNS or a solid tumor. In some embodiments, the blood malignancy is associated with activation of RAS, RAF<EK, ERK. In some embodiments, the subject has not been identified as having NF1. In some embodiments, the subject has received at least one line of systemic therapy. In some embodiments, the subject has evidence of progression on radiographic imaging. In some embodiments, the subject has received at least one line of systemic therapy (e.g., chemotherapy) and has evidence of progression on radiographic imaging. In some embodiments, the subject has recurrent LGG. In some embodiments, the subject has refractory LGG. In some embodiments, the subject has previously undergone surgery to treat the LGG. In some embodiments, the subject has previously undergone complete and partial surgical resection.

[0087] Criteria for secondary outcome measures while administering Compound A may be considered. In some embodiments, the secondary outcome measures may include safety, pharmacokinetics, motor function, effect on ECG measurements, or vision.

[0088] In some embodiments, the subjects are approximately 6 months to 25 years old. In some embodiments, the subjects are children. In some embodiments, the subjects are adolescents. In some embodiments, the subjects are adults. In some embodiments, the subjects are approximately 1 to 25 years old. In some embodiments, the subjects are 25 years old or younger. In some embodiments, the subjects are 20 years old or younger. In some embodiments, the subjects are 15 years old or younger. In some embodiments, the subjects are 10 years old or younger. In some embodiments, the subjects are 6 months to 5 years old. In some embodiments, the subjects are 6 months to 10 years old. In some embodiments, the subjects are 6 months to 15 years old. In some embodiments, the subjects are 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 years old or younger. In some embodiments, the subjects are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25 years old. In some embodiments, the subjects are measured in terms of performance status. In some embodiments, the performance status is Karnofsky performance status or Lansky performance status. In some embodiments, the Karnofsky status is greater than or equal to 50. In some embodiments, the Lansky status is greater than or equal to 50. In some embodiments, the subjects have low-grade gliomas. In some embodiments, the subjects have a history of failure to receive standard treatment. [Examples]

[0089] Examples

[0090] Example 1: Treatment schedule for compound A

[0091] Administer compound A orally once weekly (QW) at a dose of 530 mg / m 2 (not exceeding 800 mg) on days 1, 8, 15, and 22 of a 28-day cycle. Determine the body surface area (BSA) using the Mosteller formula (√((height × weight) / 3600)). Evaluate the data of the patients enrolled in this study based on the protocol-specified traditional dose limiting toxicity (DLT) criteria specified by the Safety Review Committee (SRC) to assess safety and compound A tolerance after the first 28 days of compound A treatment. If the above patients show tolerance to a dose of 530 mg / m 2 per week, continue to administer compound A at the same dose. If the above patients do not show tolerance to a dose of 530 mg / m 2 per week, administer a reduced dose (e.g., 420 mg / m 2 ). If the above patients do not show tolerance to a dose of 420 mg / m 2 per week, administer an even more reduced dose.

[0092] Repeat the treatment cycle every 28 days in the absence of disease progression or unacceptable toxicity. Patients start at the end of cycle 3 (C3) and receive an X-ray evaluation of their disease at the end of every 3 cycles. Patients continue compound A until evidence of disease progression by X-ray imaging according to the RANO criteria appears, or if recommended by their care team for other reasons.

[0093] Patients with evidence of disease progression by X-ray imaging may be allowed to continue compound A if, in the opinion of the care team, the above patients are deriving a clinical benefit from continuing treatment. The evaluation of the disease should continue for patients who are progressing and being treated.

[0094] Administer compound A at 530 mg / m 2For doses not exceeding 800 mg, the drug is administered as an oral tablet or an age-appropriate formulation (suspension or sprinkle). Patients who can swallow tablets will receive the tablet formulation. Approximately 50 patients will receive the tablet formulation. Patients who cannot swallow tablets or are unwilling to swallow tablets will receive an age-appropriate formulation once it becomes available. Approximately 10 patients will receive an age-appropriate formulation.

[0095] The patient receives 530 mg / m² on day 1 of cycle 1 (i.e., C1D1). 2 Treatment should be initiated with a quarterly dose (not exceeding 800 mg quarterly dose). Each cycle consists of continuous administration for 28 days.

[0096] Example 2. Patient-level dose, exposure, and preliminary response data

[0097] Use a 3+3 design. 350 mg / m² orally weekly. 2 Adult dose (typical adult BSA 1.7mg) 2 Based on the use of [specific data], the starting dose in pediatric studies was 80% of the adult RP2D. This corresponds to 280 mg / m² orally per week. 2 The dose was increased in a stepwise manner among patients until dose-limiting toxicity (DLT) was observed. Three different dose levels: 280 mg / m² 2 , 350 mg / m² 2 , and 420 mg / m² 2 .

[0098] Treatment was initiated at 80% of the adult dose (i.e., 280 mg / m² orally once weekly, based on the following calculation). 2 ): • Adult dose of 600 mg once weekly and average adult BSA (m³) 2 ) 1.73m 2 =350mg / m 2 • 350 mg / m² 2 80% of that = 280 mg / m² 2 Starting dose.

[0099] The dose escalation scheme is described in Table 1-A. The initial phase involves a maximum dose of 530 mg / m² per week. 2 This includes three dose increase levels to the / dose.

[0100] Pharmacokinetic studies were conducted for all patients in the Phase I component of the clinical trial, provided that intravenous access was permitted. Initial Phase 1 involved a maximum weekly dose of 530 mg / m². 2 This included three dose-increase levels. A PK test was also performed to evaluate phosphorylated ERK in peripheral blood mononuclear cells.

[0101] Preliminary analysis suggested that differences in exposure-based responses may exist. PK analysis of pediatric values ​​in mg / kg units suggested a nearly 2.2-fold difference. Furthermore, preliminary observations noted a more robust response between patients with the lowest BSA and highest exposures.

[0102] Patient-level doses, exposures, and expected exposures are illustrated in Table 3. Response data are illustrated in Table 2. [Table 2] Abbreviation: AUC 0-∞ = Area under the concentration-time curve from time 0 to infinity; BSA = Body surface area; RANO response (SPD): CR = -100%; PR = -50% or greater reduction from baseline; PD = ≥25% increase from the lowest point, SD = between -50% and +25%. Subject-8 (PNOC014-08) was 420 mg / m² 2 It was administered and, although PK data was not available, it achieved the best response of complete response (CR) according to RANO criteria. [Table 3] Abbreviation: AUC 0-∞ = Area under the concentration-time curve from time 0 to infinity; BSA = Body surface area

[0103] Further results and analysis are shown in Figures 1 and 2.

[0104] Figure 2 illustrates the Phase 1 clinical trial data for the response of these nine individual pediatric LGG (pLGG) patients to compound A over time. A reduction in lesion size was observed in six of the nine patients in the first radiographic image taken after the initiation of compound A administration. The median time to response was 10.5 weeks. Two patients achieved a complete response, which was maintained throughout the entire administration period up to two years. Three patients had a partial response, two achieved long-term stable disease, and two did not achieve a response.

[0105] Figure 1 illustrates the Phase 1 clinical trial data for these pLGG patients who achieved a complete response (100% reduction) or partial response (>50% reduction in two-dimensional tumor measurements) to treatment with compound A. Of the eight patients with RAF fusion, five achieved either a complete response or a partial response (defined as ≥50% reduction) compared to baseline, according to the RANO criteria. Two of the eight patients with RAF fusion maintained long-term stable disease. One patient with RAF fusion did not respond to compound A. One patient with NF1-related pLGG did not respond to compound A.

[0106] Example 3: Treatment schedule for compound A

[0107] This clinical trial follows a modified Bayesian adaptive Sub-TITE design (subgroup-specific time-vs-event continuous reassessment) to enable separate determination of maximum tolerated doses in two BSA subgroups (see Table 1-C). Compound A is administered as an oral tablet. The starting dose is 420 mg / m2 / dose orally every week (see Table 1-C). Dose elevation decisions are indicated by the Sub-TITE Bayesian model described above. Pharmacokinetic studies are performed on all patients in the trial. Pharmacodynamic studies (including measurement of phosphorylated ERK in peripheral blood mononuclear cells) are also performed on all patients in the trial. Tissue-based pharmacodynamic studies are performed on patients for whom tumor tissue is available.

[0108] Example 4: Phase 2 Trial to Evaluate the Efficacy and Safety of Compound A in Pediatric and Young Adult Patients with Recurrent or Progressive Low-Grade Gliomas

[0109] This study will evaluate the safety and efficacy of the oral pan-RAF inhibitor Compound A in pediatric, adolescent, and young adult patients with recurrent or progressive low-grade gliomas with known BRAF alterations, according to a Phase 2 multi-center open-label trial.

[0110] Approximately 60 pediatric patients will be treated with Compound A (oral pan-RAF inhibitor) over a planned period of 26 cycles (approximately 24 months).

[0111] Compound A will be orally administered once weekly over each 28-day treatment cycle at the recommended Phase 2 dose (RP2D) of 420 mg / m 2 (not exceeding 600 mg). Compound A will be administered as an oral tablet. For example, immediate-release tablets of two strengths (20 mg and 100 mg) may be administered. Treatment cycles will be repeated every 28 days if there is no disease progression or unacceptable toxicity. Patients will receive an evaluation of their disease at the end of every 3 cycles. Patients will continue Compound A until there is radiographic evidence of disease progression according to the RANO criteria as determined by the study investigator, unacceptable toxicity, withdrawal of consent by the patient, or death.

[0112] Patients with radiographic evidence of disease progression may be allowed to continue Compound A at the discretion of the study investigator and approval of the study sponsor if the patient is deriving clinical benefit from continuing the study treatment. The evaluation of the disease for patients who are progressing while on treatment should continue according to a regular schedule.

[0113] The primary outcome scale is determined by an independent radiology review committee (IRC) based on RANO criteria. Secondary outcome scales are also considered. For example: 1) Safety and tolerability [Time frame: from the first dose to the end of the procedure], 2) Pharmacokinetics [Time frame: from the first dose to the end of treatment] 3) Effect on QT interval (QTcF) prolongation corrected by electrocardiogram (ECG) and heart rate according to Fridericia's formula [Time frame: from the first dose to the end of treatment] 4) ORR by the investigator using the RANO criteria [Time frame: within 12 months of treatment] 5) ORR by IRC and investigators using RAPNO criteria [Timeframe: within 12 months of treatment] 6) Progression-free survival (PFS) as measured by IRCs and investigators using RANO and RAPNO criteria [Time frame: from the first dose to the end of the study], 7) Duration of response (DOR) associated with the best overall response to complete response (CR) or partial response (PR) using RANO and RAPNO criteria [Time frame: within 12 months of treatment] 8) Time to respond [Timeframe: within 12 months of treatment] 9) Clinical benefit rate [Time frame: within 12 months of the procedure] 10) Visual acuity [Time frame: within 12 months of treatment], 11) Molecular profiling [Time frame: from the first dose to the end of the study].

[0114] Other pre-defined outcome measures may be evaluated. For example: 1) Time to Response and Progress (TTP) [Timeframe: within 12 months of treatment] 2) Total tumor volume [Time frame: from the first dose to the end of the procedure], 3) Changes in diffusion coefficient [Time frame: from the first dose to the end of treatment] 4) Quality of life (QoL) and health utility [Time frame: from the first dose to the end of treatment] 5) Motor function [Time frame: from the first dose to the end of the procedure], and 6) Durability of the response [Time frame: 2 years after the completion of treatment].

[0115] Inclusion criteria may include patients between 6 months and 25 years of age with relapsed or progressive LGG with known activated BRAF activation. Inclusion criteria may also require confirmation of histopathological diagnosis of LGG and molecular diagnosis of activated BRAF alteration. In some cases, the above patients must have received at least one line of systemic therapy and have evidence of progression on radiographic imaging. In some cases, the above patients must have at least one measurable lesion as defined by the RANO criteria.

[0116] In some cases, patients may be excluded if the tumor has further previously known activated molecular changes. Patients may be excluded if there are symptoms of clinical progression in the absence of progression on radiographic imaging. In some cases, patients may be excluded if they have a known or suspected diagnosis of neurofibromatosis type 1 (NF-1). Furthermore, patients may be excluded in accordance with the clinical trial protocol.

[0117] An exemplary clinical trial design is shown in Figure 3.

[0118] Preferred embodiments of the present invention have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided merely by illustration. Many variations, modifications, and substitutions will be conceivable to those skilled in the art without departing from the present invention. It should be understood that various modifications to the embodiments of the invention described herein may be used in carrying out the present invention. The following claims define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are intended to be covered thereby. In embodiments of the present invention, for example, the following items are provided. (Item 1) A method for treating low-grade glioma (LGG) in subjects requiring treatment for LGG, wherein the method is: The procedure involves administering (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide (compound A), or a pharmaceutically acceptable salt thereof, to the subject, wherein the initial dose of compound A or the pharmaceutically acceptable salt thereof is approximately 400 mg / m² per week. 2 ~about 600mg / m 2 The process is equivalent to compound A, and includes, Here, the subject is under 20 years old. method. (Item 2) The initial dose of compound A or a pharmaceutically acceptable salt thereof is approximately 500 mg / m² per week. 2 ~about 600mg / m 2 The method described in item 1, which is equivalent to compound A. (Item 3) The initial dose of compound A or a pharmaceutically acceptable salt thereof is approximately 400 mg / m² per week. 2 ~about 500mg / m 2 The method described in item 1, which is equivalent to compound A. (Item 4) The initial dose of compound A or a pharmaceutically acceptable salt thereof is approximately 420 mg / m² per week. 2 The method described in item 1, which is equivalent to compound A. (Item 5) The initial dose of compound A or a pharmaceutically acceptable salt thereof is approximately 530 mg / m² per week. 2 The method described in item 1, which is equivalent to compound A. (Item 6) A method for treating low-grade glioma (LGG) in subjects requiring treatment for LGG, wherein the method is: The process involves administering to the subject (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide (compound A) or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an observed maximum plasma concentration (Cmax) of compound A of at least 2000 ng / mL in the subject. It includes, Here, the subject is under 20 years old. method. (Item 7) The method according to item 6, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in an amount sufficient to achieve a Cmax of compound A of 2000 ng / mL to 8000 ng / mL. (Item 8) A method for treating low-grade glioma (LGG) in subjects requiring treatment for LGG, wherein the method is: The process involves administering to the subject (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide (compound A) or a pharmaceutically acceptable salt thereof in an amount sufficient to achieve an area under the concentration curve (AUCss) of compound A of at least about 400,000 ng*h / mL. It includes, Here, the subject is under 20 years old. method. (Item 9) The method according to item 8, wherein compound A or a pharmaceutically acceptable salt thereof is administered to the subject in an amount sufficient to achieve an AUCss of compound A of 400,000 ng*h / ml to 1,600,000 ng*h / ml. (Item 10) A method for treating low-grade glioma (LGG) in subjects requiring treatment for LGG, wherein the method is: The process of administering to the subject (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide (compound A) or a pharmaceutically acceptable salt thereof, and (ii) in combination with one or more therapeutic agents for treating a skin-related condition or disorder. It includes, Here, the subject is under 20 years old. method. (Item 11) The method according to item 10, wherein the above-mentioned therapeutic agent (1 or more) is administered to pigmented skin. (Item 12) The LGG is a recurrent disease or a progressive disease as detected by radiography, as described in any one of items 1 to 11. (Item 13) The method according to any one of items 1 to 12, wherein the compound A or a pharmaceutically acceptable salt thereof is (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide. (Item 14) The method according to any one of items 1 to 13, wherein the compound A or a pharmaceutically acceptable salt thereof is administered as a liquid suspension. (Item 15) The method according to any one of items 1 to 13, wherein compound A or a pharmaceutically acceptable salt thereof is administered as a tablet. (Item 16) The method according to any one of items 1 to 15, wherein compound A or a pharmaceutically acceptable salt thereof is administered as a single dose per week. (Item 17) The method according to any one of items 1 to 15, wherein compound A or a pharmaceutically acceptable salt thereof is administered in doses of 2 to 4 times per week. (Item 18) The method according to any one of items 1 to 17, wherein the compound A or a pharmaceutically acceptable salt thereof is administered over a period of at least 24 months. (Item 19) The subject is 20 years of age or younger, and the method described in any one of items 1 to 18. (Item 20) The subject is 15 years of age or younger, and the method described in any one of items 1 to 18. (Item 21) The subject was 0.5 m 2 ~about 2.0m 2 A method according to any one of items 1 to 20, having a body surface area (BSA) of the specified amount. (Item 22) The subject was 0.5 m 2 ~about 1.5m 2 The method described in any one of items 1 to 20, having a BSA of (Item 23) The LGG is the method described in any one of items 1 to 22, wherein the LGG has one or more of the following mutations: RAS-positive mutations, RAF-positive mutations, MEK-positive mutations, and ERK-positive mutations. (Item 24) The LGG is a method described in any one of items 1 to 22, having a BRAF mutation. (Item 25) The method described in item 24, wherein the BRAF mutation is a non-V600 BRAF mutation. (Item 26) The BRAF mutation is the V600E mutation, as described in item 24. (Item 27) The method according to any one of items 1 to 26, wherein the subject is identified to have one or more of the following wild-type fusions:KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, and NFIA:RAF1. (Item 28) The subject is identified as having a KIAA1549:BRAF wild-type fusion, according to the method described in any one of items 1 to 26. (Item 29) The subject has previously received one or more treatments selected from surgery, irradiation, and chemotherapy, according to any one of items 1 to 28. (Item 30) The method according to item 29, wherein the subject has undergone complete or partial excision prior to administration of compound A or a pharmaceutically acceptable salt thereof. (Item 31) The method according to any one of the above items, wherein compound A or a pharmaceutically acceptable salt thereof is administered at a maximum dose of 600 mg. (Item 32) The method according to item 31, wherein the maximum dose is 600 mg orally (PO) once a week.

Claims

1. A composition for use in the treatment of low-grade glioma (LGG) in subjects requiring treatment of LGG, comprising a compound (compound A) which is (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof, The dose of compound A or a pharmaceutically acceptable salt thereof is approximately 350 mg / m² once a week. ２ ~About 450mg / m ２ Equivalent to compound A, The subject in this case is a composition under the age of 20.

2. The dose of compound A or a pharmaceutically acceptable salt thereof is approximately 380 mg / m² once a week. ２ A composition for use according to claim 1, which is equal to compound A.

3. The dose of compound A or a pharmaceutically acceptable salt thereof is approximately 420 mg / m² once a week. ２ A composition for use according to claim 1, which is equal to compound A.

4. The composition for use according to any one of claims 1 to 3, characterized in that it is administered in combination with one or more therapeutic agents for treating skin-related conditions or disorders.

5. The composition for use according to any one of claims 1 to 3, wherein the LGG is a recurrent disease or a progressive disease as detected by X-ray imaging.

6. The composition for use according to any one of claims 1 to 3, wherein the LGG is recurrent LGG or refractory LGG.

7. The composition for use according to any one of claims 1 to 3, wherein the LGG has an activated BRAF alteration or a BRAF mutation.

8. The composition for use according to any one of claims 1 to 3, wherein the compound A or a pharmaceutically acceptable salt thereof is (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide.

9. The composition for use according to any one of claims 1 to 3, wherein the composition is a liquid suspension.

10. The composition for use according to any one of claims 1 to 3, wherein the composition is in the form of a tablet.

11. The composition for use according to any one of claims 1 to 3, characterized in that it is administered over a period of at least 24 months.

12. The LGG is a composition for use according to any one of claims 1 to 3, wherein the LGG has a BRAF mutation.

13. The composition for use according to any one of claims 1 to 3, wherein the subject has previously undergone one or more treatments selected from surgery, irradiation, and chemotherapy, or the subject has previously undergone complete or partial excision.

14. The composition for use according to any one of claims 1 to 3, characterized in that the composition is administered in a maximum dose of 600 mg of compound A or a pharmaceutically acceptable salt thereof.

15. A composition for use in a method of treating pLGG in subjects requiring treatment of pediatric low-grade glioma (pLGG), comprising a compound (compound A) which is (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridine-2-yl)thiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof, The method includes the step of administering the composition to the subject, Here, the dose of compound A or a pharmaceutically acceptable salt thereof is approximately 350 mg / m² once a week. ２ ~About 450mg / m ２ Equivalent to compound A, The subjects in question range in age from approximately 6 months to approximately 25 years. composition.

Images