Methods of treating pediatric low grade glioma

Abstract

In one aspect, this article describes a method for treating relapsed or refractory pediatric low-grade glioma (pLGG) in subjects of need, the method comprising administering tovorafenib or a salt thereof to the subject, wherein the subject is 6 months of age or older. In some embodiments, the pediatric low-grade glioma (pLGG) carries a BRAF fusion or rearrangement, or a BRAF V600 mutation. In some embodiments, the method comprises administering an initial dose, a reduced dose, and optionally a further reduced dose.

Description

[0001] Cross-referencing This application claims the benefit of U.S. Provisional Application Serial No. 63 / 599,378, filed November 15, 2023, and U.S. Provisional Application Serial No. 63 / 637,875, filed April 23, 2024, each of which is incorporated herein by reference in its entirety. Background Technology

[0002] Each year, approximately 15,500 children under the age of 18 in the United States and around 300,000 worldwide are diagnosed with cancer. Furthermore, cancer remains the leading cause of death from illness in the United States, causing more than 1,700 deaths annually. Despite the need for safer and more effective treatments for childhood cancer, few new drugs are available for pediatric patients.

[0003] Pediatric low-grade gliomas (pLGGs) are the most common brain tumors diagnosed in children, causing severe tumor and treatment-related morbidities that can impact their life trajectories. For the vast majority of patients with recurrent cases, there is neither a standard treatment nor an approved therapy. Therefore, there is an unmet need for new, more effective treatments for patients with pLGGs. Attached Figure Description

[0004] Figure 1 FIREFLY-1 Patient Management / Consolidate Flowchart. This diagram presents efficacy data for the evaluable population (patients who received at least one dose of tovorafenib and met the pre-specified efficacy analysis criteria according to each radiological assessment method by IRC) in Group 1 (registered) as of the data cutoff date of June 5, 2023, as well as safety data from Group 1 and Group 2 (safety analysis set). Patients were enrolled in Group 1 and enrollment was closed before being transferred to Group 2 (extended). a Not radiologically confirmed. b Only patients with measurable disease at baseline, as determined by independent review, are included. HGG, high-grade glioma; IRC, Independent Radiological Review Committee; LGG, low-grade glioma; RANO, Neuro-oncology Response Assessment; RAPNO, Pediatric Neuro-oncology Response Assessment.

[0005] Figure 2A-2C It can assess the maximum variation in tumor size in patients. Figure 2A According to the RANO-HGG standard, Figure 2B RAPNO standards, and Figure 2CRANO-LGG criteria. Two patients were not shown in the waterfall plot; one patient died of PD (unrelated to tovorafenib) prior to initial tumor assessment, and one patient lacking T1 Gd+ imaging at baseline was deemed unevaluable. Dashed lines represent the growth / contraction extent of target lesions considered as one of the requirements for PD, SD, MR, PR, or CR. BRAFi, BRAF inhibitor; CR, complete response; HGG, high-grade glioma; LGG, low-grade glioma; MEKi, MEK inhibitor; MR, mild response; PD, progressive disease; PR, partial response; RANO, neuro-oncology response assessment; RAPNO, pediatric neuro-oncology response assessment; SD, stable disease.

[0006] Figure 3A and 3B Lane diagram of reaction time and treatment duration. Figure 3A According to the RANO-HGG standard, and Figure 3B RAPNO criteria. In responsive patients, the symbol indicates the onset of response (MR, PR, or CR). If the initial response improves with continued treatment (from MR to confirmed PR, or from PR to confirmed CR), the time point of the initial response and the time point of the first improvement in response are marked accordingly. BRAFi, BRAF inhibitor; HGG, high-grade glioma; LGG, low-grade glioma; MEKi, MEK inhibitor; RANO, neuro-oncology response assessment; RAPNO, pediatric neuro-oncology response assessment.

[0007] Figure 4A The visual acuity assessments of the patients are shown. Due to rounding, the total percentages may not be 100. The LogMAR range is adapted from Schultz-Bonsel K et al., Invest Ophthalmol Vis Sci. 2006; 47(3):1236-1240 and Gnekow AK et al., Glioma Klin Padiatr. 2019; 231(3):107-135. Six patients were not included in the analysis; four were blind in both eyes and therefore did not undergo visual acuity assessment, one did not undergo baseline assessment, and one discontinued treatment and did not undergo post-baseline follow-up assessment. logMAR (log minimum resolution logarithm); RANO (randomization of neuro-oncology response); RAPNO (pediatric neuro-oncology response assessment – ​​low-grade glioma). Figure 4B The correlation between neuroradiology and visual acuity in patients is shown. logMAR, minimum resolving angle logarithm; RANO, neuro-oncology response assessment; RAPNO, pediatric neuro-oncology response assessment – ​​low-grade glioma.

[0008] Figures 5A-5CIndependent Radiological Review Board based on Figure 5A RANO-HGG Figure 5B RAPNO and Figure 5C RANO-LGG criteria: This refers to the optimal change in tumor size in OPG patients for whom an evaluable response is possible. RANO-HGG, RAPNO, and RANO-LGG criteria are also used. Data from one patient (RANO-HGG and RAPNO assessments) are not included. CR: Complete response; HGG: High-grade glioma; LGG: Low-grade glioma; MR: Mild response; OPG: Visual pathway glioma; PD: Progressive disease; PR: Partial response; RANO: Neuro-oncology response assessment; RAPNO: Pediatric neuro-oncology response assessment; SD: Stable disease.

[0009] Figure 6 Swimlane plots of response time and treatment duration according to RAPNO and RANO-LGG criteria. In patients with a confirmed response, the symbol indicates the onset of the response (MR or PR). If the initial response improves with continued treatment (from MR to confirmed PR), the time point of the initial response and the time point of the first improvement in response are marked accordingly. BRAFi, BRAF inhibitor; LGG, low-grade glioma; MEKi, MEK inhibitor; PR, partial response; MR, minor response; RANO, neuro-oncology response assessment; RAPNO, pediatric neuro-oncology response assessment.

[0010] Figure 7A and 7B . Figure 7A Changes in vision of the best eye during the study period. Figure 7B Visual acuity outcome for patients with best overall confirmed radiological response (MR) according to RAPNO and RANO-LGG. Best response represents the best confirmed VA response; VA status at the end of treatment / data cutoff date is determined by a single, finally available assessment. EOT, End of Treatment; LGG, Low-Grade Glioma; LogMAR, Minimum Resolved Angle Logarithm; MR, Mild Response; RANO, Neuro-Oncology Response Assessment; RAPNO, Pediatric Neuro-Oncology Response Assessment. Summary of the Invention

[0011] In one aspect, this document describes a method for treating relapsed or refractory pediatric low-grade glioma (pLGG) in a subject of need, the method comprising administering tovorafenib or a salt thereof to the subject, wherein the subject is 6 months of age or older. In some embodiments, the pediatric low-grade glioma (pLGG) carries a BRAF fusion or rearrangement, or a BRAF V600 mutation. In some embodiments, the method comprises administering an initial dose of tovorafenib or a salt thereof to the subject. In some embodiments, the method comprises administering a reduced dose of tovorafenib or a salt thereof to the subject, and optionally a further reduced dose of tovorafenib or a salt thereof. In some embodiments, the method comprises pausing tovorafenib or a salt thereof before administering the reduced dose or the further reduced dose.

[0012] This disclosure provides a method for treating pediatric low-grade glioma (pLGG) in patients of need, the method comprising selecting a patient who has previously received MAP kinase inhibitor therapy and administering a type II pan-RAF inhibitor to the patient.

[0013] In some embodiments, the subject has radiographic progression of pLGG or no pLGG progression while receiving MAP kinase inhibitor treatment. In some embodiments, the subject has radiographic progression of pLGG while receiving MAP kinase inhibitor treatment. In some embodiments, the subject's pLGG is relapsed / refractory after MAP kinase inhibitor treatment.

[0014] In some embodiments, MAP kinase inhibitor treatment is the most recent treatment administered to the subject. In some embodiments, MAP kinase inhibitor treatment is not the most recent treatment administered to the subject. In some embodiments, the most recent treatment administered to the subject is selected from chemotherapy, radiation therapy, and surgery.

[0015] This disclosure also provides a method for treating optic pathway glioma (OPC) in a subject of need, the method comprising selecting a subject who has previously received MAP kinase inhibitor therapy and administering a type II pan-RAF inhibitor to the subject.

[0016] In some embodiments, the subject has radiographic progression of OPC or no OPC progression while receiving MAP kinase inhibitor treatment. In some embodiments, the subject has radiographic progression of OPC while receiving MAP kinase inhibitor treatment. In some embodiments, the subject's OPC is relapsed / refractory after MAP kinase inhibitor treatment.

[0017] In some implementations, the subject has previously received one or more additional therapeutic treatments, including chemotherapy, radiation therapy, and surgery.

[0018] In some implementations, the type II pan-RAF inhibitor is tovorafenib or a salt thereof.

[0019] In some embodiments, pLGG has a BRAF mutation or fusion. In some embodiments, pLGG has a BRAF mutation. In some embodiments, the BRAF mutation is the V600E mutation. In some embodiments, the BRAF mutation is a mutation other than the V600E mutation.

[0020] In some embodiments, the OPC has a BRAF mutation or fusion. In some embodiments, the OPC has a BRAF mutation. In some embodiments, the BRAF mutation is the V600E mutation. In some embodiments, the BRAF mutation is a mutation other than the V600E mutation.

[0021] In some implementations, MAP kinase inhibitor therapy includes trametinib or its salts.

[0022] In some aspects, this disclosure provides a method for treating pediatric low-grade glioma (pLGG) in a subject of need, the method comprising administering a type II pan-RAF inhibitor to the subject for 2 months or longer, wherein the pLGG shows radiographic progression after the initial month of administration.

[0023] In some embodiments, pLGG shows radiographic progression two months after initial administration. In some embodiments, the type II pan-RAF inhibitor is administered to the subject for 3 months or longer, 4 months or longer, or 5 months or longer. In some embodiments, the type II pan-RAF inhibitor is tovorafenib or a salt thereof.

[0024] In some embodiments, pLGG has a BRAF mutation or fusion. In some embodiments, pLGG has a BRAF mutation. In some embodiments, the BRAF mutation is the V600E mutation. In some embodiments, the BRAF mutation is a mutation other than the V600E mutation.

[0025] In some embodiments, the subject is selected from those who have previously received MAP kinase inhibitor therapy. In some embodiments, the subject had radiographic progression of pLGG or no pLGG progression while receiving MAP kinase inhibitor therapy. In some embodiments, the subject had radiographic progression of pLGG while receiving MAP kinase inhibitor therapy. In some embodiments, the subject's pLGG was relapsed / refractory after MAP kinase inhibitor therapy. In some embodiments, MAP kinase inhibitor therapy is the most recent treatment administered to the subject. In some embodiments, MAP kinase inhibitor therapy is not the most recent treatment administered to the subject. In some embodiments, the most recent treatment administered to the subject is selected from chemotherapy, radiation therapy, and surgery. In some embodiments, the MAP kinase inhibitor is vemurafenib. In some embodiments, the MAP kinase inhibitor is dabrafenib / trametinib. In some embodiments, the MAP kinase inhibitor is binimetinib. In some embodiments, the MAP kinase inhibitor is trametinib.

[0026] In some aspects, this disclosure provides a method for treating optic pathway glioma (OPC) in a subject of need, the method comprising administering a type II pan-RAF inhibitor to the subject for 2 months or longer, wherein the OPC shows radiographic progression after the initial month of administration.

[0027] In some embodiments, OPC shows radiographic progress two months after initial administration. In some embodiments, the type II pan-RAF inhibitor is administered to the subject for 3 months or longer, 4 months or longer, or 5 months or longer. In some embodiments, the type II pan-RAF inhibitor is tovorafenib or a salt thereof.

[0028] In some embodiments, the OPC has a BRAF mutation or fusion. In some embodiments, the OPC has a BRAF mutation. In some embodiments, the BRAF mutation is the V600E mutation. In some embodiments, the BRAF mutation is a mutation other than the V600E mutation.

[0029] In some embodiments, the subject is selected from those who have previously received MAP kinase inhibitor therapy. In some embodiments, the subject has radiographic progression of OPC or no OPC progression at the time of MAP kinase inhibitor therapy. In some embodiments, the subject has radiographic progression of OPC at the time of MAP kinase inhibitor therapy. In some embodiments, the subject's pLGG is relapsed / refractory after MAP kinase inhibitor therapy. In some embodiments, MAP kinase inhibitor therapy is the most recent treatment administered to the subject. In some embodiments, MAP kinase inhibitor therapy is not the most recent treatment administered to the subject. In some embodiments, the most recent treatment administered to the subject is selected from chemotherapy, radiation therapy, and surgery.

[0030] In some implementations, the subject has previously received one or more additional therapeutic treatments, including chemotherapy, radiation therapy, and surgery.

[0031] In some implementations, approximately 350 mg / m² is administered to the subject weekly. 2 Approximately 400 mg / m 2 Tovorafenib or its salts. In some embodiments, approximately 380 mg / m² is administered to the subject weekly. 2 Tovorafenib or its salts. In some embodiments, approximately 400 mg / m² is administered to the subject weekly. 2 Approximately 450 mg / m 2 Tovorafenib or its salts. In some embodiments, approximately 420 mg / m² is administered to the subject weekly. 2 Tovorafenib or its salts. In some embodiments, tovorafenib or its salts are administered to the subject for 10 weeks or longer. In some embodiments, tovorafenib or its salts are administered to the subject for 16 weeks or longer.

[0032] In some embodiments, tovorafenib or its salts are administered as tablets or liquid formulations. In some embodiments, tovorafenib or its salts are administered with food.

[0033] In some implementations, tovorafenib or its salts are not administered with food. Detailed Implementation

[0034] definition In this application, unless otherwise stated, the use of “or” means “and / or”. As used herein, the terms “and / or” and “any combination thereof” and their grammatical equivalents are used interchangeably. These terms can represent any combination specifically conceived. For illustrative purposes only, the phrases “A, B and / or C” or “A, B, C or any combination thereof” can mean “A alone; B alone; C alone; A and B; B and C; A and C; and A, B and C”. Unless the context specifically dictates separate use, the term “or” can be used in combination or separately.

[0035] The term "about" or "approximately" can mean within an acceptable margin of error for a specific value as determined by a person skilled in the art, depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to practice in the art, "about" can mean within one or more standard deviations. Alternatively, "about" can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 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 can mean within orders of magnitude of the value, within five times the value, or within twice the value.

[0036] As used in this specification and claims, the terms “comprising” (and any form of comprising), “having” (and any form of having), “including” (and any form of including), or “containing” (and any form of containing) are inclusive or open-ended and do not exclude additional unstated elements or method steps. It is contemplated that any embodiments discussed in this specification can be implemented with respect to any method or composition of this disclosure, and vice versa. Furthermore, the compositions of this disclosure can be used to implement the methods of this disclosure.

[0037] The references in the specification to “some implementation schemes,” “implementation schemes,” “a particular implementation scheme,” or “other implementation schemes” mean that a specific feature, structure, or characteristic described in connection with an implementation scheme is included in at least some of the implementation schemes of this disclosure, but not necessarily in all of the implementation schemes of this disclosure.

[0038] As used herein, the term "treatment" is intended to encompass the full spectrum of interventions for the cancer a subject has, such as administering compounds like tovorafenib to relieve, slow, stop, or reverse one or more symptoms of cancer and delay cancer progression, even if the cancer is not actually eliminated. Treatment may include, for example, a reduction in the severity, number, or frequency of symptoms, such as inhibition of tumor growth, arrest of tumor growth, or regression of existing tumors.

[0039] As used herein, the term "therapeutic effective amount" refers to an amount effective at the dose and duration necessary to achieve the desired therapeutic outcome. Therapeutic effective amounts of a composition can vary depending on factors such as an individual's condition, age, sex, weight, and the ability of the protein to elicit the desired response in the individual. A therapeutic effective amount is also an amount that may have a beneficial therapeutic effect beyond any toxic or harmful effects of the composition.

[0040] As used in this article, the term “object” refers to a mammal, and “mammal” includes, but is not limited to, humans.

[0041] The “pharmaceutically acceptable salt” applicable to this disclosure can be an acid salt or base salt that is generally considered in the art to be suitable for use in contact with human or animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications. Such salts include mineral salts and organic acid salts of basic residues (such as amines) and alkali metal salts or organic salts of acidic residues (such as carboxylic acids). Specific pharmaceutical 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, pyric acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanonic acids such as acetic acid, HOOC-(CH2)n-COOH (where n is 0-4), etc. Similarly, 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 the knowledge of the art that other pharmaceutically acceptable salts include those listed in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, page 1418 (1985). Generally, pharmaceutically acceptable acid or base salts can be synthesized by any conventional chemical method from a parent compound containing a basic or acidic moiety. In short, such salts can be prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in a suitable solvent.

[0042] The ranges provided in this document should be understood as abbreviations of all values ​​within that range. For example, the range 1 to 50 should be understood as including any number, combination of numbers, or subrange of any 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 all intermediate decimal values ​​between the aforementioned integers, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. Regarding subranges, specifically consider “nested subranges” extending from either endpoint of the range. For example, nested subranges of the exemplary range of 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 another direction.

[0043] Unless otherwise stated, the structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention but with hydrogen atoms replaced by deuterium or tritium, or carbon atoms replaced by carbons enriched in 13C or 14C, are within the scope of this disclosure.

[0044] Some of the compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this disclosure. Unless otherwise stated, the structures described herein are also intended to include all stereochemical forms of the structures; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are within the scope of this disclosure.

[0045] Raf inhibitors In some embodiments, this document describes a Raf inhibitor, which is (R)-2-(1-(6-amino-5-chloropyrimidin-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide (compound A) or a pharmaceutically acceptable salt or solvation thereof. The structure of compound A is shown below: Compound A. Compound A, or a pharmaceutically acceptable salt or solvation thereof, is described in US8293752B2. Compound A is also known as tovorafenib, DAY101, and formally as TAK-580, BIIB024, or MLN2480. In some embodiments, the Raf inhibitor is (R)-2-(1-(6-amino-5-chloropyrimidin-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazolyl-5-carboxamide. Compound A is also known as 6-amino-5-chloro-N-[(1R)-1-[5-[[[5-chloro-4-(trifluoromethyl)-2-pyridinyl]amino]carbonyl]-2-thiazolyl]ethyl]-4-pyrimidinecarboxamide and is marketed under the trade name OJEMDA. In some embodiments, the Raf inhibitor is tovorafenib. 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 a crystalline form of compound A. In some embodiments, the Raf inhibitor is a hydrate of compound A. In some embodiments, the Raf inhibitor is a crystalline form of compound A. In some embodiments, the Raf inhibitor is... .

[0046] In some embodiments, pharmaceutically acceptable salts of tovorafenib are described herein. Suitable pharmaceutically acceptable salts include, for example, those described in SM Berge et al., d J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl)4 salts. This disclosure also contemplates the quaternization of any basic nitrogen-containing group. Water-soluble, oil-soluble, or dispersible products can be obtained through such quaternization. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0047] Treatment This disclosure provides for the treatment of patients with BRAF Methods for treating relapsed / refractory pLGG in children and young adults. Specifically, this disclosure provides a method for treating subjects with tovorafenib monotherapy.

[0048] This disclosure provides a method for treating pediatric low-grade glioma (pLGG) in a subject of need, the method comprising selecting a subject who has previously received MAP kinase inhibitor therapy and administering a type II pan-RAF inhibitor to the subject. In one aspect, this disclosure provides a method for treating optic pathway glioma (OPC) in a subject of need, the method comprising selecting a subject who has previously received MAP kinase inhibitor therapy and administering a type II pan-RAF inhibitor to the subject. In some embodiments, the type II pan-RAF inhibitor is tovorafenib. In some embodiments, the type II pan-RAF inhibitor is a salt of tovorafenib.

[0049] In some embodiments, the subject has radiographic progression of pLGG or no pLGG progression while receiving MAP kinase inhibitor treatment. In some embodiments, the subject has radiographic progression of pLGG while receiving MAP kinase inhibitor treatment. In some embodiments, the subject has a partial response to pLGG while receiving MAP kinase inhibitor treatment. In some embodiments, the subject has stable pLGG while receiving MAP kinase inhibitor treatment. In some embodiments, the subject's pLGG is relapsed / refractory after MAP kinase inhibitor treatment. In some embodiments, the MAP kinase inhibitor is vemurafenib. In some embodiments, the MAP kinase inhibitor is dabrafenib / trametinib. In some embodiments, the MAP kinase inhibitor is bimetinib. In some embodiments, the MAP kinase inhibitor is trametinib.

[0050] In some embodiments, MAP kinase inhibitor therapy is the most recent treatment administered to the subject. In some embodiments, MAP kinase inhibitor therapy is not the most recent treatment administered to the subject. In some embodiments, the most recent treatment administered to the subject is selected from chemotherapy, radiation therapy, and surgery. In some embodiments, the subject had received one line of prior therapy prior to administration of a type II pan-RAF inhibitor (such as tovorafenib). In some embodiments, the subject had received two lines of prior therapy prior to administration of a type II pan-RAF inhibitor (such as tovorafenib). In some embodiments, the subject had received three lines of prior therapy prior to administration of a type II pan-RAF inhibitor (such as tovorafenib). In some embodiments, the subject had received four to ten lines of prior therapy prior to administration of a type II pan-RAF inhibitor (such as tovorafenib). In some embodiments, the subject had received one line of prior therapy prior to administration of a type II pan-RAF inhibitor (such as tovorafenib). In some embodiments, the subject had received at least three lines of prior therapy prior to administration of a type II pan-RAF inhibitor (such as tovorafenib).

[0051] In some implementations, the subject has previously received one or more additional therapeutic treatments, including chemotherapy, radiation therapy, and surgery.

[0052] In some implementations, the type II pan-RAF inhibitor is tovorafenib or a salt thereof.

[0053] In some embodiments, pLGG has a BRAF mutation or fusion. In some embodiments, pLGG has a BRAF mutation. In some embodiments, the BRAF mutation is the V600E mutation. In some embodiments, the BRAF mutation is a mutation other than the V600E mutation.

[0054] In one respect, this disclosure also provides for the treatment of patients with BRAF Methods for treating relapsed / refractory OPC in children and young adults. In some embodiments, this disclosure provides a method of treating subjects with tovorafenib monotherapy.

[0055] In some embodiments, the subject has radiographic progression of OPC or no OPC progression while receiving MAP kinase inhibitor treatment. In some embodiments, the subject has radiographic progression of OPC while receiving MAP kinase inhibitor treatment. In some embodiments, the subject's OPC is relapsed / refractory after MAP kinase inhibitor treatment.

[0056] In some embodiments, the MAP kinase inhibitor treatment includes trametinib or a salt thereof. In some embodiments, the MAP kinase inhibitor treatment includes a MEK inhibitor. In some embodiments, the MEK inhibitor is trametinib. In some embodiments, the MEK inhibitor is bimetinib. In some embodiments, the MEK inhibitor is cobimetinib. In some embodiments, the MEK inhibitor is selumetinib. In some embodiments, the MAP kinase inhibitor treatment includes an EGFR inhibitor. In some embodiments, the MAP kinase inhibitor treatment includes a VEGFR inhibitor. In some embodiments, the MAP kinase inhibitor treatment includes a PDGFR inhibitor. In some embodiments, the MAP kinase inhibitor treatment includes a G protein inhibitor. In some embodiments, the MAP kinase inhibitor treatment includes a RAS inhibitor. In some embodiments, the MAP kinase inhibitor treatment includes a RAF inhibitor. In some embodiments, the MAP kinase inhibitor treatment includes a MEK1 / 2 inhibitor. In some embodiments, the MAP kinase inhibitor treatment includes a MEK5 inhibitor. In some embodiments, the MAP kinase inhibitor treatment includes a p38 inhibitor. In some embodiments, the MAP kinase inhibitor treatment is a combination therapy. In some implementations, MAP kinase inhibitor therapy is a combination of dabrafenib and trametinib.

[0057] In some aspects, this disclosure provides a method for treating pediatric low-grade glioma (pLGG) in a subject of need, the method comprising administering a type II pan-RAF inhibitor to the subject for 2 months or longer, wherein the pLGG shows radiographic progression after the initial month of administration. In some aspects, this disclosure provides a method for treating optic pathway glioma (OPC) in a subject of need, the method comprising administering a type II pan-RAF inhibitor to the subject for 2 months or longer, wherein the OPC shows radiographic progression after the initial month of administration.

[0058] In some respects, advances in radiology or other assessments are determined by RAPNO. In some respects, advances in radiology or other assessments are determined by RANO-LGG. In some respects, advances in radiology or other assessments are determined by RANO-HGG.

[0059] In some embodiments, pLGG shows radiographic progression two months after initial administration. In some embodiments, the type II pan-RAF inhibitor is administered to the subject for 3 months or longer, 4 months or longer, or 5 months or longer. In some embodiments, the type II pan-RAF inhibitor is tovorafenib or a salt thereof. In some embodiments, OPC shows radiographic progression two months after initial administration. In some embodiments, the type II pan-RAF inhibitor is administered to the subject for 3 months or longer, 4 months or longer, or 5 months or longer. In some embodiments, the type II pan-RAF inhibitor is tovorafenib or a salt thereof.

[0060] In some embodiments, pLGG has a BRAF mutation or fusion. In some embodiments, OPC has a BRAF mutation or fusion. In some embodiments, pLGG has a BRAF mutation. In some embodiments, OPC has a BRAF mutation. In some embodiments, the BRAF mutation is a V600E mutation. In some embodiments, the BRAF mutation is a mutation other than the V600E mutation. In some embodiments, pLGG has one or more of the following mutations: RAS-positive mutation, RAF-positive mutation, MEK-positive mutation, and ERK-positive mutation. In some embodiments, OPC has one or more of the following mutations: RAS-positive mutation, RAF-positive mutation, MEK-positive mutation, and ERK-positive mutation. In the embodiments, patients with advanced metastatic or resectable melanoma having a MAPK mutation are included. In some embodiments, pLGG has a BRAF mutation. In some embodiments, pLGG has a V600E mutation. In some embodiments, pLGG has a V600D mutation. In some embodiments, pLGG has a V600K mutation. In some embodiments, OPC has a V600E mutation. In some embodiments, OPC has a V600D mutation. In some embodiments, OPC has a V600K mutation. In some embodiments, OPC has a non-V600E mutation. In some embodiments, pLGG has a non-V600E mutation. In some embodiments, the BRAF mutation is a non-V600 BRAF mutation. In some embodiments, the object 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 object is identified as having the SRGAP3:RAF1 fusion. In some embodiments, the object is identified as having the KIAA1549:BRAF fusion. In some implementations, the object has a KIAA1549:BRAF fusion. In some implementations, the object has a STARD3NL:BRAF fusion. In some implementations, the object has a BCAS1:BRAF fusion.In some embodiments, the object has KHDRBS2:BRAF fusion. In some embodiments, the object has CCDC6:BRAF fusion. In some embodiments, the object has FAM131B:BRAF fusion. In some embodiments, the object has SRGAP:BRAF fusion. In some embodiments, the object has CLCN6:BRAF fusion. In some embodiments, the object has GNAI1:BRAF fusion. In some embodiments, the object has MRKN1:BRAF fusion. In some embodiments, the object has GIT2:BRAF fusion. In some embodiments, the object has GTF21:BRAF fusion. In some embodiments, the object has FXR1:BRAF fusion. In some embodiments, the object has RNF130:BRAF fusion. In some embodiments, the object has GTF21:BRAF fusion. In some embodiments, the object has BRAF:MACF1 fusion. In some embodiments, the object has TMEM106B:BRAF fusion. In some embodiments, the object has PPC1CC:BRAF fusion. In some embodiments, the object has CUX1:BRAF fusion. In some embodiments, the object has an SRGAP3:RAF1 fusion. In some embodiments, the object has a QK1:RAF1 fusion. In some embodiments, the object has an FYCO:RAF1 fusion. In some embodiments, the object has an ATG7:RAF1 fusion. In some embodiments, the object has an NFIA:RAF1 fusion. In some embodiments, the object has an AGK:BRAF fusion. In some embodiments, the object has an ETV6:BRAF fusion. In some embodiments, the object has an APPL2-RAF1 fusion. In some embodiments, the object has a BRAF gene fusion. In some embodiments, the object has a CRAF gene fusion. In some embodiments, the methods described herein include identifying BRAF fusions or rearrangements, or BRAF V600 mutations in the object by genomic profiling assays. Genomic profiling assays can be any suitable assay known in the art. In some implementations, the genome profiling assay is performed using FOUNDATIONONE®, FOUNDATIONONE® HEME, FOUNDATIONONE® CDX™, EXODX®, Guardant360, MSK-IMPACT™, ILLUMINA® TruSight, or any combination thereof. In some implementations, the genome profiling assay is performed using FOUNDATIONONE.

[0061] In some embodiments, the subject is selected from those who have previously received MAP kinase inhibitor therapy. In some embodiments, the subject had radiographic progression of pLGG or no pLGG progression at the time of MAP kinase inhibitor therapy. In some embodiments, the subject had radiographic progression of pLGG at the time of MAP kinase inhibitor therapy. In some embodiments, the subject's pLGG was relapsed / refractory after MAP kinase inhibitor therapy. In some embodiments, MAP kinase inhibitor therapy is the most recent treatment administered to the subject. In some embodiments, MAP kinase inhibitor therapy is not the most recent treatment administered to the subject. In some embodiments, the most recent treatment administered to the subject is selected from chemotherapy, radiation therapy, and surgery.

[0062] In some embodiments, the subject has previously received toporafenib and is on a tovorafenib pharmacological leave. In some embodiments, the method described herein includes restarting tovorafenib treatment for the subject on pharmacological leave. In some embodiments, the subject has been on a pharmacological leave of at least one month. In some embodiments, the subject has been on a pharmacological leave of at least three months. In some embodiments, the subject has been on a pharmacological leave of at least six months. In some embodiments, the subject has been on a pharmacological leave of at least nine months. In some embodiments, the subject has been on a pharmacological leave of at least one year. In some embodiments, the subject has been on a pharmacological leave of at least two years.

[0063] In some implementations, the subject has previously received one or more additional therapeutic treatments, including chemotherapy, radiation therapy, and surgery.

[0064] In some embodiments, the methods disclosed herein include combining or administering a type II pan-RAF inhibitor (such as tovorafenib or a salt thereof) with a second therapeutic agent. The second therapeutic agent may include an anti-infective agent, an acne treatment agent (e.g., an agent for managing skin toxicity), a drug for managing cerebral edema, an antiemetic, an anticonvulsant, an agent for treating neurocognitive disorders, or an agent for a skin condition. The second therapeutic agent may comprise an imaging agent, a viral vaccine, a neurosurgical anesthetic, an antiemetic, or an analgesic / antipyretic.

[0065] In some implementations, approximately 400 mg / m² is administered to the subject weekly. 2 Approximately 450 mg / m 2 Tovorafenib or its salts. In some embodiments, approximately 420 mg / m² is administered to the subject weekly. 2 Tovorafenib or its salts. In some embodiments, tovorafenib or its salts are administered to the subject for 10 weeks or longer. In some embodiments, tovorafenib or its salts are administered to the subject for 16 weeks or longer.

[0066] In some implementations, approximately 400 mg / m² is administered orally to the subject weekly. 2 Approximately 450 mg / m 2 Tovorafenib or its salts. In some embodiments, approximately 420 mg / m² is administered orally to the subject weekly. 2 Tovorafenib or its salts. In some embodiments, tovorafenib or its salts are administered to the subject for 10 weeks or longer. In some embodiments, tovorafenib or its salts are administered to the subject for 16 weeks or longer.

[0067] In some implementations, approximately 350 mg / m² is administered to the subject weekly. 2 Approximately 400 mg / m 2 Tovorafenib or its salts. In some embodiments, approximately 350 mg / m² is administered orally to the subject weekly. 2 Approximately 400 mg / m 2 Tovorafenib or its salts. In some embodiments, approximately 380 mg / m² is administered to the subject weekly. 2 Tovorafenib or its salts. In some embodiments, approximately 380 mg / m² is administered orally to the subject weekly. 2 Tovorafenib or its salts. In some embodiments, approximately 600 mg of tovorafenib or its salts are administered to the subject weekly. In some embodiments, tovorafenib or its salts are administered to the subject for 10 weeks or longer. In some embodiments, tovorafenib or its salts are administered to the subject for 16 weeks or longer.

[0068] In one aspect, this document discloses a method for improving the vision of a subject in need, wherein the method includes administering a type II pan-RAF inhibitor (such as tovorafenib or a salt thereof) to the subject. In some embodiments, the subject has pLGG. In some embodiments, the subject has OPC. In some embodiments, the subject has visual pathway pLGG. In some embodiments, the tumor size of the subject's pLGG has decreased. In some embodiments, the tumor size of the subject's pLGG has not decreased. In some embodiments, the tumor size of the subject's OPC has decreased. In some embodiments, the tumor size of the subject's OPC has not decreased. Tumor size can be assessed via imaging means (including RAPNO, RANO-LGG, or RANO-HGG). In some embodiments, the subject had mild visual impairment prior to administration of the type II pan-RAF inhibitor. In some embodiments, the subject had moderate visual impairment prior to administration of the type II pan-RAF inhibitor. In some embodiments, the subject had severe visual impairment prior to administration of the type II pan-RAF inhibitor. In some embodiments, the subject had profound visual impairment prior to administration of the type II pan-RAF inhibitor. In some embodiments, the visual pathway pLGG is OPC. In some implementations, the object suffers from OPC.

[0069] This article describes a method for treating cancers such as gliomas (e.g., low-grade gliomas, optic pathway gliomas), the method comprising based on the subject's body surface area (BSA) (e.g., mg / m²). 2 ) Administer tovorafenib or its pharmaceutically acceptable salts or solvates. BSA can be determined by any suitable calculation method. In some embodiments, BSA is determined using the Mosteller formula (√((height × weight) / 3600)). In some embodiments, BSA is determined at the beginning of each administration cycle.

[0070] In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of up to about 600 mg. In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of up to about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of up to about 600 mg of tovorafenib. In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of up to about 800 mg of tovorafenib.

[0071] In some implementations, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of up to 1200 mg / m².2 Administered in doses specified in some embodiments. Tovorafenib or its pharmaceutically acceptable salts or solvates are administered at a maximum of 1000 mg / m² per dose. 2 Administered in doses specified in some embodiments. Tovorafenib or its pharmaceutically acceptable salts or solvates are administered at a maximum dose of 800 mg / m². 2 Administered in doses specified in some embodiments. Tovorafenib or its pharmaceutically acceptable salts or solvates are administered at a maximum dose of 600 mg / m². 2 Administered in doses specified in some embodiments. Tovorafenib or its pharmaceutically acceptable salts or solvates are administered at a maximum of 500 mg / m² per dose. 2 Administered in doses specified in some embodiments. Tovorafenib or its pharmaceutically acceptable salts or solvates are administered at a maximum of 300 mg / m² per dose. 2 Administered in doses specified in some embodiments. Tovorafenib or its pharmaceutically acceptable salts or solvates are administered at a maximum of 200 mg / m² per dose. 2 The amount applied.

[0072] In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered once weekly at a starting dose. In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered 2, 3, 4, 5, 6, or 7 times weekly. In some embodiments, the starting dose is approximately 825 mg / m² per week. 2 In some implementations, the starting dose is approximately 660 mg / m² per week. 2 A. In some implementations, the starting dose is approximately 530 mg / m² per week. 2 In some implementations, the starting dose is approximately 420 mg / m² per week. 2 In some implementations, the starting dose is approximately 380 mg / m² per week. 2 In some implementations, the starting dose is approximately 410 mg / m² per week. 2 Approximately 430 mg / m 2 In some implementations, the starting dose is approximately 400 mg / m² per week. 2 Approximately 450 mg / m 2 In some implementations, the starting dose is approximately 350 mg / m² per week. 2 Approximately 450 mg / m 2 In some implementations, the starting dose is approximately 350 mg / m² per week. 2 Approximately 400 mg / m 2 In some implementations, the starting dose is approximately 350 mg / m² per week. 2In some implementations, the starting dose is approximately 280 mg / m² per week. 2 In some implementations, the initial dose is approximately 600 mg / m² per week. 2 Approximately 700 mg / m 2 In some implementations, the initial dose is approximately 500 mg / m² per week. 2 Approximately 550 mg / m 2 In some implementations, the initial dose is approximately 400 mg / m² per week. 2 Approximately 450 mg / m 2 In some implementations, the initial dose is approximately 400 mg / m² per week. 2 Approximately 500 mg / m 2 In some implementations, the initial dose is approximately 100 mg / m² per week. 2 Approximately 200 mg / m 2 In some implementations, the initial dose is approximately 200 mg / m² per week. 2 Approximately 300 mg / m 2 In some implementations, the initial dose is approximately 250 mg / m² per week. 2 Approximately 300 mg / m 2 In some implementations, administration is based on the free base of tovorafenib. In some implementations, administration is once weekly.

[0073] In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered as a maintenance dose once weekly. In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered 2, 3, 4, 5, 6, or 7 times weekly. In some embodiments, the maintenance dose is approximately 825 mg / m² per week. 2 In some implementations, the maintenance dose is approximately 660 mg / m² per week. 2 In some implementations, the maintenance dose is approximately 530 mg / m² per week. 2 In some implementations, the maintenance dose is approximately 420 mg / m² per week. 2 In some implementations, the maintenance dose is approximately 350 mg / m² per week. 2 In some implementations, the maintenance dose is approximately 280 mg / m² per week. 2 In some implementations, the maintenance dose is approximately 600 mg / m² per week. 2 Approximately 700 mg / m 2 In some implementations, the maintenance dose is approximately 500 mg / m² per week. 2 Approximately 550 mg / m 2In some implementations, the maintenance dose is approximately 400 mg / m² per week. 2 Approximately 450 mg / m 2 In some implementations, the maintenance dose is approximately 420 mg / m² per week. 2 In some implementations, the maintenance dose is approximately 410 mg / m² per week. 2 Approximately 430 mg / m 2 In some implementations, the maintenance dose is approximately 350 mg / m² per week. 2 Approximately 450 mg / m 2 In some implementations, the maintenance dose is approximately 400 mg / m² per week. 2 Approximately 500 mg / m 2 In some implementations, the maintenance dose is approximately 200 mg / m² per week. 2 Approximately 300 mg / m 2 In some implementations, the maintenance dose is approximately 250 mg / m² per week. 2 Approximately 300 mg / 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, administration is based on the free base of tovorafenib. In some embodiments, administration is once weekly.

[0074] In some implementations, tovorafenib or its pharmaceutically acceptable salts or solvates are administered to the subject based on body surface area (BSA). In some implementations, approximately 380 mg / m² is administered once weekly. 2 Tovorafenib or its pharmaceutically acceptable salts or solvates. In some formulations, approximately 400 mg / m² is administered once weekly. 2 Tovorafenib or its pharmaceutically acceptable salts or solvates. In some formulations, approximately 500 mg / m² is administered once weekly. 2 Tovorafenib or its pharmaceutically acceptable salts or solvates. In some formulations, approximately 600 mg / m² is administered once weekly. 2 Tovorafenib or its pharmaceutically acceptable salts or solvates. In some formulations, approximately 380 mg / m² is administered orally once weekly. 2 Tovorafenib. In some implementations, it is administered orally once weekly at a dose of approximately 380 mg / m². 2The maximum oral dose of tovorafenib once weekly is 600 mg. In some embodiments, tovorafenib is administered orally once weekly at a maximum dose of 600 mg. In some embodiments, approximately 400 mg of tovorafenib is administered orally once weekly. In some embodiments, approximately 500 mg of tovorafenib is administered orally once weekly. In some embodiments, approximately 600 mg of tovorafenib is administered orally once weekly. In some embodiments, tovorafenib is administered with or without food. In some embodiments, tovorafenib is administered with food. In some embodiments, tovorafenib is not administered with food.

[0075] In some embodiments, about 125 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, about 150 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, about 175 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, about 200 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, about 225 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, about 275 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, about 300 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, about 350 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, approximately 375 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, approximately 450 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, approximately 525 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, approximately 600 mg of troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly. In some embodiments, troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly as an oral suspension. In some embodiments, troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly as an oral suspension at a concentration of approximately 25 mg / mL. In some embodiments, 300 mg / 12 mL is delivered per suspension vial. In some embodiments, troporafenib or a pharmaceutically acceptable salt or solvate thereof is administered to the subject based on body surface area (BSA).

[0076] In some embodiments, approximately 125 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 150 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 175 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 200 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 225 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 275 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 300 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 350 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 375 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 450 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 525 mg of toporafenib is administered orally once weekly. In some embodiments, approximately 600 mg of toporafenib is administered orally once weekly. In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly as an oral suspension. In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof is administered orally once weekly as an oral suspension at a concentration of about 25 mg / mL. In some embodiments, 300 mg / 12 mL is delivered per suspension vial. In some embodiments, tovorafenib is administered to the subject based on body surface area (BSA).

[0077] In some implementations, tovorafenib or its pharmaceutically acceptable salts or solvates are administered to the subject based on the recommended doses in Table A.

[0078] Table A. Recommended tovorafenib tablet dosage based on body surface area The recommended dose of tovorafenib based on body surface area (BSA) is 380 mg / m² orally once weekly. 2 (The maximum recommended dose is 600 mg orally once weekly), with or without food, until disease progression or intolerable toxicity occurs. Tovorafenib can be administered as immediate-release tablets (see Table A) or as an oral suspension (see Table B).

[0079] Table B. Recommended Dosage of Tovorafenib Oral Suspension Based on Body Surface Area 1Toporafenib oral suspension has a concentration of 25 mg / mL. Each vial of toporafenib oral suspension delivers 300 mg / 12 mL.

[0080] In some embodiments, troporafenib or a pharmaceutically acceptable salt or solvation thereof is administered as a liquid formulation (such as a suspension). In some embodiments, the liquid formulation is administered in amounts from about 1 mL to about 50 mL. In some embodiments, the liquid formulation is administered in amounts from about 5 mL to about 25 mL. In some embodiments, about 125 mg of troporafenib as a liquid formulation (e.g., about 5 mL) or a pharmaceutically acceptable salt or solvation thereof is administered once weekly. In some embodiments, about 150 mg of troporafenib as a liquid formulation (e.g., about 6 mL) or a pharmaceutically acceptable salt or solvation thereof is administered once weekly. In some embodiments, about 175 mg of troporafenib as a liquid formulation (e.g., about 7 mL) or a pharmaceutically acceptable salt or solvation thereof is administered once weekly. In some embodiments, about 200 mg of troporafenib as a liquid formulation (e.g., about 8 mL) or a pharmaceutically acceptable salt or solvation thereof is administered once weekly. In some embodiments, about 225 mg of toporafenib (e.g., about 9 mL) or a pharmaceutically acceptable salt or solvate thereof, as a liquid formulation, is administered once weekly. In some embodiments, about 275 mg of toporafenib (e.g., about 11 mL) or a pharmaceutically acceptable salt or solvate thereof, as a liquid formulation, is administered once weekly. In some embodiments, about 300 mg of toporafenib (e.g., about 12 mL) or a pharmaceutically acceptable salt or solvate thereof, as a liquid formulation, is administered once weekly. In some embodiments, about 350 mg of toporafenib (e.g., about 14 mL) or a pharmaceutically acceptable salt or solvate thereof, as a liquid formulation, is administered once weekly. In some embodiments, about 375 mg of toporafenib (e.g., about 15 mL) or a pharmaceutically acceptable salt or solvate thereof, as a liquid formulation, is administered once weekly. In some embodiments, about 450 mg of toporafenib (e.g., about 18 mL) or a pharmaceutically acceptable salt or solvate thereof, as a liquid formulation, is administered once weekly. In some embodiments, about 525 mg of toporafenib (e.g., about 21 mL) as a liquid formulation or a pharmaceutically acceptable salt or solvation thereof is administered once weekly. In some embodiments, about 600 mg of toporafenib (e.g., about 24 mL) as a liquid formulation or a pharmaceutically acceptable salt or solvation thereof is administered once weekly. In some embodiments, toporafenib or a pharmaceutically acceptable salt or solvation thereof is toporafenib.

[0081] In some implementations, the method of treating pLGG described herein may include one or more of the following steps (a) - (e): when tovorafenib or its pharmaceutically acceptable salts or solvates are administered as a suspension. (a) Before using tovorafenib oral suspension for the first time, ensure that caregivers (and, where applicable, patients) read and understand the “Instructions for Use” before preparing, measuring and administering tovorafenib.

[0082] (b) Reconstitute the powder in each supply bottle with exactly 14 mL of room temperature water to form an oral suspension of toporafenib. After reconstitution, each mL contains 25 mg of toporafenib.

[0083] (c) Administer 300 mg of tovorafenib per vial (in 12 mL). For doses greater than 300 mg, reconstitute two vials to achieve the desired dose. Divide the dose as evenly as possible between the two vials (e.g., for a 325 mg dose, 6 mL and 7 mL).

[0084] (d) Immediately after preparation, administer the tovorafenib oral suspension using the provided oral administration syringe or feeding tube (minimum 12 French).

[0085] (e) If the tovorafenib oral suspension is not administered within 15 minutes of preparation, instruct the patient to discard it.

[0086] In some implementations, the method described herein includes dose reduction.

[0087] Table C provides recommended dose reductions for adverse reactions to tovorafenib tablets, and Table D provides recommended dose reductions for adverse reactions to tovorafenib oral suspension.

[0088] Table C. Tovorafenib tablets: Recommended dose reduction for adverse reactions Table D. Tovorafenib Oral Suspension: Recommended Dose Reduction for Adverse Reactions In some implementations, for patients with the following BSA: o ≥0.3 m 2 But less than 0.9 m 2 Use only tovorafenib oral suspension (see Table A). o ≥0.9 m 2 Use tablets (see Table A) or tovorafenib oral suspension (see Table B). Take tovorafenib with or without food.

[0089] Swallow the tablet whole with water. Do not chew, cut, or crush it.

[0090] Continue weekly dosing until disease progression or intolerable toxicity occurs.

[0091] For patients with BSA ≥ 0.9, tovorafenib tablets and tovorafenib oral suspension can be used interchangeably.

[0092] In some embodiments, if a dose is missed by 3 days or less, the subject can take the missed dose as soon as possible and then take the next dose on the originally scheduled date. In some embodiments, if a dose is missed by more than 3 days, the subject can skip that dose and take the next dose on the originally scheduled date. In some embodiments, if a dose is missed, the subject can take the missed doses at intervals of at least four days.

[0093] In some embodiments, tovorafenib tablets may cause vomiting. In some embodiments, if vomiting occurs less than 2, 5, 10, 15, 20, 30, 45, or 60 minutes after swallowing the tablet, the subject may take another dose. In some embodiments, if vomiting occurs more than 10, 15, 20, 30, 45, 60, 90, 120, or 240 minutes after swallowing the tablet, the subject may take the next dose on their originally scheduled date. In some embodiments, if vomiting occurs immediately after taking a dose, the subject may repeat the dose. In some embodiments, tovorafenib oral suspension may cause vomiting. In some embodiments, if vomiting occurs less than 15 minutes after swallowing the oral suspension, the subject may repeat the dose. In some embodiments, if vomiting occurs more than 15 minutes after swallowing the oral suspension, the subject will receive the next dose at the originally scheduled time.

[0094] In some embodiments, each vial of the provided tovorafenib oral suspension is reconstituted with exactly 14 mL of room temperature water to form the tovorafenib oral suspension. In some embodiments, for doses greater than 300 mg, two vials are reconstituted to achieve the required dose. In some embodiments, the oral suspension is administered immediately after preparation using the provided oral dosing syringe or feeding tube (minimum 12 French). In some embodiments, if the tovorafenib oral suspension is not administered within 15 minutes of preparation, it is discarded.

[0095] In one aspect, this article discloses a method for treating relapsed or refractory pediatric low-grade glioma (pLGG) in subjects of need, the method comprising administering tovorafenib or a salt thereof to the subject, wherein the pediatric low-grade glioma (pLGG) carries a BRAF fusion or rearrangement or a BRAF V600 mutation, wherein the subject is 6 months or older; and wherein, (i) when the subject has a body surface area (BSA) of 0.30–0.35 m², tovorafenib or a salt thereof is administered once weekly at an initial dose of about 125 mg, and if the subject is intolerant to the initial dose, tovorafenib or a salt thereof is administered once weekly at a reduced dose of about 100 mg, and if the subject is intolerant to the reduced dose, tovorafenib or a salt thereof is administered once weekly at a further reduced dose of about 75 mg; (ii) when the subject has a body surface area (BSA) of 0.36–0.42 m², tovorafenib or a salt thereof is administered once weekly at a further reduced dose of about 150 mg. (iii) When the subject has a body surface area (BSA) of 0.43–0.48 m², administer tovorafenib or its salt once weekly at an initial dose of about 175 mg, and if the subject does not tolerate the initial dose, administer tovorafenib or its salt once weekly at a reduced dose of about 150 mg, and if the subject does not tolerate the reduced dose, administer tovorafenib or its salt once weekly at a further reduced dose of about 125 mg; (iv) When the subject has a body surface area (BSA) of 0.49–0.54 m², administer tovorafenib or its salt once weekly at an initial dose of about 200 mg. (v) When the subject has a body surface area (BSA) of 0.55–0.63 m², administer tovorafenib or its salt once weekly at a starting dose of about 225 mg, and if the subject does not tolerate the starting dose, administer tovorafenib or its salt once weekly at a reduced dose of about 200 mg, and if the subject does not tolerate the reduced dose, administer tovorafenib or its salt once weekly at a further reduced dose of about 150 mg; (vi) When the subject has a body surface area (BSA) of 0.64–0.63 m², administer tovorafenib or its salt once weekly at a starting dose of about 225 mg, and if the subject does not tolerate the starting dose, administer tovorafenib or its salt once weekly at a reduced dose of about 200 mg, and if the subject does not tolerate the reduced dose, administer tovorafenib or its salt once weekly at a further reduced dose of about 150 mg;(viii) When the body surface area (BSA) is 77 m², administer tovorafenib or its salt once weekly at a starting dose of about 275 mg, and if the subject is intolerant to the starting dose, administer tovorafenib or its salt once weekly at a reduced dose of about 225 mg, and if the subject is intolerant to the reduced dose, administer tovorafenib or its salt once weekly at a further reduced dose of about 200 mg; (vii) When the subject has a body surface area (BSA) of 0.78–0.83 m², administer tovorafenib or its salt once weekly at a starting dose of about 300 mg, and if the subject is intolerant to the starting dose, administer tovorafenib or its salt once weekly at a reduced dose of about 250 mg, and if the subject is intolerant to the reduced dose, administer tovorafenib or its salt once weekly at a further reduced dose of about 200 mg; (vii) When the subject has a body surface area (BSA) of 0.84–0.89 m², administer tovorafenib or its salt once weekly at a starting dose of about 350 mg. (v) When the subject has a body surface area (BSA) of 0.90–1.05 m², administer tovorafenib or its salt once weekly at an initial dose of about 375 mg, and if the subject does not tolerate the initial dose, administer tovorafenib or its salt once weekly at a reduced dose of about 325 mg, and if the subject does not tolerate the reduced dose, administer tovorafenib or its salt once weekly at a further reduced dose of about 275 mg; (x) When the subject has a body surface area (BSA) of 1.06–1.25 m², administer tovorafenib or its salt once weekly at an initial dose of about 450 mg. (i) When the subject has a body surface area (BSA) of 1.26–1.39 m², administer tovorafenib or its salt once weekly at a starting dose of about 525 mg, and if the subject does not tolerate the starting dose, administer tovorafenib or its salt once weekly at a reduced dose of about 450 mg, and if the subject does not tolerate the reduced dose, administer tovorafenib or its salt once weekly at a further reduced dose of about 375 mg; or (xii) When the subject has a BSA of ≥1.For a body surface area (BSA) of 40 m², administer tovorafenib or its salts once weekly at a starting dose of approximately 600 mg. If the subject is intolerant to the starting dose, administer tovorafenib or its salts once weekly at a reduced dose of approximately 500 mg. If the subject is intolerant to the reduced dose, administer tovorafenib or its salts once weekly at a further reduced dose of approximately 400 mg.

[0096] In one aspect, this article discloses a method for treating relapsed or refractory pediatric low-grade glioma (pLGG) in subjects of need, the method comprising oral administration of tovorafenib or a salt thereof to the subject, wherein the pediatric low-grade glioma (pLGG) carries a BRAF fusion or rearrangement or a BRAF V600 mutation, and wherein the subject is 6 months of age or older; and in, (i) When the object has 0.30-0.35 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 125 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 100 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 75 mg of tovorafenib once a week; (ii) When the object has 0.36-0.42 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 150 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 125 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 100 mg of tovorafenib once a week; (iii) When the object has 0.43-0.48 m 2When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 175 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 150 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 125 mg of tovorafenib once a week; (iv) When the object has 0.49-0.54 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 200 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 175 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 150 mg of tovorafenib once a week; (v) When the object has 0.55-0.63 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 225 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 200 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 150 mg of tovorafenib once a week; (vi) When the object has 0.64-0.77 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 275 mg once weekly or approximately 380 mg / m².2 Tovorafeni once a week, The reduced dose is equivalent to approximately 225 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 200 mg of tovorafenib once a week; (vii) When the object has 0.78-0.83 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 300 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 250 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 200 mg of tovorafenib once a week; (ⅷ) When the object has 0.84-0.89 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 350 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 300 mg of tovorafenib once weekly, and The further reduced dose is equivalent to approximately 250 mg of tovorafenib once a week; (x) When the object has 0.90-1.05 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 375-400 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 325 mg of tovorafenib once weekly, and The further reduced dose is equivalent to approximately 275 mg of tovorafenib once a week; (x) When the object has a diameter of 1.06-1.25 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 400-500 mg (e.g., 450 mg) once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 375-400 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 325 mg of tovorafenib once a week; (xi) When the object has 1.26-1.39 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 500-525 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 400-450 mg of tovorafenib once a week, and The further reduced dose is equivalent to approximately 375 mg of tovorafenib once weekly; and (xii) When the object has ≥1.40 m 2 When determining the body surface area (BSA), the method includes administering an initial dose of tovorafenib or a salt thereof to the subject and a reduced dose of tovorafenib or a salt thereof, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 600 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 500 mg of tovorafenib once weekly, and The further reduced dose is equivalent to approximately 400 mg of tovorafenib once a week.

[0097] In some implementations, the object has a diameter of 0.30-0.35 m. 2The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to approximately 125 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to approximately 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 100 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 75 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0098] In some implementations, the object has a diameter of 0.36-0.42 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to approximately 150 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to approximately 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 125 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 100 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0099] In some implementations, the object has a diameter of 0.43-0.48 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to approximately 175 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to approximately 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 150 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 125 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0100] In some implementations, the object has a diameter of 0.49–0.54 m.2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to approximately 200 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to approximately 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 175 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 150 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0101] In some implementations, the object has a diameter of 0.55-0.63 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to approximately 225 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to approximately 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 200 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 150 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0102] In some implementations, the object has a diameter of 0.64–0.77 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to approximately 275 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to approximately 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 225 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 200 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0103] In some implementations, the object has a diameter of 0.78-0.83 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to approximately 300 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to approximately 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 250 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 200 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0104] In some implementations, the object has a diameter of 0.84-0.89 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to approximately 350 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to approximately 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 300 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 250 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0105] In some implementations, the object has a diameter of 0.90-1.05 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to about 375-400 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 375 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 400 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 380 mg / m². 2Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to approximately 325 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to approximately 275 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0106] In some implementations, the object has a diameter of 1.06-1.25 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to about 400-500 mg (e.g., 450 mg) of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 400 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 450 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 500 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 375-400 mg of toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 375 mg of toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 400 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 325 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0107] In some implementations, the object has a diameter of 1.26–1.39 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method further includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to about 500-525 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 500 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 525 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 380 mg / m². 2Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 400-450 mg of toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 400 mg of toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 450 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 375 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0108] In some implementations, the object has a diameter of ≥1.40 m. 2 The method involves administering an initial dose of tovorafenib or a salt thereof to the subject, followed by a reduced dose of tovorafenib or a salt thereof. In some embodiments, the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. In some embodiments, the initial dose is equivalent to about 600 mg of tovorafenib once weekly. In some embodiments, the initial dose is equivalent to about 380 mg / m². 2 Toporafenib once weekly. In some embodiments, the reduced dose is equivalent to about 500 mg of toporafenib once weekly. In some embodiments, the further reduced dose is equivalent to about 400 mg of toporafenib once weekly. In some embodiments, toporafenib or a salt thereof is toporafenib.

[0109] In some embodiments, the method described herein includes suspending tovorafenib or its salts before administering a reduced dose. In some embodiments, the method described herein includes suspending tovorafenib or its salts before administering a further reduced dose. In some embodiments, the method described herein includes suspending tovorafenib or its salts after administering an initial dose. In some embodiments, the method described herein includes suspending tovorafenib or its salts after administering a reduced dose. In some embodiments, tovorafenib or its salts are suspended according to Table E. In some embodiments, a reduced dose is administered to the subject according to Table E. In some embodiments, a further reduced dose is administered to the subject according to Table E.

[0110] In some embodiments, the method described herein includes assessing the subject for adverse reactions selected from: bleeding, skin toxicity (including photosensitivity); hepatotoxicity; and other adverse reactions. In some embodiments, bleeding adverse reactions include intolerable grade 2; any grade 3; any grade 4 occurring for the first time; and / or recurrent grade 4. In some embodiments, when a subject experiences a bleeding adverse reaction, the subject discontinues tovolafenib or a salt thereof, and optionally, a lower dose (e.g., a reduced or further reduced dose) of tovolafenib or a salt thereof is administered. In some embodiments, skin toxicity adverse reactions include intolerable grade 2, and / or grade 3 or 4. In some embodiments, when a subject experiences a skin toxicity adverse reaction, the subject discontinues tovolafenib or a salt thereof, and optionally, a lower dose (e.g., a reduced or further reduced dose) of tovolafenib or a salt thereof is administered. In some embodiments, hepatotoxicity adverse reactions include grade 3 AST or ALT and / or grade 3 bilirubin. In some embodiments, hepatotoxicity adverse reactions include any grade 4 occurring for the first time or recurrent grade 4. In some embodiments, when a subject experiences an adverse reaction of hepatotoxicity, the subject is instructed to discontinue toporafenib or its salts and optionally, a lower dose (e.g., a reduced or further reduced dose) of toporafenib or its salts is administered, or if the laboratory abnormality resolves within 8 days, the same dose is administered. In some embodiments, other adverse reactions include intolerable grade 2, any grade 3, any grade 4 occurring for the first time, and / or recurrent grade 4. In some embodiments, when a subject experiences an adverse reaction, the subject is instructed to discontinue toporafenib or its salts and optionally, a lower dose (e.g., a reduced or further reduced dose) of toporafenib or its salts is administered. In some embodiments, the method further includes permanently discontinuing toporafenib or its salts. In some embodiments, the method further includes monitoring the subject's growth. In some embodiments, the method further includes confirming the absence of NF1 in the subject. In some embodiments, the method further includes identifying or confirming BRAF alterations in the subject before initiating use of toporafenib or its salts.

[0111] In some implementations, the starting dose is administered to the subject for more than 2 years. In some implementations, the starting dose is administered to the subject for more than 1 year. In some implementations, the starting dose is administered to the subject until disease progression or intolerable toxicity occurs.

[0112] In some embodiments, the starting dose is administered to the subject for 1–4 weeks. In some embodiments, the starting dose is administered to the subject for approximately 1–20, 1–12, 2–12, 4–8, or 8–20 weeks. In some embodiments, the starting dose is administered to the subject for at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the starting dose is administered to the subject for up to 2, 4, 8, 12, 16, 20, or 56 weeks. In some embodiments, the starting dose is administered to the subject until the subject experiences an adverse event during treatment. In some embodiments, the adverse events during treatment are those provided in Table 10. In some embodiments, the adverse events during treatment are grade 3 or higher. In some embodiments, the adverse events during treatment are grade 2 or higher. In some embodiments, the starting dose is administered to the subject until the subject experiences a treatment-related adverse event. In some embodiments, the treatment-related adverse events are those provided in Table 10. In some embodiments, the treatment-related adverse events are grade 3 or higher. In some embodiments, the treatment-related adverse events are grade 2 or higher.

[0113] In some implementations, the reduced dose is administered to the subject for more than 2 years. In some implementations, the reduced dose is administered to the subject for more than 1 year. In some implementations, the reduced dose is administered to the subject until disease progression or intolerable toxicity occurs.

[0114] In some embodiments, the reduced dose is administered to the subject for 1-4 weeks. In some embodiments, the reduced dose is administered to the subject for approximately 1-20, 1-12, 2-12, 4-8, or 8-20 weeks. In some embodiments, the reduced dose is administered to the subject for at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the reduced dose is administered to the subject for up to 2, 4, 8, 12, 16, 20, or 56 weeks. In some embodiments, the reduced dose is administered to the subject until the subject experiences an adverse event that occurred during treatment. In some embodiments, the adverse event that occurred during treatment is the event provided in Table 10. In some embodiments, the adverse event that occurred during treatment is grade 3 or higher. In some embodiments, the adverse event that occurred during treatment is grade 2 or higher. In some embodiments, the reduced dose is administered to the subject until the subject experiences a treatment-related adverse event. In some embodiments, the treatment-related adverse event is the event provided in Table 10. In some embodiments, the treatment-related adverse event is grade 3 or higher. In some embodiments, the treatment-related adverse event is grade 2 or higher.

[0115] In some implementations, subjects are given a further reduced dose for more than 2 years. In some implementations, subjects are given a further reduced dose for more than 1 year. In some implementations, subjects are given a further reduced dose until disease progression or intolerable toxicity occurs.

[0116] In some embodiments, the subject is given a further reduced dose for 1-4 weeks. In some embodiments, the subject is given a further reduced dose for about 1-20, 1-12, 2-12, 4-8, or 8-20 weeks. In some embodiments, the subject is given a further reduced dose for at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the subject is given a further reduced dose for up to 2, 4, 8, 12, 16, 20, or 56 weeks. In some embodiments, the subject is given a further reduced dose until the subject experiences an adverse event that occurred during treatment. In some embodiments, the adverse events that occurred during treatment are those provided in Table 10. In some embodiments, the adverse events that occurred during treatment are grade 3 or higher. In some embodiments, the adverse events that occurred during treatment are grade 2 or higher. In some embodiments, the subject is given a further reduced dose until the subject experiences a treatment-related adverse event. In some embodiments, the treatment-related adverse events are those provided in Table 10. In some embodiments, the treatment-related adverse events are grade 3 or higher. In some implementation schemes, treatment-related adverse events are classified as grade 2 or higher.

[0117] In one aspect, this article describes a method for treating relapsed or refractory pediatric low-grade gliomas (pLGG) in subjects of need, the method comprising administering tovorafenib or a salt thereof to the subject, wherein the subject is 6 months of age or older. In some embodiments, tovorafenib or a salt thereof is tovorafenib. In some embodiments, tovorafenib or a salt thereof is administered at approximately 380 mg / m². 2 The amount is administered as the starting dose (or the amount according to Tables A and B), and if the subject is not tolerant to the starting dose, tovorafenib or its salts are administered at a reduced dose according to Tables C and D, and optionally at a further reduced dose.

[0118] In one aspect, this article discloses a method for treating recurrent or refractory pediatric low-grade gliomas (pLGG) in subjects of need, the method comprising administering tovorafenib or a salt thereof to the subject, wherein the subject is 6 months of age or older; and wherein, (i) when the subject has a tumor size of 0.30–0.89 m... 2 When the body surface area (BSA) is measured, it is taken once a week (e.g., at approximately 380 mg / m²). 2(ii) When the subject has a blood glucose level of 0.90–1.12 mg / dL, the dose of tovorafenib or its salt is administered as an oral liquid formulation (e.g., a liquid suspension), 2 When BSA is present, tovorafenib or its salts are administered once weekly in an oral liquid or solid dosage form at a dose of approximately 400 mg, (iii) when the subject has a blood glucose level of 1.13–1.39 mg. 2 When BSA is present, tovorafenib or its salts are administered once weekly in an oral liquid or solid dosage form at a dose of approximately 500 mg, and (iv) when the subject has at least 1.40 mg. 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid or solid dosage form at a dose of approximately 600 mg.

[0119] In some implementations, pediatric low-grade gliomas (pLGG) carry BRAF fusions or rearrangements, or BRAF V600 mutations.

[0120] In some implementations, the method includes confirming the presence of BRAF fusions or rearrangements or BRAFV600 mutations before initiating treatment with tovorafenib or its salts.

[0121] In some embodiments, the method includes selecting subjects with PLGG who carry BRAF fusions or rearrangements or BRAF V600 mutations. In some embodiments, the method includes selecting subjects by evaluating liver function tests, including ALT, AST, and bilirubin.

[0122] In some implementations, tovorafenib or its salt is tovorafenib (i.e., in the free base form).

[0123] In some implementations, at approximately 380 mg / m 2 The dosage of tovorafenib or its salt is applied.

[0124] In some implementations, at approximately 380 mg / m 2 The initial dose is tovorafenib or its salt.

[0125] In some implementations, when the object has a diameter of 0.90-1.12 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in a solid dosage form at a dose of approximately 400 mg.

[0126] In some implementations, when the object has a diameter of 1.13-1.39 m 2 When BSA is present, tovorafenib or its salts are administered once weekly in a dose of approximately 500 mg as a solid dosage form.

[0127] In some implementations, when the object has a depth of at least 1.40 m2 When BSA is present, tovorafenib or its salt is administered once weekly in a solid dosage form at a dose of approximately 600 mg.

[0128] In some implementations, when the object has a diameter of approximately 0.30-0.35 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 125 mg.

[0129] In some implementations, when the object has a diameter of approximately 0.30-0.35 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 125 mg.

[0130] In some implementations, when the object has a diameter of approximately 0.30-0.35 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 5 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0131] In some implementations, when the object has a diameter of approximately 0.36-0.42 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 150 mg.

[0132] In some implementations, when the object has a diameter of approximately 0.36-0.42 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 150 mg.

[0133] In some implementations, when the object has a diameter of approximately 0.36-0.42 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 6 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0134] In some implementations, when the object has a diameter of approximately 0.43-0.48 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 175 mg.

[0135] In some implementations, when the object has a diameter of approximately 0.43-0.48 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 175 mg.

[0136] In some implementations, when the object has a diameter of approximately 0.43-0.48 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 7 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0137] In some implementations, when the object has a diameter of approximately 0.49-0.54 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 200 mg.

[0138] In some implementations, when the object has a diameter of approximately 0.49-0.54 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 200 mg.

[0139] In some implementations, when the object has a diameter of approximately 0.49-0.54 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 8 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0140] In some implementations, when the object has a diameter of approximately 0.55-0.63 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 225 mg.

[0141] In some implementations, when the object has a diameter of approximately 0.55-0.63 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 225 mg.

[0142] In some implementations, when the object has a diameter of approximately 0.55-0.63 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 9 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0143] In some implementations, when the object has a diameter of approximately 0.64–0.77 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 275 mg.

[0144] In some implementations, when the object has a diameter of approximately 0.64–0.77 m 2When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 275 mg.

[0145] In some implementations, when the object has a diameter of approximately 0.64–0.77 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 11 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0146] In some implementations, when the object has a diameter of approximately 0.78-0.83 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 300 mg.

[0147] In some implementations, when the object has a diameter of approximately 0.78-0.83 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 300 mg.

[0148] In some implementations, when the object has a diameter of approximately 0.78-0.83 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 12 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0149] In some implementations, when the object has a diameter of approximately 0.84-0.89 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 350 mg.

[0150] In some implementations, when the object has a diameter of approximately 0.84-0.89 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 350 mg.

[0151] In some implementations, when the object has a diameter of approximately 0.84-0.89 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 14 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0152] In some implementations, when the object has a diameter of approximately 0.90-1.05 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 375 mg.

[0153] In some implementations, when the object has a diameter of approximately 0.90-1.05 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 375 mg.

[0154] In some implementations, when the object has a diameter of approximately 0.90-1.05 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 15 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0155] In some implementations, when the object has a diameter of approximately 1.06-1.25 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 450 mg.

[0156] In some implementations, when the object has a diameter of approximately 1.06-1.25 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 450 mg.

[0157] In some implementations, when the object has a diameter of approximately 1.06-1.25 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 18 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0158] In some implementations, when the object has a diameter of approximately 1.26–1.39 m 2 When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 525 mg.

[0159] In some implementations, when the object has a diameter of approximately 1.26–1.39 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 525 mg.

[0160] In some implementations, when the object has a diameter of approximately 1.26–1.39 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 21 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0161] In some implementations, when the object has a diameter of ≥1.40 m 2When BSA is present, tovorafenib or its salt is administered once weekly at a dose of approximately 600 mg.

[0162] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is present, tovorafenib or its salt is administered once weekly in an oral liquid formulation (e.g., liquid suspension) at a dose of approximately 600 mg.

[0163] In some implementations, when the object has a diameter of ≥1.40 m 2 When administering BSA, tovolafenib or its salt as an oral liquid formulation (e.g., a liquid suspension) is administered in an amount of about 24 mL, wherein tovolafenib is present in the oral liquid formulation at about 25 mg / mL.

[0164] In some implementations, tovorafenib or its salts are applied according to the amounts specified in Table A or Table B.

[0165] In some implementations, the method includes dose reduction of tovorafenib or its salts.

[0166] In some implementations, dose reduction includes administering tovorafenib or its salts at a dose that is approximately 5% to 30% less than the dose prior to dose reduction.

[0167] In some implementations, dose reduction includes administering tovorafenib or a salt thereof in an amount that is about 10% to 20% less than the dose prior to dose reduction.

[0168] In some implementations, dose reduction includes administering tovorafenib or its salts at a dose that is approximately 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20% less than the dose prior to dose reduction.

[0169] In some implementations, dose reduction includes administering tovorafenib or a salt thereof to the subject according to Table C or Table D.

[0170] In some implementations, when the object has a diameter of 1.13-1.39 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 400 mg.

[0171] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 500 mg.

[0172] In some implementations, when the object has a diameter of 0.30-0.35 m 2When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 100 mg.

[0173] In some implementations, when the object has a diameter of 0.30-0.35 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 100 mg.

[0174] In some implementations, when the object has a diameter of 0.30-0.35 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 4 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0175] In some implementations, when the object has a diameter of 0.36-0.42 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 125 mg.

[0176] In some implementations, when the object has a diameter of 0.36-0.42 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 125 mg.

[0177] In some implementations, when the object has a diameter of 0.36-0.42 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in a volume of about 5 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0178] In some implementations, when the object has a diameter of 0.43-0.48 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 150 mg.

[0179] In some implementations, when the object has a diameter of 0.43-0.48 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 150 mg.

[0180] In some implementations, when the object has a diameter of 0.43-0.48 m 2When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 6 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0181] In some implementations, when the object has a diameter of 0.49-0.54 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 175 mg.

[0182] In some implementations, when the object has a diameter of 0.49-0.54 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 175 mg.

[0183] In some implementations, when the object has a diameter of 0.49-0.54 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 7 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0184] In some implementations, when the object has a diameter of 0.55-0.63 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 200 mg.

[0185] In some implementations, when the object has a diameter of 0.55-0.63 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 200 mg.

[0186] In some implementations, when the object has a diameter of 0.55-0.63 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 8 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0187] In some implementations, when the object has a diameter of 0.64-0.77 m 2 When BSA is present, dose reduction includes administration of tovorafenib or its salt once weekly at a dose of approximately 225 mg.

[0188] In some implementations, when the object has a diameter of 0.64-0.77 m 2When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 225 mg.

[0189] In some implementations, when the object has a diameter of 0.64-0.77 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 9 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0190] In some implementations, when the object has a diameter of 0.78-0.83 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 250 mg.

[0191] In some implementations, when the object has a diameter of 0.78-0.83 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 250 mg.

[0192] In some implementations, when the object has a diameter of 0.78-0.83 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in a volume of about 10 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0193] In some implementations, when the object has a diameter of 0.84-0.89 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 300 mg.

[0194] In some implementations, when the object has a diameter of 0.84-0.89 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 300 mg.

[0195] In some implementations, when the object has a diameter of 0.84-0.89 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in a volume of about 12 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0196] In some implementations, when the object has a diameter of 0.90-1.05 m 2When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 325 mg.

[0197] In some implementations, when the object has a diameter of 0.90-1.05 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 325 mg.

[0198] In some implementations, when the object has a diameter of 0.90-1.05 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in a volume of about 13 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0199] In some implementations, when the object has a diameter of 1.06-1.25 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 375 mg.

[0200] In some implementations, when the object has a diameter of 1.06-1.25 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 375 mg.

[0201] In some implementations, when the object has a diameter of 1.06-1.25 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 15 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0202] In some implementations, when the object has a diameter of 1.26-1.39 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 450 mg.

[0203] In some implementations, when the object has a diameter of 1.26-1.39 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 450 mg.

[0204] In some implementations, when the object has a diameter of 1.26-1.39 m 2When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in a volume of about 18 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0205] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is present, dose reduction includes administering tovorafenib or its salts once weekly at a dose of approximately 500 mg.

[0206] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts as an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 500 mg.

[0207] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is administered, dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in a volume of about 20 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0208] In some implementations, the method includes a second dose reduction of tovorafenib or a salt thereof.

[0209] In some implementations, the second dose reduction involves administering tovorafenib or a salt thereof at a dose that is approximately 5% to 30% less than the dose prior to the dose reduction.

[0210] In some implementations, the second dose reduction involves administering tovorafenib or a salt thereof in an amount that is about 10% to 20% less than the dose before the dose reduction.

[0211] In some implementations, the second dose reduction includes administering tovorafenib or a salt thereof at a dose that is approximately 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20% less than the dose prior to the dose reduction.

[0212] In some implementations, the second dose reduction includes administering tovorafenib or a salt thereof to the subject according to Table C or Table D.

[0213] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 400 mg.

[0214] In some implementations, when the object has a diameter of 0.30-0.35 m 2When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 75 mg.

[0215] In some implementations, when the object has a diameter of 0.30-0.35 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 75 mg.

[0216] In some implementations, when the object has a diameter of 0.30-0.35 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 3 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0217] In some implementations, when the object has a diameter of 0.36-0.42 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 100 mg.

[0218] In some implementations, when the object has a diameter of 0.36-0.42 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 100 mg.

[0219] In some implementations, when the object has a diameter of 0.36-0.42 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 4 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0220] In some implementations, when the object has a diameter of 0.43-0.48 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 125 mg.

[0221] In some implementations, when the object has a diameter of 0.43-0.48 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 125 mg.

[0222] In some implementations, when the object has a diameter of 0.43-0.48 m 2When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 5 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0223] In some implementations, when the object has a diameter of 0.49-0.54 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 150 mg.

[0224] In some implementations, when the object has a diameter of 0.49-0.54 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 150 mg.

[0225] In some implementations, when the object has a diameter of 0.49-0.54 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 6 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0226] In some implementations, when the object has a diameter of 0.55-0.63 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 150 mg.

[0227] In some implementations, when the object has a diameter of 0.55-0.63 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 150 mg.

[0228] In some implementations, when the object has a diameter of 0.55-0.63 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 6 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0229] In some implementations, when the object has a diameter of 0.64-0.77 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 200 mg.

[0230] In some implementations, when the object has a diameter of 0.64-0.77 m 2When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 200 mg.

[0231] In some implementations, when the object has a diameter of 0.64-0.77 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 8 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0232] In some implementations, when the object has a diameter of 0.78-0.83 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 200 mg.

[0233] In some implementations, when the object has a diameter of 0.78-0.83 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 200 mg.

[0234] In some implementations, when the object has a diameter of 0.78-0.83 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 8 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0235] In some implementations, when the object has a diameter of 0.84-0.89 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 250 mg.

[0236] In some implementations, when the object has a diameter of 0.84-0.89 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 250 mg.

[0237] In some implementations, when the object has a diameter of 0.84-0.89 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 10 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0238] In some implementations, when the object has a diameter of 0.90-1.05 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once weekly at a dose of approximately 275 mg.

[0239] In some implementations, when the object has a diameter of 0.90-1.05 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 275 mg.

[0240] In some implementations, when the object has a diameter of 0.90-1.05 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 11 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0241] In some implementations, when the object has a diameter of 1.06-1.25 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once weekly at a dose of approximately 325 mg.

[0242] In some implementations, when the object has a diameter of 1.06-1.25 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 325 mg.

[0243] In some implementations, when the object has a diameter of 1.06-1.25 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 13 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0244] In some implementations, when the object has a diameter of 1.26-1.39 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 375 mg.

[0245] In some implementations, when the object has a diameter of 1.26-1.39 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 375 mg.

[0246] In some implementations, when the object has a diameter of 1.26-1.39 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in a volume of about 15 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0247] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt once a week at a dose of approximately 400 mg.

[0248] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is present, the second dose reduction involves administering tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of approximately 400 mg.

[0249] In some implementations, when the object has a diameter of ≥1.40 m 2 When BSA is administered, the second dose reduction involves administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 16 mL, wherein tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

[0250] In some embodiments, the oral liquid formulation is a suspension. In some embodiments, the oral liquid formulation is a reconstituted tovorafenib suspension. In some embodiments, each mL of the reconstituted tovorafenib suspension contains 25 mg of tovorafenib and one or more of the following inactive ingredients: artificial strawberry flavor, colloidal silica, copovidone, maltodextrin, mannitol, microcrystalline cellulose, dimethicone, sodium lauryl sulfate, and / or sucralose. In some embodiments, each mL of the reconstituted tovorafenib suspension contains 25 mg of tovorafenib and the following inactive ingredients: artificial strawberry flavor, colloidal silica, copovidone, maltodextrin, mannitol, microcrystalline cellulose, dimethicone, sodium lauryl sulfate, and sucralose. In some embodiments, each mL of the reconstituted strawberry-flavored tovorafenib suspension contains 25 mg of tovorafenib. In some embodiments, each vial delivers 300 mg of tovorafenib (in 12 mL). In some implementations, tovorafenib is packaged as a clear glass vial along with a push-in vial adapter and a 20 mL oral syringe.

[0251] In some implementations, when the object has a diameter of 1.13-1.39 m 2When BSA is used, dose reduction includes administration of tovorafenib or its salts once weekly in an oral liquid or solid dosage form at a dose of approximately 400 mg.

[0252] In some implementations, when the object has a depth of at least 1.40 m 2 When BSA is used, dose reduction includes administration of tovorafenib or its salts once weekly in an oral liquid or solid dosage form at a dose of approximately 500 mg.

[0253] In some implementations, pLGG has a BRAF mutation or fusion.

[0254] In some implementations, pLGG carries BRAF fusions, rearrangements, or BRAF V600 mutations.

[0255] In some implementations, if a subject misses a dose for 3 days or less, the missed dose is administered to the subject, and the next dose is administered to the subject on the originally scheduled date.

[0256] In some implementations, the missed dose is administered to the subject no more than 3 days after the originally scheduled date.

[0257] In some implementations, if a subject misses a dose for more than 3 days, the missed dose is skipped, and the subject is given the next dose on the originally scheduled date.

[0258] In some implementations, when a subject misses a dose, the missed dose and the next dose are administered to the subject at least four days apart.

[0259] In some implementations, each dose of tovorafenib or its salt is administered to the subject at least four days apart.

[0260] In some implementations, pLGG has a BRAF mutation.

[0261] In some implementations, the BRAF mutation is replaced by the V600E mutation.

[0262] In some implementations, the BRAF mutation is a mutation other than the V600E mutation.

[0263] In some implementations, the subjects are selected from those who have previously received MAP kinase inhibitor treatment.

[0264] In some implementations, the subject either has radiographic progression of pLGG or no progression of pLGG while receiving MAP kinase inhibitor treatment.

[0265] In some implementations, the subject exhibits radiographic progression of pLGG while receiving MAP kinase inhibitor treatment.

[0266] In some implementations, the subjects exhibited relapsed / refractory pLGG after MAP kinase inhibitor treatment.

[0267] In some implementations, MAP kinase inhibitor therapy is the most recent treatment administered to the subject.

[0268] In some implementations, MAP kinase inhibitor treatment is not the most recent treatment administered to the subject.

[0269] In some implementations, the most recent treatment administered to the subject is selected from chemotherapy, radiation therapy, and surgery.

[0270] In some implementations, the subject has previously received one or more additional therapeutic treatments, including chemotherapy, radiation therapy, and surgery.

[0271] In some implementation schemes, approximately 400 mg / m² is administered orally to the subject weekly. 2 Approximately 450 mg / m 2 Tovorafenib or its salts.

[0272] In some implementations, approximately 420 mg / m² is administered orally to the subject weekly. 2 Tovorafenib or its salts.

[0273] In some implementation schemes, approximately 350 mg / m² is administered orally to the subject weekly. 2 Approximately 400 mg / m 2 Tovorafenib or its salts.

[0274] In some implementation schemes, approximately 380 mg / m² is administered orally to the subject weekly. 2 Tovorafenib or its salts.

[0275] In some implementations, tovorafenib or its salts are administered to the subject for 10 weeks or longer.

[0276] In some implementations, tovorafenib or its salts are administered to the subject for 16 weeks or longer.

[0277] In some implementations, tovorafenib or its salts are administered as tablets or liquid formulations.

[0278] In some implementations, tovorafenib or its salt is administered with food.

[0279] In some implementations, tovorafenib or its salts are not administered with food.

[0280] In some implementations, tovorafenib or its salt is tovorafenib.

[0281] In some embodiments, tovorafenib or its salts are administered as an oral liquid suspension. In some embodiments, tovorafenib or its salts are administered as an oral liquid suspension when the dose is less than 400 mg. In some embodiments, tovorafenib or its salts are administered as a solid dosage form such as tablets. In some embodiments, tovorafenib or its salts are administered as a solid dosage form such as tablets when the dose is 400 mg or more.

[0282] In some implementations, the steady-state maximum concentration (Cmax) of tovorafenib is approximately 6.9 μg / mL (23%), and the area under the concentration-time curve (AUC) is approximately 508 μg / mL. The peak plasma concentration of tovorafenib was 31% (h / mL), and the time to reach steady state was approximately 12 days (33%). In some embodiments, the median (min, maxima) time (Tmax) to reach peak plasma concentration of tovorafenib after a single dose of tablet or oral suspension was approximately 3 hours (1.5 hours, 4 hours).

[0283] In one aspect, this article describes a method for treating recurrent or refractory pediatric low-grade glioma (pLGG) in subjects of need, the method comprising administering tovorafenib to a subject aged 6 months or older, and wherein tovorafenib is administered in a dose amount and / or dose reduction amount according to one or more of Tables A, B, C, D and E.

[0284] In some implementations, Table E provides recommended dose adjustments for tovorafenib in response to adverse reactions. In some implementation schemes, approximately 280 mg / m² is administered once weekly. 2 Tovorafenib or its pharmaceutically acceptable salts or solvates. In some formulations, approximately 350 mg / m² is administered once weekly. 2 Tovorafenib. In some implementations, it is administered at approximately 420 mg / m² once weekly. 2 Tovorafenib. In some implementations, approximately 530 mg / m² is administered once weekly. 2 Tovorafinil.

[0285] In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof may be administered to the subject for a prolonged period of 30, 60, 120, 180, 240, 300, 360, 720, 1440, 1880, or 3600 days. In some embodiments, tovorafenib or a pharmaceutically acceptable salt or solvate thereof may be administered to the subject for a prolonged period 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, tovorafenib or a pharmaceutically acceptable salt or solvate thereof may be administered to the subject for a prolonged period 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, tovorafenib or a pharmaceutically acceptable salt or solvate thereof may be administered for a prolonged period in the amounts disclosed herein.

[0286] In some embodiments, tovorafenib or its salts are administered as tablets or liquid formulations. In some embodiments, tovorafenib or its salts are administered with food. In some embodiments, tovorafenib or its salts are not administered with food.

[0287] In some implementations, the target population is approximately 6 months to 25 years old. In some implementations, the target population is children. In some implementations, the target population is adolescents. In some implementations, the target population is adults. In some implementations, the target population is approximately 1 year to 25 years old. In some implementations, the target population is 25 years old or younger. In some implementations, the target population is 20 years old or younger. In some implementations, the target population is 15 years old or younger. In some implementations, the target population is 10 years old or younger. In some implementations, the target population is 6 months to 5 years old. In some implementations, the target population is 6 months to 10 years old. In some implementations, the target population is 6 months to 15 years old. In some implementations, the target population is 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 years old or younger. In some implementations, the subjects are aged 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. In some implementations, the subjects' performance status is measured. In some implementations, the performance status is defined as Karnofsky or Lansky performance status. In some implementations, the Karnofsky performance status is greater than or equal to 50. In some implementations, the Lansky performance status is greater than or equal to 50. In some implementations, the subjects have low-grade gliomas. In some implementations, the subjects have failed standard treatment.

[0288] In one aspect, this disclosure provides a treatment method according to Example 1.

[0289] As demonstrated in Example 1 (FIREFLY-1 trial), tovorafenib monotherapy in patients with BRAF To produce clinically significant, rapid and durable tumor responses in children and young adults with altered relapsed / refractory pLGG.

[0290] BRAF Genomic alterations are the most common oncogenic driver in pediatric low-grade gliomas (pLGG). The ongoing Phase 2 FIREFLY-1 (PNOC026) trial, Group 1 (n=77), investigated the oral, selective, centrally penetrating type II RAF inhibitor tovorafenib (420 mg / m²). 2 Once a week; maximum 600 mg) in patients with BRAF Efficacy in patients with modified relapsed / refractory pLGG. Group 2 (n=60) was an expanded cohort that included patients with [a condition] after Group 1 was closed. RAFPatients with altered pLGG received treatment access. Based on independent review, the overall response rate (ORR) met the pre-specified primary endpoint of Group 1, assessed according to the RANO-HGG criteria for high-grade glioma response (RANO-HGG), with a 67% overall response rate; the median duration of response (DOR) was 16.6 months, and the median time to response (TTR) was 3.0 months (secondary endpoint). Other selected secondary endpoints for Group 1 included ORR, DOR, and TTR assessed according to the RANO-HGG criteria, and safety (assessed in all treated patients and was the primary endpoint for Group 2, n=137). The ORR based on RAPNO-LGG (including mild responses) was 51%, with a median DOR of 13.8 months and a median TTR of 5.3 months. The most common treatment-related adverse events (TRAEs) were changes in hair color (76%), elevated creatine phosphokinase (56%), and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine patients (7%) experienced a TRAE that led to discontinuation of tovorafenib. These data suggest that tovorafenib may be a targeted therapy for... BRAF Effective treatment for altered relapsed / refractory pLGG.

[0291] In Example 1, patients had received a median of three lines of prior systemic therapy, and more than half of the patients had previously received RAF and / or MEK inhibitors. Tumor response was assessed using three response evaluation criteria (RANO-HGG, RAPNO, and RANO-LGG). BRAF This was confirmed in altered types (mutations and fusions) and in patients with prior MAPKi use (including those who progressed after MAPKi as their most recent prior treatment). As shown in Example 1, a consistent pattern of improvement in response over time was observed on both T1- and T2-weighted MRI sequences.

[0292] Example 1 was designed with the ORR assessed by IRC as the primary endpoint, evaluated according to RANO-HGG. These criteria are primarily based on T1-weighted contrast-enhanced imaging to assess tumor response. According to RANO-HGG, the FIREFLY-1 trial met its primary endpoint by rejecting the null hypothesis that the ORR of vincristine monotherapy observed in this setting would be 21%.

[0293] For patients with pLGG, a reduction in contrast-enhanced tumor may not represent all aspects of antitumor activity. The RAPNO working group's recommendations highlight the lack of standardized response criteria in pLGG clinical trials and the biological differences between pediatric and adult gliomas. The RAPNO criteria focus on T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging for assessing response to pLGG, rather than changes in contrast-enhanced disease. This may be beneficial because pLGG has different clinical and biological characteristics than adult LGG, and assessing the contrast-enhanced portion of the tumor may not be the optimal indicator of response in this population. RAPNO takes into account: changes in tumor-associated cysts; including MR category (tumor reduction of 25%–<50%); and given their clinical importance in pLGG, recommends including visual outcomes in response assessments (visual pathway and hypothalamic pLGG). Therefore, assessments of tumor response by the IRC based on RAPNO and RANO-LGG (both primarily assessing tumor response based on non-enhanced disease measured by T2 / FLAIR) were included in this trial as secondary and post-hoc exploratory endpoints, respectively (see Example 1). Sustained tumor size reduction was observed in most patients, representing a clinically significant change based on T2 / FLAIR-based assessment criteria. In Group 1, ORR and CBR were very similar for RAPNO and RANO-LGG. Despite the limited number of patients, response times appeared to be shorter for patients with BRAF V600E mutations (2.8 and 2.9 months, respectively) under both assessment criteria compared to patients with tumors carrying BRAF fusions (5.5 and 5.5 months).

[0294] Although responses to toporafenib are typically early, dynamic analyses of tumor size over time using RAPNO and RANO-LGG have shown that some patients who continued treatment after initial radiographic progression (PD) assessment subsequently experienced significant tumor shrinkage, suggesting a delayed response to treatment. Studies have shown that this effect may be related to transient immune cell infiltration of the tumor, leading to an initial increase in the apparent tumor burden. Immune cells, particularly microglia, may account for up to 40% of all cells in pilocytic astrocytomas and can explain differences in RNA expression profiles across tumor locations and subtypes. The possibility of a delayed response to toporafenib after the initial apparent increase in tumor size highlights the challenge of assessing efficacy in this patient population using established response evaluation criteria and increases the likelihood that some patients may benefit from toporafenib treatment until radiographic progression is confirmed by a second MRI scan. Looking ahead, for patients receiving toporafenib treatment and experiencing early radiographic progression, follow-up imaging studies 8–12 weeks after initial PD can be recommended in the absence of evidence of clinical progression.

[0295] This trial evaluated the effects of tovorafenib on different aspects of pLGG tumor biology and response by simultaneously employing T1-weighted contrast enhancement (RANO-HGG) and T2 / FLAIR-based methods (RAPNO and RANO-LGG). While establishing an optimal single response assessment standard for this heterogeneous disease presents unique challenges, proven responses to tovorafenib over time were observed across three different neuro-oncology response assessment criteria.

[0296] In Example 1, given that more than half of the patients had previously received MAPKi treatment, the ORR of over 50% reported with RAPNO and RANO-LGG in this trial using tovorafenib is particularly noteworthy.

[0297] According to Example 1, regarding the safety and tolerability characteristics of tovorafenib monotherapy in children and young adults with pLGG, the treatment-associated adverse events (TRAEs) were primarily grade 1 or 2, and only nine (7%) of the 137 patients discontinued treatment due to a TRAE. Besides laboratory abnormalities, the most common TRAEs of any grade were hair color changes, fatigue, maculopapular rash, dry skin, acneiform dermatitis, pruritus, and paronychia. Although grade 1 and 2 laboratory abnormalities were commonly reported as adverse events (AEs), most were not accompanied by any clinical symptoms or required no clinical intervention or treatment change. The most common ≥ grade 3 TRAEs included elevated CPK, anemia, and maculopapular rash. Other common ≥ grade 3 treatment-associated adverse events (TEAEs) (not assessed as being associated with tovorafenib), including seizures, were consistent with the effects of the underlying disease.

[0298] Overall, adverse events were consistent with those observed in the Phase 1 trial of toporafenib in adults receiving once-weekly dosing and were similar to those of other targeted agents used as a treatment for pLGG, including MAPKI, with a few notable exceptions. Hair color changes (already reported in clinical studies of pediatric pLGG patients treated with other MAPK inhibitors) occurred more frequently with toporafenib. However, fever, diarrhea, and weight gain—common adverse reactions to BRAF inhibitor / MEK inhibitor combination therapy—were less frequently reported as being associated with toporafenib, and no significant discontinuation of treatment was observed. Unlike those observed with MEK inhibitors, no signs of ocular toxicity, adverse effects on cardiac function, or abnormal weight gain were observed in children treated with toporafenib. While rashes were common in children treated with toporafenib, no life-threatening skin reactions were reported, and no squamous cell carcinoma or keratoacanthoma was observed.

[0299] There were no treatment-related deaths during the trial, and TRAEs requiring treatment discontinuation were uncommon. Intratumoral hemorrhage was reported in 15 patients, leading to treatment discontinuation in three. However, half (eight of the 15) of patients with intratumoral hemorrhage were asymptomatic, with the hemorrhage area only identified on routine trial MRI. Of the seven patients with symptomatic intratumoral hemorrhage, three were assessed by investigators as consistent with the natural course of their underlying tumors and unrelated to tovorafenib. Of the four patients with symptomatic hemorrhage considered by investigators to be potentially related to tovorafenib, two had a history of intratumoral hemorrhage prior to study initiation, the third had a disseminated tumor with leptomeningeal disease, and the fourth had bone marrow failure secondary to prior treatment with multiple alkylating agents, which was diagnosed before the onset of intratumoral hemorrhage. Although the incidence of intratumoral hemorrhage in this patient population is not well described, case reports suggest that the risk of intratumoral hemorrhage may be underestimated in pLGG tumor types with heterogeneous histology, morphology, and prior interventions.

[0300] Reduced growth rate has been observed in children treated with tovorafenib. In patients reporting a complete endocrinological assessment, wrist imaging supported preservation of growth potential, with no evidence of advanced bone age or premature fusion of growth plates. Furthermore, in the FIREFLY-1 and previous studies, patients with available data after discontinuation of tovorafenib showed varying degrees of growth rate recovery, including catch-up growth. A more detailed analysis of growth during and after tovorafenib treatment is planned. It is noteworthy that children with cancer and those with midline CNS tumors such as pLGG often present with endocrine abnormalities, which may affect growth trajectory and the likelihood of reaching genetic height potential. In one report, nearly half of children with hypothalamic / optic chiasm gliomas presented with at least one endocrine disorder, most commonly growth hormone deficiency. Standardized data on growth are lacking in this patient population, and future pLGG-targeted therapy studies should include baseline and longitudinal assessments of endocrine function, as well as monitoring of growth rate during treatment. Long-term follow-up of FIREFLY-1 patients after treatment cessation is ongoing to assess the impact of the temporary decrease in growth rate on final adult height. In summary, these results demonstrate that tovorafenib monotherapy is generally well-tolerated, and in patients with... BRAF The altered pLGG showed encouraging, clinically significant, rapid, and durable evidence of clinical activity in children and young adults. Therefore, tovorafenib may be a potential treatment option. BRAFModified pLGG offers important treatment options due to its superior safety profile compared to currently available pLGG therapies, with a positive benefit-risk ratio. Notably, the availability of the liquid formulation, the weekly dosing regimen, and the absence of food effects allow for better adherence to prescribed treatment protocols. Most patients manage common adverse events with only brief dose interruptions. These data provide strong evidence for the ongoing Phase 3 LOGGIC / FIREFLY-2 (NCT05566795) trial, which compares tovorafenib monotherapy with current standard-of-care chemotherapy in children and young adults with pLGG requiring primary systemic therapy.

[0301] On the other hand, this disclosure provides a treatment method according to Example 2.

[0302] As shown in Example 2, under radiological evaluation criteria, tovorafenib monotherapy in relapsed / refractory patients... BRAF The modified OPG exhibited antitumor activity and was generally well-tolerated. In some implementations, the subjects' vision remained stable or improved.

[0303] In Example 2, a subgroup analysis of the international, multicenter, single-arm phase 2 FIREFLY-1 trial showed that tovorafenib monotherapy was effective in patients with BRAF Clinically significant, rapid, and durable tumor responses were achieved in children and young adults with altered sporadic relapsed / refractory OPG. Tumor responses were observed in all three response assessment criteria in the OPG subgroups: RANO-HGG (ORR, 64%), RAPNO (50%), and RANO-LGG (55%). A consistent pattern of response improvement over time was observed based on both response criteria (RAPNO and RANO-LGG) using T2 / FLAIR-weighted MRI sequences. Given that patients had received a median of three lines of prior systemic therapy and that more than two-thirds of patients had previously received MEK and / or BRAF inhibitors, the imaging responses in this OPG subgroup support tovorafenib monotherapy.

[0304] In Example 2, visual acuity (VA) assessment showed improvement in the best eye in 39% of patients, stability in 53% of patients, and deterioration in only 8% of patients. During tovorafenib treatment, visual acuity improved or remained stable (i.e., preserved) in 92% of patients in the OPG subgroup. The improvement in VA (across assessment criteria) in 40-50% of patients with the best overall response and stable disease suggests that achieving this important functional outcome does not always require tumor shrinkage.

[0305] regardless BRAFVisual acuity (VA) was preserved regardless of the type of alteration (fusion vs. mutation), whether the patient had previously received MAPKi treatment, or whether they had received ≤3 or >3 lines of prior systemic therapy. For most patients, VA remained stable or improved overall, regardless of baseline VA, except for two patients with moderate impairment at baseline and one patient with very severe / more severe impairment at baseline (Table 7). Clinically, visual acuity deteriorates the longer the time since initial diagnosis. However, in this cohort of patients treated with tovorafenib for OPG, visual acuity was preserved during tovorafenib treatment (when patients were categorized into interquartile groups based on the time since initial diagnosis).

[0306] A single-center retrospective study evaluated the effect of first-line chemotherapy on visual acuity in 42 patients with NF1-related (71%) or sporadic OPG (29%). During treatment, visual acuity improved in 14% of evaluable patients (n=35), and remained stable in 77% (91% preserved). Another retrospective study of 30 patients from middle-income countries with sporadic (77%) or NF1-related OPG (23%) showed that visual acuity was preserved in nine out of ten evaluable patients (90%) after treatment (primarily chemotherapy). In patients with severe, previously treated sporadic relapsed / refractory OPG, tovorafenib demonstrated superior activity in improving or preserving visual acuity compared to these retrospective studies on the effects of chemotherapy on visual acuity.

[0307] In Example 2, radiological and VA outcomes were completely concordant in 45%, 42%, and 37% of patients, respectively, based on RANO-HGG, RAPNO, and RANO-LGG, and completely concordant in only 6%, 0%, and 3% of patients (all with radiological response and worsening VA). The remaining assessments were partially concordant, with the largest group of patients having radiological response and stable VA. Notably, for both RAPNO and RANO-LGG assessments, significant improvements in VA were observed in some patients with minimal changes in maximum tumor size.

[0308] The safety profile of tovorafenib monotherapy in the OPG subgroup 1 was similar to that previously reported in the safety analysis set of the combined population of treated patients in FIREFLY-1 groups 1 and 2. In the OPG subgroup, three patients (7%) reported tumor bleeding as TRAE.

[0309] According to Example 2, in this cohort of children and adolescents with relapsed / refractory OPG, tovorafenib monotherapy (based on both contrast-enhanced response criteria and T2 / FLAIR-weighted sequence response criteria) achieved clinically meaningful, durable, and rapid tumor response. Tovorafenib was well-tolerated, with only 10% of patients discontinuing treatment due to TEAE. VA was preserved in 92% of patients during treatment. Tovorafenib may be beneficial for patients with... BRAF This provides important new treatment options for patients with altered relapse / refractory OPG.

[0310] This disclosure also provides tovorafenib tablets and tovorafenib oral suspensions for oral use. In some embodiments, tovorafenib is administered as an oral tablet. In some embodiments, tovorafenib is administered as an oral suspension.

[0311] In some implementations, tovorafenib or its salts are kinase inhibitors used to treat patients aged 6 months and older with relapsed or refractory pediatric low-grade gliomas (LGG) harboring BRAF fusions, rearrangements, or BRAF V600 mutations.

[0312] In some implementations, the dosage and administration instructions are as follows: (1) confirm the presence of BRAF fusions, rearrangements, or BRAF V600 mutations before initiating treatment with tovorafenib; (2) recommend a tovorafenib dose based on body surface area (see Table A); (3) administer tovorafenib orally once weekly, with or without food; (4) swallow the tablet whole with water, without chewing, cutting, or crushing. In some implementations, for instructions on the preparation and administration of the tovorafenib oral suspension and for dose adjustments for adverse reactions, please refer to the complete prescribing information. In some implementations, the dosage and administration instructions are as follows: confirm the presence of BRAF fusions, rearrangements, or BRAF V600 mutations before initiating treatment with tovorafenib. In some implementations, the dosage and administration instructions are as follows: recommend a tovorafenib dose based on body surface area (see Table A or Table B). In some implementations, the dosage and administration instructions are as follows: administer tovorafenib orally once weekly, with or without food. In some implementations, the tablet is swallowed whole with water, without chewing, cutting, or crushing.

[0313] In some implementations, the presence of a BRAF fusion, rearrangement, or BRAFV600 mutation is confirmed prior to initiation of tovorafenib treatment. In some implementations, tovorafenib (or its salt) is administered orally once weekly, with or without food. In some implementations, tovorafenib (or its salt) is administered by swallowing a tablet whole with water.

[0314] In some embodiments, the dosage form and strength are: 100 mg tablets and 25 mg / mL oral suspension. In some embodiments, the dosage form and strength are: 100 mg tablets. In some embodiments, the dosage form and strength are: 25 mg / mL oral suspension. In some embodiments, the dosage form and strength are: 100 mg tablets. In some embodiments, the dosage form and strength are: 25 mg / mL oral suspension. In some embodiments, each tablet contains 100 mg of tovorafenib and the following inactive ingredients: copovidone, colloidal silica, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and Opadry® Orange. In some embodiments, each mL of reconstituted tovorafenib suspension contains 25 mg of tovorafenib and the following inactive ingredients: artificial strawberry flavor, colloidal silica, copovidone, maltodextrin, mannitol, microcrystalline cellulose, dimethicone, sodium lauryl sulfate, and sucralose.

[0315] In some embodiments, tovorafenib or a salt thereof is administered in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent prevents or treats bleeding. In some embodiments, the second therapeutic agent prevents or treats skin toxicities, including photosensitivity. In some embodiments, the second therapeutic agent prevents or treats maculopapular rash and photosensitivity. In some embodiments, the second therapeutic agent promotes growth. In some embodiments, the second therapeutic agent prevents or treats growth retardation. In some embodiments, the second therapeutic agent helps maintain the growth rate of the subject. In some embodiments, the second therapeutic agent prevents or treats embryo-fetal toxicity. In some embodiments, the second therapeutic agent is selected from antiviral therapeutic agents, bacterial pneumonia therapeutic agents, and sepsis therapeutic agents. In some embodiments, the second therapeutic agent is selected from antiviral agents and antibacterial agents. In some embodiments, the antibacterial therapeutic agent is used for pneumonia. In some embodiments, the antibacterial therapeutic agent is used for sepsis. In some embodiments, the antiviral therapeutic agent is used for viral infections. In some embodiments, the second therapeutic agent is for treating rash, fever, vomiting, or bleeding. In some implementations, the second therapeutic agent treats or alleviates rashes (including erythema multiforme, eczema, erythematous rash, maculopapular rash, follicular rash, pruritic rash, maculopapular rash, rashes, rash popular, pustular rash, exfoliative rash, drug eruption, dermatitis, and bullous dermatitis), discoloration, dry skin, acneiform dermatitis, pruritus, fatigue, fever, edema (including lip edema, periorbital edema, peripheral edema, localized edema, facial edema, and vulvar edema), headache, vomiting (including dry heaves and hematemesis), constipation, nausea, abdominal pain, diarrhea (including colitis and enterocolitis), stomatitis (including oral ulcers, mucosal inflammation, aphthous ulcers, and cheilitis), bleeding (including tumor bleeding, gastrointestinal bleeding, subdural hemorrhage, epistaxis, intracranial tumor hemorrhage, upper gastrointestinal bleeding, lower gastrointestinal bleeding, vaginal bleeding, gingival bleeding, and postoperative bleeding). Post-hemorrhagic, hemoptysis, and rectal bleeding), viral infections (including rhinovirus infection, enterovirus infection, viral upper respiratory tract infection, viral enterocolitis and oral herpes, viral gastroenteritis, influenza, rhinovirus infection, respiratory syncytial virus infection, enterovirus infection, coronavirus infection, herpes simplex, parainfluenza virus infection, adenovirus upper respiratory tract infection, viremia, adenovirus infection, viral conjunctivitis, viral ocular infection, metapneumovirus infection, parvovirus infection, respiratory syncytial virus bronchiolitis, viral respiratory tract infection, viral pharyngitis, viral rhinitis, and viral tonsillitis), upper respiratory tract infection, paronychia, or combinations thereof. In some embodiments, additional therapeutic agents treat or alleviate the abnormality. In some embodiments, the abnormality is decreased phosphate, increased AST, increased creatine kinase, increased LDH, increased ALT, decreased potassium, increased bilirubin, decreased albumin, decreased sodium, decreased hemoglobin, decreased lymphocytes, or decreased white blood cells, increased lymphocytes, or combinations thereof.

[0316] In some embodiments, the second therapeutic agent is a corticosteroid. In some embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the NSAID is selected from ibuprofen and acetaminophen. In some embodiments, the second therapeutic agent is an antiemetic. In some embodiments, the second therapeutic agent is an antihistamine. In some embodiments, the antihistamine is bismuth subsalicylate. In some embodiments, the second therapeutic agent is an antiplatelet drug, an anticoagulant, or astatin. In some embodiments, the second therapeutic agent is for treating skin rash or fatigue. In some embodiments, the second therapeutic agent is a stimulant. In some embodiments, the stimulant is selected from modafinil, methylphenidate, amphetamine (d-phenylamphetamine), amantadine, and dextroamphetamine. In some embodiments, the second therapeutic agent is for treating dry skin, constipation, nausea, or upper respiratory tract infection, or a combination thereof. In some embodiments, the second therapeutic agent is an alpha-hydroxy acid. In some embodiments, the second therapeutic agent is a laxative. In some embodiments, the second therapeutic agent is an antiemetic. In some embodiments, the antiemetic is selected from antagonists of dopamine, serotonin, neurokinin, histamine, and acetylcholine. In some embodiments, the second therapeutic agent is an antibiotic or antiviral agent for upper respiratory tract infections. In some embodiments, the second therapeutic agent is a vitamin or mineral supplement. In some embodiments, the vitamin or mineral supplement is a phosphate or potassium salt. In some embodiments, the second therapeutic agent is a treatment for or relief of decreased phosphate, decreased hemoglobin, increased creatinine kinase, decreased neutrophils, increased alanine aminotransferase, increased bilirubin, increased aspartate aminotransferase, decreased lymphocytes, and decreased potassium, or combinations thereof. In some embodiments, the second therapeutic agent is administered concurrently with tovorafenib. In some embodiments, the second therapeutic agent and tovorafenib are administered sequentially. In some embodiments, the second therapeutic agent is administered less frequently than tovorafenib. In some embodiments, the second therapeutic agent is administered more frequently than tovorafenib. In some embodiments, the second treatment agent is administered before topolafenib. In other embodiments, the second treatment agent is administered after topolafenib.

[0317] In some implementations, the patient has a Karnofsky / Lansky performance status of 80 to 100.

[0318] In some embodiments, tovorafenib or its salts are not administered in combination with CYP2C8 inhibitors. In some embodiments, tovorafenib or its salts are not administered in combination with CYP3A4 substrates. In some embodiments, tovorafenib or its salts are not administered in combination with hormonal contraceptives. In some embodiments, tovorafenib or its salts are not administered in combination with CYP2C8 inducers. In some embodiments, tovorafenib or its salts are not administered in combination with moderate or strong CYP2C8 inducers.

[0319] In some implementations, the recommended dose of tovorafenib based on body surface area (BSA) is 380 mg / m² orally once weekly. 2 (The maximum recommended dose is 600 mg orally once a week). In some implementations, tovorafenib may be administered as an immediate-release tablet (see Table A) or as an oral suspension (see Table B).

[0320] In some embodiments, the dosage form and strength are 100 mg tablets. In some embodiments, the dosage form and strength are powders for oral suspension: 25 mg / mL.

[0321] In some implementations, patients receive a body surface area-based dose of toporafenib orally once weekly until disease progression, intolerable toxicity, or loss of clinical benefit. In some implementations, patients receive a body surface area-based dose of toporafenib orally once weekly. In some implementations, patients receive toporafenib until disease progression. In some implementations, patients receive toporafenib until intolerable toxicity occurs. In some implementations, patients receive toporafenib until loss of clinical benefit.

[0322] Example: Example 1. Experimental Design and Results FIREFLY-1 (PNOC026; NCT04775485) is an ongoing phase 2, multicenter, open-label study in patients who have received at least one prior systemic therapy. RAF Tovorafenib monotherapy was evaluated in children, adolescents, and young adults with altered pediatric low-grade gliomas (pLGG) or advanced solid tumors. The trial consisted of three treatment groups, with patients enrolled from 32 centers in 11 countries. Group 1 enrolled patients with activating gliomas. BRAF Changes (including BRAFV600 mutations and) KIAA1549 :: BRAF Patients with relapsed or refractory pLGG (fusion) were included. Group 2 (pLGG expansion cohort) enrolled patients with activating pLGG. RAF Patients with altered relapsed or refractory pLGG, and group 3 is currently enrolling patients carrying activating pLGG. RAF Patients with fused, advanced solid tumors. Identification using molecular assays. RAF The change is that this molecular assay is routinely performed as part of standard diagnostic testing in laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories. BRAF The categories of fusion include BRAF Serial repetition BRAF Rearrangement and involving KIAA1549 Other partner genes BRAF Integration.

[0323] Biological sex and / or gender were not considered in the trial design because no biological sex difference was observed in previous pLGG clinical trials, although one report indicated a slightly higher incidence of pLGG in males than females, consistent with the prevalence seen in childhood cancers. The current trial recruits any patient, regardless of biological or gender. Participant biological sex is based on parental or self-reported information. Patients' gender was not collected or considered as part of this trial because less attention was paid to collecting gender-related information during protocol writing and initiation of the FIREFLY-1 trial.

[0324] On days 1, 8, 15, and 22 of a 28-day cycle, administer the recommended Phase 2 dose of 420 mg / m². 2 Toporafenib is administered orally (tablets or liquid formulation) once weekly (not exceeding 600 mg). Treatment cycles are repeated every 28 days until radiographic evidence of disease progression, unacceptable toxicity, decision to enter a pharmacological leave, withdrawal of informed consent, or death, as determined by the investigator according to RANO-HGG criteria. Patients with radiographic evidence of disease progression are permitted to continue toporafenib treatment if the investigator believes, and with sponsor approval, that the patient has received clinical benefit from continued trial treatment. Patients will be treated with toporafenib for a planned period of 26 cycles (approximately 24 months), after which they can continue receiving toporafenib or choose to enter a pharmacological leave at any point in time. During this pharmacological leave, patients may be re-treated with toporafenib if radiographic evidence of disease progression is present.

[0325] An independent Data Safety Monitoring Board (DSMB) was established prior to the start of the trial and remained in place throughout the trial. Medical monitoring of the trial was provided by the sponsor and utilized a safety review board, which included the principal investigator (or their designee) from each active clinical center.

[0326] The protocol, protocol amendments, informed consent forms, pediatric consent forms, investigator brochures, and other relevant documents were all approved by the institutional review committee / independent ethics committee of each trial center. Depending on applicable local regulations, the protocol and all protocol amendments were reviewed and approved by the relevant competent authority.

[0327] This trial was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines, including the Declaration of Helsinki, the Council for International Organizations of Medical Sciences (CIOMS) International Ethics Guidelines, applicable International Council for Harmonisation Good Clinical Practice Guidelines, and other applicable laws and regulations. In accordance with local regulations, all patients and / or their legally authorized representatives provided written informed consent and pediatric consent prior to enrollment in this trial. No direct compensation was offered to patients or their families for participation in the trial.

[0328] Data collection The required clinical data was entered into the electronic case report form (eCRF) using a fully validated, secure, and web-accessible electronic data capture (EDC) system—Medidata Classic Rave. ® As of March 2, 2022, the system complies with the requirements of Title 21, Part 11 of the Federal Regulations (21 CRF). Automated validation and editing checks in the EDC and offline listings are programmed to capture data discrepancies in the eCRF and allow for modification and validation of the input data. Investigators validate and sign the eCRF in the EDC to confirm the completeness and accuracy of the collected clinical data. The sponsor can demonstrate that all data and metadata will be permanently archived. Data is permanently retained in the EDC and TMF (Trial Master File). Furthermore, this data has been submitted to the U.S. FDA.

[0329] qualifications The trial protocol outlines complete inclusion and exclusion criteria. In short, eligible patients in Group 1 were aged 6 months to 25 years (inclusive) and had histopathologically confirmed pLGG (with prior systemic therapy of at least one first line and evidence of radiographic progression), and documented known activating leukemia. BRAFAmputation and measurable disease as defined by the Neuro-oncology Response Assessment – ​​High-Grade Gliomas (RANO-HGG) criteria, with a Karnofsky Performance Status score ≥50 (age ≥16 years) or Lansky Performance Status score (age <16 years) and adequate organ function. Radiotherapy to the measurable lesion must have been completed at least 6 months prior to tovorafenib administration, and the patient must have fully recovered from any acute toxic effects of prior anticancer chemotherapy and any prior surgery. Patients must have adequate bone marrow and organ function within 28 days prior to the first dose of tovorafenib, including a left ventricular ejection fraction (LVEF) ≥50% as measured by echocardiography or multi-gated acquisition (MUGA) scan, or a fractional shortening (FS) ≥25% as measured by echocardiography. At enrollment, archived tumor tissue should be obtained whenever available. Tissue biopsy is only required during screening if archived tumor tissue samples are unavailable.

[0330] Patients are excluded if their tumor carries additional previously known or anticipated activating molecular alterations, if they have clinically progressive symptoms but no radiographically recurrent or radiographically progressive disease, if they are known or suspected to have neurofibromatosis type 1 by genetic testing or current diagnostic criteria, if they have a history or current evidence of central serous retinopathy, retinal vein occlusion, or an eye disease present at baseline that is considered a risk factor for either of these diseases, if they have clinically significant active cardiovascular disease, or if they remain neurologically unstable despite adequate treatment.

[0331] test endpoint Response was assessed using three different radiological response assessment criteria: RANO-HGG (which primarily assesses tumor response based on T1-weighted contrast-enhanced imaging), and Pediatric Neuro-Oncology Response Assessment-LGG (RAPNO) and RANO-LGG (both primarily assess tumor response based on non-enhanced disease measured by T2 / FLAIR). The characteristics of these different response criteria are summarized in Extended Data Table 1. According to the trial design, patients were initially enrolled based on investigator eligibility assessments according to RANO-HGG. Investigator response assessments based on RANO-HGG were also the criteria upon which treatment was discontinued due to PD. Responses were subsequently analyzed according to all three criteria through a blinded, independent central review.

[0332] Table 1. Patient and baseline characteristics: n=137 The primary endpoint for Group 1 was overall response rate (ORR), defined as the proportion of patients with a confirmed complete response (CR) or partial response (PR) as assessed by an independent radiological review committee (IRC) according to RANO-HGG criteria. Secondary endpoints for Group 1 included clinical benefit rate (CBR), progression-free survival (PFS), duration of response (DOR), and time to response, all assessed by the IRC using RANO-HGG criteria. CBR was defined as the proportion of patients with a confirmed response or stable disease lasting any duration, 6 months or longer, or 12 months or longer. ORR, CBR, PFS, DOR, and time to response were also assessed by the IRC according to the Pediatric Neuro-Oncology Response Assessment (RAPNO) criteria. Secondary endpoints for safety included assessments of adverse events, laboratory abnormalities, and cardiac function (QTcF, PR interval, QRS interval, heart rate, or ECG waveform morphology relative to baseline). Post-hoc exploratory endpoints for Group 1 included ORR and CBR as assessed by the IRC according to RANO-HGG criteria. For RAPNO and RANO-LGG ORR assessments, patients with confirmed mild responses are considered responders, according to published guidelines. Changes in quality of life and health utility indicators are exploratory goals.

[0333] Evaluate Disease assessment in Group 1 was performed via MRI of the brain and spine, and was conducted during a screening period of up to 28 days prior to the first dose, at the end of cycle 3, and at the end of every three cycles thereafter. Repeated spinal scans were only required after screening in patients with known or clinically suspected intraspinal disease. Patients with optic pathway glioma (OPG) or potential visual impairment associated with a primary malignancy underwent visual acuity testing at each imaging disease assessment.

[0334] The central imaging laboratory is used. Imaging Endpoints (IE) (Scottsdale, AZ) is a research and imaging core laboratory that provides blinded, independent central review of response assessments using a dual-reader plus adjudicator model. It utilizes neuroradiologists trained in all three response assessment criteria as readers for the following assessments: RANO-HGG, RAPNO-LGG, and RANO-LGG. All activities of IE meet or exceed GCP standards, and IE has undergone a GCP audit by the sponsor. Prior to the initiation of the study, a prospective imaging protocol was developed for the FIREFLY-1 study. This protocol outlines the processes for initial image review, data transfer, and data review and retrieval, and is adhered to throughout the study. As the centralized imaging core laboratory, IE is responsible for the collection, quality control, archiving, and BICR of FIREFLY-1 trial images. IE is responsible for managing the implementation of image analysis systems, reporting methods, analytical standards, and reader management, including accreditation, training, and supervision.

[0335] Viewer performance is assessed by evaluating viewer variability at defined and pre-specified milestones during ongoing image interpretation. Variability metrics include inter-viewer and intra-viewer variability to monitor viewing consistency. If viewer acceptance rates exceed warning or alert limits, IE will determine appropriate unbiased action.

[0336] For this disclosure, safety was assessed in the safety analysis sets of Groups 1 and 2, which included all enrolled patients who had received at least one dose of the investigational drug. The assessment period for adverse events (AEs) began from the first dose of tovorafenib and continued until 30 days after the last dose. For this trial, an adverse event was defined as occurring during treatment if it occurred at any time between the first dose of the investigational drug and 30 days after the last dose. A treatment-related adverse event is any treatment-related event that the investigator assesses, based on its relevance to the time of treatment initiation and an assessment of other potential causes, as having a reasonable probability of at least a causal relationship with the investigational drug. An adverse event is considered a serious adverse event if it meets one of the following criteria: requiring or prolonging hospitalization, life-threatening, causing disability, or an event that the investigator considers medically significant (regardless of the symptom or Common Criteria for Adverse Events [CTCAE] grade).

[0337] Routine laboratory tests were performed locally and included pregnancy testing for women of childbearing age (during the screening period and on day 1 of each cycle), assessment of hematological parameters and serum chemistry (during the screening period, on days 1 and 15 of cycle 1, and on day 1 of cycle 2 and on day 1 of each subsequent cycle), and assessment of thyroid function (during the screening period, on day 1 of cycles 1–3, and on day 1 of every other cycle thereafter). Planned cardiac function assessments included a centrally reviewed 12-lead resting ECG (in triplicate at baseline, on days 1 and 15 of cycle 1, on day 1 of cycles 2 and 4, and on day 1 of every three cycles thereafter) and echocardiography or multi-gated acquisition scans (using the same technique throughout, on day 1 of cycles 2 and 4, and on day 1 of every three cycles thereafter). Creatine phosphokinase levels were assessed during the screening period, on day 1 of cycles 2 and 4, and on day 1 of every four cycles thereafter.

[0338] In patients aged 2 years or older, health-related quality of life assessments were performed on the patient or their parent / caregiver every three cycles using the PedsQL-Core, PedsQL-Cancer, and PROMIS® questionnaires. The PROMIS® questionnaire was administered only to English-speaking patients enrolled in the United States, Australia, and the United Kingdom.

[0339] Statistical considerations Regarding the “evaluable” population, “efficacy-evaluable” patients are all patients enrolled in this trial who received at least one dose of the trial treatment and met the pre-specified efficacy analysis criteria (RANO-HGG, RAPNO, RANO-LGG); patients in the “DOR-evaluable” population are those with evaluable efficacy and a best overall confirmed response of CR, PR, or minor response (MR; for RAPNO, RANO-LGG). The “safety” population consists of all patients enrolled in this trial who received at least one dose of the trial treatment. This disclosure presents efficacy data from the Group 1 evaluable population and safety data from Groups 1 and 2 as of the data cutoff date of June 5, 2023.

[0340] The primary endpoint analysis was performed in the evaluable population, which included all enrolled patients who had received at least one dose of toporafenib and were identified by the IRC as having measurable disease at baseline according to the RANO-HGG criteria. Assuming a true potential ORR of 40% for toporafenib in this disease population, a sample size of 60 patients in the evaluable population was considered to provide 88% power at the two-sided 0.05 level to reject the 21% null hypothesis ORR. Hypothesis testing was performed using an exact binomial test. Responses according to the RAPNO and RANO-LGG criteria were assessed in the evaluable population, which included all enrolled patients who had received at least one dose of toporafenib and were identified by the IRC as having measurable disease at baseline according to the RAPNO and RANO-LGG criteria, respectively.

[0341] In Group 1, a pre-specified subgroup analysis of ORR treatment effect consistency is planned for subgroups defined as follows: BRAF Change( BRAF Fusions and BRAF mutations), number of previous lines of treatment, previous MAPKi status (previous MEKi and / or previous BRAFi), sex, age group (6 months to <2 years, 2 to <6 years, 6 to <12 years, 12 to <16 years, 16 to ≤25 years) and race.

[0342] ORR and CBR were calculated using the Clopper-Pearson method, and their 95% CIs were determined. PFS and DOR were estimated using the Kaplan-Meier method and summarized along with their corresponding two-sided 95% CIs. A waterfall plot was generated for the optimal percentage change in the sum of the vertical diameters of measurable lesions for each patient.

[0343] Safety endpoints were analyzed using descriptive statistical analysis based on the safety populations in Groups 1 and 2. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.1 by systemic organ classification and preferred terminology, and graded according to the National Cancer Institute (NCI) CTCAE version 5.0.

[0344] Statistical analysis was performed using SAS v9.4.

[0345] Management of adverse skin events The trial protocol includes guidelines for the management of rash / dermatitis, consistent with the stepwise approach proposed by Song et al. (2019) for the prevention and treatment of common skin adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors. Dermatological assessments were performed at baseline and thereafter as directed by symptoms. Patients were referred to a dermatologist if skin symptoms impaired function (e.g., if the patient was unable to sleep or sit still) or caused psychosocial distress, and / or when management techniques failed to resolve the condition. All trial patients were advised to follow gentle skin care routines, including brief warm showers / baths, the use of a mild, fragrance-free cleanser, and the immediate application of a thick, fragrance-free moisturizer (creams are preferred over lotions) after showering. Additionally, all patients were advised to use sunscreen with an SPF of 30+ prophylactically when outdoors, reapplying every 2 hours, and to wear sun-protective clothing. Specific guidelines were also provided for the management of mild or moderate / severe follicular reactions, eczematous reactions, paronychia or periungual reactions, or hand-foot syndrome.

[0346] If grade 2 macules or papules, erythema with pruritus or other related symptoms, localized desquamation, or other lesions covering <50% of the body surface area (BSA) occur, a reduction of one dose level in tovorafenib once a week may be considered. If grade 3 or higher severe generalized erythroderma or macules, papules, or vesicular lesions, desquamation covering ≥50% of the BSA, or generalized exfoliative, ulcerative, or bullous dermatitis occurs, tovorafenib administration should be delayed until improvement is observed. A dermatologist should be consulted, and a reduction of two dose levels or discontinuation of tovorafenib administration may be considered until remission to grade 1 or baseline.

[0347] Plan modification The protocol modifications primarily aimed to add two new groups to the trial, introduce the tovorafenib reconstituted powder formulation, and incorporate other changes based on regulatory feedback. The complete trial protocol for this version (some confidential information has been edited) is available in the supplemental information supporting this document.

[0348] Version 2.0, October 23, 2020 The main modification is to reduce the recommended phase 2 dose of tovorafenib from 530 mg / m². 2 Change to 420 mg / m 2 The maximum dose was reduced from 800 mg once weekly to 600 mg. The planned number of cycles was reduced from 27 to 26 (patients may continue trial treatment thereafter if criteria are met), and the upper age limit was increased from 18 years to 25 years (inclusive).

[0349] Clinical trial registration The study is registered at clinicaltrials.gov under number NCT04775485 and at EudraCT under number #2020-003657-30.

[0350] result end The primary endpoint for Group 1 was ORR as assessed by the IRC according to RANO-HGG. Secondary endpoints for Group 1 included ORR as assessed by the IRC according to RAPNO, clinical benefit rate (CBR), progression-free survival (PFS), DOR, and time to response as assessed by the IRC according to RANO-HGG and RAPNO, and safety and tolerability as assessed by the type, frequency, and severity of adverse events (AEs) and laboratory abnormalities (the primary endpoint for Group 2). Additional planned secondary endpoints not reported in this manuscript are described in detail in the full trial protocol in the supplemental information and include pharmacokinetics, the effects of tovorafenib on the QT interval (QTcF) and other ECG parameters corrected by Fredericia, changes in visual acuity, and the consistency of molecular profiling methods. The characteristics of the three different radiological response assessment criteria used for efficacy assessment in the trial are summarized in Table 1.

[0351] Patients and Treatment Between April 22, 2021 and January 26, 2023, 137 patients were enrolled in Group 1 and Group 2 and received tovorafenib, with 77 in Group 1 and 60 in Group 2. Seven patients (9%) in Group 1 and 21 patients (35%) in Group 2 received tovorafenib as a liquid formulation; all other patients received the tablet formulation. As of the data cutoff date, 102 patients were still under treatment. Figure 1 The most common reasons for discontinuing treatment were progressive disease (PD) and adverse events (AEs). Patient demographics and baseline characteristics are summarized in Table 1, and were similar across groups. Of the 137 patients, the median age was 9 years (range 1–24 years), the majority were white (58%), and the majority had astrocytomas (93%). The most common tumor locations were the visual pathway (50%) and deep midline structures (15%). 74% of patients had hepatitis B carriers. KIAA1549 :: BRAF Fusion tumors, 10% of patients have involved BRAF Chromosomal rearrangements (detected by fluorescence in situ hybridization or in situ hybridization, and assumed to represent) KIAA1549 :: BRAF or others BRAF (fusion), and 16% of patients had BRAF V600E mutations. Patients had received a median of three lines of prior therapy (range 1-10), of which 61% had previously received MEK and / or BRAF inhibitors.

[0352] The IRC considered that 69 patients in Group 1 who received ≥1 dose of tovorafenib had measurable disease at baseline according to RANO-HGG. The IRC considered that 76 patients in Group 1 had evaluable efficacy based on RAPNO and RANO-LGG (which assesses response using T2-weighted imaging). All patients in Groups 1 and 2 who received ≥1 dose of tovorafenib ( n A security analysis was performed on (=137).

[0353] Patients in Group 1 received a median of 18 treatment cycles (range 1–26), with a median treatment adherence of 100% (range 93–100) (treatment adherence [%] = actual total dose [mg] / expected total dose [mg] × 100%). The median duration of treatment (DOT) was 15.8 months (range 0.7–23.7), of which 66% ( n =51) Continued treatment. Both patients completed 26 treatment cycles and opted into a medication break. Neither patient underwent subsequent imaging examinations after starting their medication break. As of the data cutoff date of June 5, 2023, all other patients (excluding those who discontinued medication early) were still on treatment. Patients in Group 2 had received a median of 11 treatment cycles (range 2–15), with a median treatment adherence of 100% (range 83–100). The median DOT was 9.7 months (range 1.2–13.3), with 85% ( n =51) Continue treatment. During treatment with tovorafenib, the Karnofsky or Lansky performance status score did not decline from baseline.

[0354] RANO-HGG (primary and secondary endpoints) In patients with evaluable disease, the ORR (primary endpoint) according to RANO-HGG was 67% (95% CI 54-78), including 12 (17%) patients with complete response (CR) and 34 (49%) patients with partial response (PR). The best overall response (BOR) was in stable disease (SD) in eighteen (26%) patients, resulting in a CBR of 93% (Table 2). BRAF In patients with fused tumors, the ORR was 69% (95% CI 56–81); and in patients with tumors carrying the BRAF V600E mutation, the ORR was 50% (95% CI 19–81). In 59% of evaluable patients who had previously received a MAPK inhibitor (MAPKi) treatment, the ORR was 71% (95% CI 54–84), and in patients who had not previously received a MAPK inhibitor treatment, the ORR was 61% (95% CI 41–78).

[0355] Figure 2A It showed the best tumor response relative to baseline, and Figure 2A The DOT and reaction time are displayed. At 13% ( n In patients with PR (=9), CR (complete remission) occurred with continued treatment following initial PR. The median time to initial response (PR or CR) was 3.0 months (range 2.6–16.6), and the median duration of response (DOR) was 16.6 months (95% CI 11.6 – not reached [NR]). The median progression-free survival (PFS) was 19.4 months (95% CI 16.9 – NR). Among patients who progressed during treatment according to RANO-HGG and continued to receive tovorafenib, 10 patients underwent at least one evaluation at a planned follow-up visit after PD. Tumor dynamics in these patients are as described in the extended data. Figure 1 As shown in figure a, the tumors of six of these patients shrank to near complete remission (CR).

[0356] RAPNO (Secondary endpoint) According to RAPNO, the ORR was 51% (95% CI, 40–63), including 28 patients (37%; 95% CI 26–49) with PR (≥50% reduction from baseline by sum of vertical diameter products [SPPD]) and 11 patients (14%; 95% CI 8–24) with mild response (MR; 25–49% reduction from baseline by SPPD). Twenty-three (30%) patients had a BOR of SD, resulting in a CBR of 82%. BRAF ORR was similar in patients with fused tumors (52%; 95% CI 39–64) and patients with tumors carrying the BRAF V600E mutation (50%; 95% CI 21–79), as well as in patients who had previously received MAPKi treatment (49%; 95% CI 34–64) and patients who had not previously received MAPKi treatment (55%; 95% CI 36–73) (Table 2).

[0357] Table 2. Patient responses in Group 1 according to radiological criteria a ORR, CBR, and BOR for RAPNO and RANO-LGG include MR (i.e., ORR = CR + PR + MR; CBR = CR + PR + MR + SD [calculated based on SD of any duration, SD ≥ 6 months, and SD ≥ 12 months]). For CR, PR, and MR, the reaction needs to be confirmed by a subsequent scan approximately 3 months after the initial reaction. b 95% CI was calculated using the Kaplan-Meier method.c Subgroup analyses of ORR based on RAPNO-based IRC assessment were performed (sex, age group, race, geographic location [US / outside the US]). Although small patient numbers in some subgroups limited the interpretation of these data, responses were observed in all subgroups, and no significant ORR trend was observed (Extended Data, Figure 3). BRAF Patients with duplicates or rearrangements are considered to be in BRAF Fusion group. BOR, best overall response; CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DOR, duration of response; HGG, high-grade glioma; LGG, low-grade glioma; MAPKi, mitogen-activated protein kinase inhibitor; MR, mild response; n / a, not applicable; NR, not achieved; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; RANO, neuro-oncology response assessment; RAPNO, pediatric neuro-oncology response assessment; SD, stable disease; TTR, time to response.

[0358] Figure 2B The best tumor response relative to baseline was shown, with most tumors showing some degree of shrinkage. Figure 3B The DOT and reaction time are displayed. At 29% ( n In patients with BRAF V600E mutations (=22), confirmed partial responses (PRs) occurred with continued treatment following the initial MR. Overall, the median time to initial response (MR or PR) was 5.3 months (range 1.6–11.2), 2.8 months (range 1.6–3.0) in patients with tumors carrying the BRAF V600E mutation, and... BRAF The median duration of response (DOR) was 5.5 months (range 2.3–11.2) in patients with fused tumors. The median DOR was 13.8 months (95% CI 11.3–NR), and the median progression-free survival (PFS) was 13.8 months (95% CI 8.3–16.9) in 76 patients.

[0359] According to IRC assessment, 31 patients initially had disease progression (PD) based on RAPNO, but continued tovorafenib treatment because the investigator determined there was no PD based on RANO-HGG, consistent with the trial design and primary endpoint assessment. Except for two patients, all patients were asymptomatic or without signs of clinical progression. A graph of tumor size (SPPD) over time in several of these patients shows subsequent tumor shrinkage after the initial PD assessment (extended data). Figure 1 b).

[0360] RANO-LGG (Post-hoc exploratory endpoint) The ORR based on RANO-LGG was 53% (95% CI 41–64), including 20 patients (26%; 95% CI 17–38) with PR and 20 patients (26%; 95% CI 17–38) with MR. Twenty-three (30%) patients had a BOR of SD, resulting in a CBR of 83%. BRAF ORR was similar in patients with fusion and BRAF V600E-mutant tumors as well as in patients previously treated with MAPKi or those who had not previously treated with MAPKi (Table 2).

[0361] Figure 2C This showed the best tumor response relative to baseline, and most tumors also showed some reduction in size. In 18% ( n In patients with BRAF V600E mutations (=14), confirmed partial responses (PRs) occurred with continued treatment following the initial MR. Overall, the median time to initial response (MR or PR) was 5.5 months (range 1.6–11.3), and 2.9 months (range 1.6–11.3) in patients with tumors carrying the BRAF V600E mutation, and in patients with tumors carrying the BRAF V600E mutation. BRAF The median duration of response (DOR) was 5.5 months (range 2.3–11.0) in patients with fused tumors. The median DOR was 14.4 months (95% CI 11.0–NR), and the median PFS was 13.9 months (95% CI 11.1–19.1).

[0362] Similar to the RAPNO analysis, there exists a subset of patients who, according to IRC assessment, initially had disease progression (PD) based on RANO-LGG but continued treatment because they did not have PD based on RANO-HGG. A plot of tumor size (SPPD) over time in several of these patients shows the pattern of subsequent tumor shrinkage following the initial PD assessment.

[0363] Response of patients with progressive disease to tovorafenib during treatment with MAPKi as their most recent prior therapy (Post-hoc analysis) Post-hoc analyses were performed using all three radiological criteria to assess the response to tovorafenib in patients who received MAPKi as their most recent first-line therapy and discontinued treatment due to progression. For RANO-HGG, 33% (n=15) of patients who progressed with MAPKi as their most recent prior therapy achieved CR or PR with tovorafenib; similar trends were observed for RAPNO and RANO-LGG (which included MR as an endpoint): 33% (n=13) achieved PR or MR (31% [n=12] achieved PR) and 30% (n=12) achieved PR or MR (20% [n=8] achieved PR) respectively (Extended Data Table 2).

[0364] Security Of the 137 patients (Groups 1 and 2), 118 (86%) had been treated for at least 6 months and 67 (49%) for at least 1 year. All patients experienced at least one treatment-related adverse event (TEAE). The most common TEAEs of any grade occurring in ≥20% of patients were discoloration (76%), anemia (59%), and elevated creatine phosphokinase (CPK) (58%) (Table 3). 63% of patients experienced ≥3 grade TEAEs, the most common being elevated CPK (12%), anemia (11%), and maculopapular rash (8%). The most common treatment-related adverse events (TRAEs) of any grade generally followed similar trends to the most common TEAEs. ≥3 grade TRAEs occurred in 42% of patients and followed similar trends to the most common ≥3 grade TEAEs, although fever was less frequently assessed as a related event. Two patients had grade 5 / fatal TEAEs, neither of which were assessed as treatment-related (one patient in group 1 had disease progression, and one patient in group 2 with disseminated leptomeningeal mixed glioma-neuronal tumor experienced tumor hemorrhage 21 days after the last dose of tovorafenib (treatment was discontinued due to disease progression).

[0365] Table 3. Adverse events occurring during treatment and treatment-related adverse events (safety analysis set, n =137) TEAE, TRAE, and laboratory abnormalities occurred in ≥20% of patients, and all ≥3 grade TRAEs occurred in ≥1 patient. TEAE, TRAE, and laboratory abnormalities: each event was counted only once per patient and shown as the worst CTCAE grade reported for each event experienced by the patient. MedDRA version 23.1; CTCAE version 5.0. AE, Adverse Event; ALT, Alanine Aminotransferase; APTT, Activated Partial Thromboplastin Time; AST, Aspartate Aminotransferase; COVID-19, Coronavirus Disease 2019; CPK, Creatine Phosphokinase; CSF, Cerebrospinal Fluid; CTCAE, Common Terminology Standard for Adverse Events; LDH, Lactate Dehydrogenase; MedDRA, Dictionary of Regulatory Activities in Medicine; RTI, Respiratory Tract Infection; TEAE, Treatment-Induced Adverse Event; TRAE, Treatment-Related Adverse Event; WBC, White Blood Cells.

[0366] Reduced growth rate was observed in patients treated with tovorafenib. At cycle 13 (n=74), the median height z-score decreased to 0.7, or less than one standard deviation. 80% of these patients maintained a height z-score within one standard deviation of baseline. The remaining patients experienced a decrease of 1 to 2 standard deviations relative to baseline. At the time of this report, treatment-intervention bone age results were available for 11 patients. Nine of the 11 patients were reported to be within the normal age range, one patient was interpreted as delayed, and one patient with a 3.5-year advanced bone age before treatment initiation had a 2.5-year advanced bone age reported during treatment. To date, there is no evidence of advanced bone age or premature growth plate closure. In patients with available height data after treatment cessation, growth rate is recovering.

[0367] 45% of patients reported serious TEAEs, the most common being fever (most cases were confused with concurrent infectious diseases), seizures, and vomiting (5% each). 15% of patients experienced serious TAEs, the most common being tumor hemorrhage (3%), decreased appetite, hyponatremia, and vomiting (2% each). Two of the four patients with serious tumor hemorrhage TAEs had a history of intratumoral hemorrhage prior to initiation of tovorafenib, and in all four patients, the serious tumor hemorrhage event had resolved.

[0368] Nine patients (7%) experienced a TAE leading to tovorafenib discontinuation, most commonly tumor bleeding (three patients) and decreased growth rate (two patients). Dose-reduction-leading TAEs were observed in 33 patients (24%), most commonly maculopapular rash (4%) and decreased appetite (3%). Dosage-discontinuing TAEs occurred in 50 patients (37%), most commonly maculopapular rash (9%), vomiting, fatigue, elevated alanine aminotransferase (ALT), and elevated CPK (4% each). The median duration of dosing discontinuation due to any TAE was 14 days or two doses.

[0369] Example 2. Experimental Design and Results of Visual Pathway Gliomas (OPG) Sporadic optic pathway gliomas (OPGs) are usually caused by factors affecting the visual pathway. BRAF Oncogenic genomic alterations (including) KIAA1549:: BRAF Driven by fusion and BRAF V600E point mutation. The ongoing Phase 2 FIREFLY-1 (PNOC026; NCT04775485) trial is evaluating the investigational, oral, selective, CNS-penetrating type II RAF inhibitor tovorafenib in patients with RAFEfficacy and safety of tovorafenib monotherapy in patients with relapsed / refractory pLGG or advanced solid tumors. As assessed by an independent radiology review committee (IRC) according to the Neuro-oncology Response Assessment - High Grade Glioma (RANO-HGG), Pediatric Neuro-oncology Response Assessment - LGG (RAPNO), and RANO-LGG criteria, tovorafenib monotherapy in patients with... BRAF Rapid and durable tumor responses were achieved in children and young adults with altered pLGG. OPG was the largest tumor location subgroup in the FIREFLY-1 trial's registry, representing an important population of patients with sporadic relapsed / refractory pLGG. The efficacy of tovorafenib in the OPG subgroup of FIREFLY-1 group 1 was analyzed, focusing on radiological and visual acuity (VA) outcomes, and the incidence of adverse events (AEs) in this subgroup was analyzed, along with the trial safety analysis set of 137 patients with pLGG and ophthalmic adverse events (AESIs) of particular interest in the group 1 OPG subgroup. Group 1 of the trial enrolled patients with carriers of activated pLGG. BRAF Alterations (including BRAF V600E mutations and) KIAA1549 :: BRAF Patients with relapsed or refractory pLGG (fusion-related) were included in the trial. Group 2 was an expanded pLGG cohort, which included patients with pLGG after Group 1 was closed. RAF The modified pLGG provided treatment accessibility for patients. Both groups 1 and 2 were fully enrolled. In the primary registry analysis, efficacy was assessed in the 77 patients enrolled in group 1, and safety was assessed in all 137 treated patients in groups 1 and 2.

[0370] During a 28-day cycle, the recommended Phase 2 dose of 420 mg / m² was administered. 2 Tovorafenib is administered orally (tablets or liquid formulation) once weekly (not exceeding 600 mg). Treatment continues until radiographic evidence of disease progression as determined by the treatment investigator according to RANO-HGG criteria, unacceptable toxicity, decision to enter a pharmacological leave, withdrawal of informed consent by the patient, or death. Patients with disease progression are permitted to continue tovorafenib treatment if they are deemed to have received clinical benefit from continued trial treatment. Patients undergo a planned 26-cycle course of treatment, after which they may continue receiving tovorafenib or choose to enter a pharmacological leave at any point in time. During this pharmacological leave, if radiographic disease progression occurs, the patient may be re-treated with tovorafenib.

[0371] The trial was approved by the institutional review committee / independent ethics committee at each trial center. The trial was conducted in accordance with current ethical principles and trial standards. In accordance with local regulations, all patients and / or their legal authorized representatives provided written informed consent and pediatric consent prior to enrollment in this trial.

[0372] test endpoint Response assessment in the primary and current subgroup analyses was performed using three different radiological response assessment criteria: RANO-HGG (primarily based on T1-weighted contrast-enhanced imaging to assess tumor response), and RAPNO16 and RANO-LGG (both primarily based on non-enhanced disease measured via T2 / fluid-attenuated inversion recovery (FLAIR) sequences to assess tumor response). Patients were enrolled based on measurable disease assessed by the investigator according to RANO-HGG. Investigator response assessments based on RANO-HGG were also the criteria upon which treatment was discontinued due to progressive disease. Responses were subsequently analyzed according to all three radiological assessment criteria through blinded, independent central review.

[0373] The primary endpoint for Group 1 was the objective response rate (ORR) assessed by an independent radiology review committee (IRC) according to the RANO-HGG criteria. Secondary endpoints included ORR assessed by the IRC according to the RAPNO criteria, and clinical benefit rate (CBR), progression-free survival, duration of response (DOR), and time to response (TTR) assessed by the IRC using both the RANO-HGG and RAPNO criteria. Post-hoc exploratory endpoints for Group 1, which were added to the statistical analysis plan prior to the primary analysis at the request of regulatory authorities, included ORR and CBR assessed by the IRC according to the RANO-HGG criteria.

[0374] Evaluate Diseases in Group 1 were assessed by MRI of the brain and spine during the screening period (up to 28 days before the first dose) and at the end of every three cycles thereafter. Safety assessments have been previously described. AEs considered to be of particular interest (AESIs) included rhabdomyolysis / myopathy, ventricular arrhythmias, intratumoral hemorrhage, a second primary malignancy, ophthalmic events, and decreased growth rate. The sponsor’s senior safety physician further reviewed and adjudicated their clinical relevance and assessed their clinical relevance to the anticipated events of interest. This report presents ophthalmic AESIs that were adjudicated as positive. Patients with OPG or potential visual impairment associated with their tumor underwent ophthalmic examinations at baseline, at each imaging disease assessment, and at the end of treatment. These examinations were performed by an ophthalmologist or other qualified central clinical personnel and included: slit-lamp examination, particularly for corneal / lens abnormalities; fundus examination and commentary on retinal abnormalities; visual fields to-confrontation; optic disc appearance; and best-corrected visual field (BCVA) as assessed according to local institutional practice.

[0375] Functional VA assessment is age-specific and includes the use of Teller Acuity Cards. ® (All patients), HOTV, or other early treatment study visual acuity charts for diabetic retinopathy (in patients who are developmentally capable of performing them). Assess each eye separately at the recommended testing distance of 3 meters (or according to local standard practice). If BCVA data obtained at a particular visit is deemed unreliable due to poor cooperation, repeat the test after 1 to 2 weeks, and report only the visit deemed to produce the most reliable data. To reduce scoring variability, the same BCVA testing method should be used throughout treatment. BCVA is reported as a log-log minimum resolving angle (logMAR) score, where 0 represents normal visual acuity, and a positive value indicates reduced VA.

[0376] VA response was defined based on the outcome of the best-responding eye: i.e., if data were available for both eyes, the determination of response and progression was based on the best-responding eye. The VA status of this eye was used to determine the logMAR range group at baseline. If the response outcomes were identical in both eyes, the baseline logMAR was used to define the best-responding eye. A confirmed VA response was defined as a reduction of at least 0.2 logMAR relative to baseline over two consecutive visits (i.e., every 3 cycles / interval of approximately 12 weeks). Confirmed VA progression was defined as an increase of at least 0.2 logMAR relative to baseline over two consecutive assessments. If the criteria for VA response or VA progression were not met, VA was considered stable. To assess the degree of clinical-radiological correlation between different response assessment criteria, the consistency between the best-responding eye VA and radiological outcomes from the start of tovorafenib treatment to the last follow-up was analyzed. Complete consistency indicated that the VA and radiological assessment results were consistent; partial consistency indicated that one parameter improved (positive) or worsened (negative) while the other parameter remained stable; complete inconsistency indicated conflicting results.

[0377] Statistical considerations In this post-hoc subgroup analysis, efficacy was analyzed in all patients in Group 1 whose tumors were classified as having visual pathway involvement. The evaluable population for efficacy was the same as described previously for the primary analysis. Waterfall plots were generated for the best variation in the sum of measurable vertical diameters of lesions for each patient. Duration of response was estimated using the Kaplan-Meier method. Responseing patients who did not experience progression at the data cutoff date were censored on the date of their last adequate radiographic disease assessment. Safety assessments were based on the safety populations in Groups 1 and 2, as well as the OPG subgroup in Group 1. Statistical analysis was performed using SAS v9.4. The analysis was based on the data cutoff date of June 5, 2023.

[0378] Patients and Treatment Between April 22, 2021 and January 26, 2023, 42 patients with optic pathway tumors were enrolled in Group 1. Their demographic and baseline characteristics are summarized in Table 4. The median age of the patients was 8 years (range 2–16 years); the majority of patients were male and white (57% each). 81% of the patients had tumors with KIAA1549::BRAF Fusion, 7% of patients have involved BRAF Chromosomal rearrangements (detected by fluorescence in situ hybridization and assumed to represent) KIAA1549 :: BRAF or others BRAF (Fusion), and 12% of patients had BRAF V600E mutations. Patients had a median of 3 lines of prior therapy (range 1–9), and 69% had received prior MEK and / or BRAF inhibitors. VA data for six of the 42 patients were not included in this analysis: four patients did not undergo VA assessment due to bilateral blindness, one patient did not undergo baseline visual acuity assessment, and one patient did not undergo post-baseline assessment. Of the remaining 36 patients, 8 (22%) had a baseline VA of normal (-0.1 to 0.15) in the best eye, 15 (42%) had mild impairment (0.2 to 0.5), 7 (19%) had moderate impairment (0.6 to 0.9), and 3 (8%) each had severe impairment (1.0 to 1.4) or very severe impairment (>1.4) (logMAR range). The median duration of tovorafenib treatment in the OPG subgroup was 69% of patients (29 / 42) who were still on treatment at the data cutoff date.

[0379] Table 4. Patient and baseline characteristics Imaging results The IRC considered that 39 of the 42 patients in this analysis had measurable disease at baseline according to the RANO-HGG criteria and were therefore evaluable for response. All 42 patients had measurable disease according to both the RAPNO and RANO-LGG criteria. According to the contrast-enhanced RANO-HGG criteria, the ORR and CBR (for stable disease of any duration) were 64% and 95%, respectively (Table 5). According to the two T2 / FLAIR-based RAPNO and RANO-LGG criteria, the ORR (50% and 55%) and CBR (88% and 90%) were nearly similar. The waterfall plot of the best tumor response showed that most tumors showed some degree of shrinkage according to both the T1-weighted contrast-enhanced (RANO-HGG) criteria and the T2 / FLAIR-based (RAPNO and RANO-LGG) criteria. Figures 5A-5CTumor shrinkage occurred in OPGs carrying BRAF fusions and BRAF V600E mutations, as well as in patients who had previously received mitogen-activated protein kinase inhibitor (MAPKi) therapy and those who had not.

[0380] Table 5. Responses according to radiological assessment criteria and the correlation between visual response and radiological response. Treatment duration and response time based on RAPNO and RANO-LGG criteria, such as Figure 6 As shown. In 11 (26%) patients, a confirmed partial response followed by continued treatment occurred after an initial mild response according to the RAPNO criteria. Similarly, according to the RANO-LGG criteria, a confirmed partial response followed by continued treatment occurred in 6 (14%) patients after an initial mild response. Initial responses tended to be rapid, with a median TTR of 5.5 months according to each of the three assessment criteria (Table 5). Responses tended to be durable, with median DORs of 16.8 months (95% CI 9.0 - not reached [NR]), 13.8 months (95% CI 11.3 - NR), and 14.4 months (95% CI 5.8 - NR) according to RANO-HGG, RAPNO, and RANO-LGG, respectively.

[0381] Visual acuity results Of the 36 OPG patients with baseline and at least one other time point data for VA response, 14 (39%) showed the best ocular VA improvement, 19 (53%) remained stable (i.e., no improvement or worsening), and 3 (8%) worsened (Table 6). Therefore, during treatment with tovorafenib, VA was preserved (i.e., improved or stabilized) in 92% of patients. Figure 7A A waterfall plot showing the optimal changes in VA in the best eye. The proportion of patients with VA retention among those with carriers... BRAF Patient subgroups with OPG fusions and BRAF V600E mutations, patients who had previously received MAPKi therapy and those who had not, and patients who had received ≤3 lines of prior systemic therapy and those who had received >3 lines of prior systemic therapy were similar (Table 6). VA response analysis based on baseline VA showed a consistent pattern of visual preservation in most patients across all subgroups. VA improvement was observed in ≥43% of patients in each subgroup, with no significant correlation to baseline VA (Table 7). Interquartile groups of 36 patients with VA response data (baseline and assessment at at least one other time point) based on time since initial diagnosis showed visual preservation in all quartiles (Table 8).

[0382] Table 6. Visual response during treatment based on baseline characteristics (n=36) a Table 7. Optimal visual acuity response based on baseline visual acuity (n=36) a Table 8. Quartile visual acuity response (best eye) over time since initial diagnosis (n=36) a Visual response-radiological response correlation The agreement between VA and radiological results was generally similar across different response criteria (Table 5). For RANO-HGG, the complete agreement and partial agreement rates were 45% and 48%, respectively, with only two cases of complete disagreement. For RAPNO, the complete agreement and partial agreement rates were 42% and 58%, respectively, with no cases of complete disagreement. For RANO-LGG, the complete agreement and partial agreement rates were 37% and 60%, respectively, with one case of complete disagreement.

[0383] Table 9 shows the visual acuity (VA) response based on the best overall response according to different radiological assessment criteria. Among patients with a radiological response to tovorafenib, visual acuity improved in 38% of patients according to RANO-HGG, 53% according to RAPNO, and 33% according to RANO-LGG. Visual acuity also improved in 40%, 36%, and 50% of patients with a best overall response of stable disease, according to RANO-HGG, RAPNO, and RANO-LGG, respectively. Figure 7B The Sankey plot shows the VA results for patients with confirmed mild responses according to the RAPNO and RANO-LGG criteria. In all these patients, VA improved or remained stable relative to baseline category by the end of treatment / data cutoff date, regardless of the response criteria. Security Table 10 lists the most common treatment-related adverse events (TEAEs; occurring in ≥20% of patients) and treatment-related adverse events (TRAEs) of grade ≥3 occurring in at least one patient. The trends for TEAEs and TRAEs in the Group 1 OPG subgroup are similar to those reported for all patients in Groups 1 and 2 (safety population).

[0384] Table 10. Adverse events during treatment and treatment-related adverse events (Group 1 OPG subgroup safety analysis set, n=42) Four patients (10%) had treatment-related adverse events (TEAEs) leading to discontinuation, including autoimmune hemolytic anemia, decreased growth rate, tumor hemorrhage, and premature ventricular contractions (one patient each). Autoimmune hemolytic anemia was considered unrelated to tovorafenib, while the other three events were considered treatment-related adverse events (TRAEs). Fifteen patients (36%) had TRAEs leading to dose reduction; the most common was decreased appetite (two patients [5%]). Fifteen patients (36%) had TRAEs leading to dose interruption; the most common were elevated aspartate aminotransferase, maculopapular rash, and vomiting (two patients each [5%]).

[0385] The incidence of ophthalmic AESIs was also assessed in the FIREFLY-1 safety population and the OPG subgroup 1 based on the MedDRA systemic organ classification for “ocular disorders” (excluding the selected high-level group terms “congenital ocular disorders (excluding glaucoma)”, “ocular neuromuscular disorders”, and “ocular tumors”). Eight of the 137 patients (6%) in the overall safety population had ophthalmic AESIs that were ruled positive (all grade 1–2), detailed in Supplementary Table S5, the most common of which was color vision deficiency (color perception deficit), experienced by three patients (2%). No uveitis events were reported, and no events involving the retina were reported. Three of the 42 patients (7%) in the OPG subgroup developed AESIs, including two patients (5%) with color vision deficiency (Table 11).

[0386] Table 11. Ophthalmic AESIs Determined Positive in the Safety Population Example 3 The methods disclosed herein are further described in the clinical protocol of DAY101-001.

[0387] Example 4 The methods disclosed herein are further described in the clinical study-statistical analysis plan of DAY101-001.

Claims

1. A method for treating recurrent or refractory pediatric low-grade glioma (pLGG) in a subject of need, the method comprising administering tovorafenib or a salt thereof to the subject. The pediatric low-grade gliomas (pLGG) described herein carry BRAF fusions or rearrangements or BRAF V600 mutations. The age of the subject is 6 months or older; and in, (i) When the object has a diameter of 0.30-0.35 m 2 When the body surface area (BSA) is reached, the tovolafenib or its salt is administered once weekly at a starting dose of about 125 mg, and if the subject is not tolerant to the starting dose, the tovolafenib or its salt is administered once weekly at a reduced dose of about 100 mg, and if the subject is not tolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of about 75 mg. (ii) When the object has a diameter of 0.36-0.42 m 2 When the body surface area (BSA) is reached, the tovolafenib or its salt is administered once weekly at an initial dose of about 150 mg, and if the subject is not tolerant to the initial dose, the tovolafenib or its salt is administered once weekly at a reduced dose of about 125 mg, and if the subject is not tolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of about 100 mg. (iii) When the object has a diameter of 0.43-0.48 m 2 When the body surface area (BSA) is [value], the tovolafenib or its salt is administered once weekly at an initial dose of about 175 mg, and if the subject is not tolerant to the initial dose, the tovolafenib or its salt is administered once weekly at a reduced dose of about 150 mg, and if the subject is not tolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of about 125 mg. (iv) When the object has a diameter of 0.49-0.54 m 2 When the body surface area (BSA) is [value], the tovolafenib or its salt is administered once weekly at an initial dose of about 200 mg, and if the subject is not tolerant to the initial dose, the tovolafenib or its salt is administered once weekly at a reduced dose of about 175 mg, and if the subject is not tolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of about 150 mg. (v) When the object has a diameter of 0.55-0.63 m 2 When the body surface area (BSA) is [value], the tovolafenib or its salt is administered once weekly at a starting dose of about 225 mg, and if the subject is not tolerant to the starting dose, the tovolafenib or its salt is administered once weekly at a reduced dose of about 200 mg, and if the subject is not tolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of about 150 mg. (vi) When the object has a diameter of 0.64-0.77 m 2 When the body surface area (BSA) is [value], the tovorafenib or its salt is administered once weekly at an initial dose of about 275 mg, and if the subject is not tolerant to the initial dose, the tovorafenib or its salt is administered once weekly at a reduced dose of about 225 mg, and if the subject is not tolerant to the reduced dose, the tovorafenib or its salt is administered once weekly at a further reduced dose of about 200 mg. (vii) When the object has a diameter of 0.78-0.83 m 2 When the body surface area (BSA) is reached, the tovolafenib or its salt is administered once weekly at an initial dose of about 300 mg, and if the subject is not tolerant to the initial dose, the tovolafenib or its salt is administered once weekly at a reduced dose of about 250 mg, and if the subject is not tolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of about 200 mg. (ⅷ) When the object has 0.84-0.89 m 2 When the body surface area (BSA) is [value], the tovolafenib or its salt is administered once weekly at an initial dose of about 350 mg, and if the subject is not tolerant to the initial dose, the tovolafenib or its salt is administered once weekly at a reduced dose of about 300 mg, and if the subject is not tolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of about 250 mg. (ix) When the object has a diameter of 0.90-1.05 m 2 When the body surface area (BSA) is [value], the tovolafenib or its salt is administered once weekly at an initial dose of approximately 375 mg, and if the subject is intolerant to the initial dose, the tovolafenib or its salt is administered once weekly at a reduced dose of approximately 325 mg, and if the subject is intolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of approximately 275 mg. (x) When the object has a diameter of 1.06-1.25 m 2 When the body surface area (BSA) is [value], the tovorafenib or its salt is administered once weekly at an initial dose of about 450 mg, and if the subject is intolerant to the initial dose, the tovorafenib or its salt is administered once weekly at a reduced dose of about 375 mg, and if the subject is intolerant to the reduced dose, the tovorafenib or its salt is administered once weekly at a further reduced dose of about 325 mg. (xi) When the object has 1.26-1.39 m 2 When the body surface area (BSA) is [value], the tovolafenib or its salt is administered once weekly at a starting dose of about 525 mg, and if the subject is not tolerant to the starting dose, the tovolafenib or its salt is administered once weekly at a reduced dose of about 450 mg, and if the subject is not tolerant to the reduced dose, the tovolafenib or its salt is administered once weekly at a further reduced dose of about 375 mg. or (xii) When the object has ≥1.40 m 2 When the body surface area (BSA) is [value missing], the tovorafenib or its salt is administered once weekly at an initial dose of approximately 600 mg, and if the subject is intolerant to the initial dose, the tovorafenib or its salt is administered once weekly at a reduced dose of approximately 500 mg, and if the subject is intolerant to the reduced dose, the tovorafenib or its salt is administered once weekly at a further reduced dose of approximately 400 mg.

2. A method for treating recurrent or refractory pediatric low-grade glioma (pLGG) in a subject of need, the method comprising orally administering tovorafenib or a salt thereof to the subject. The pediatric low-grade gliomas (pLGG) described herein carry BRAF fusions or rearrangements or BRAF V600 mutations. The age of the subject is 6 months or older; and in, (i) When the object has a diameter of 0.30-0.35 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 125 mg once a week or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 100 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 75 mg of tovorafenib once a week; (ii) When the object has a diameter of 0.36-0.42 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 150 mg once a week or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 125 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 100 mg of tovorafenib once a week; (iii) When the object has a diameter of 0.43-0.48 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 175 mg once a week or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 150 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 125 mg of tovorafenib once a week; (iv) When the object has a diameter of 0.49-0.54 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 200 mg once a week or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 175 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 150 mg of tovorafenib once a week; (v) When the object has a diameter of 0.55-0.63 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 225 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 200 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 150 mg of tovorafenib once a week; (vi) When the object has a diameter of 0.64-0.77 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 275 mg once a week or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 225 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 200 mg of tovorafenib once a week; (vii) When the object has a diameter of 0.78-0.83 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 300 mg once a week or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 250 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 200 mg of tovorafenib once a week; (ⅷ) When the object has 0.84-0.89 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 350 mg once a week or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 300 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 250 mg of tovorafenib once a week; (ix) When the object has a diameter of 0.90-1.05 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 375-400 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 325 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 275 mg of tovorafenib once a week; (x) When the object has a diameter of 1.06-1.25 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 400-500 mg (e.g., 450 mg) once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 375-400 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 325 mg of tovorafenib once a week; (xi) When the object has 1.26-1.39 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose is equivalent to approximately 500-525 mg once weekly or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 400-450 mg of tovorafenib once weekly, and The further reduced dose mentioned above is equivalent to approximately 375 mg of tovorafenib once weekly; and (xii) When the object has ≥1.40 m 2 When determining the body surface area (BSA) of the subject, the method includes administering an initial dose of tovorafenib or a salt thereof and a reduced dose of tovorafenib or a salt thereof to the subject, and wherein the method optionally includes administering a further reduced dose of tovorafenib or a salt thereof to the subject. The starting dose mentioned above is equivalent to approximately 600 mg once a week or approximately 380 mg / m². 2 Tovorafeni once a week, The reduced dose is equivalent to approximately 500 mg of tovorafenib once a week.

3. The further reduced dose is equivalent to approximately 400 mg of tovorafenib once weekly. The method according to claim 1 or 2, wherein the tovorafenib or a salt thereof is tovorafenib.

4. The method according to any one of claims 1 to 3, wherein the tovorafenib or its salt is administered as an oral liquid suspension.

5. The method according to any one of claims 1 to 3, wherein when the dose is less than 400 mg, the tovorafenib or its salt is administered as an oral liquid suspension.

6. The method according to any one of claims 1 to 3, wherein the tovorafenib or its salt is administered as a solid dosage form such as a tablet.

7. The method according to any one of claims 1 to 3, wherein when the dose is 400 mg or more, the tovorafenib or its salt is administered as a solid dosage form such as a tablet.

8. The method according to any one of claims 1 to 7, wherein the tovorafenib or a salt thereof is administered to the subject once a week in an amount not exceeding about 600 mg.

9. The method according to any one of claims 1 to 8, wherein the method comprises selecting a subject suffering from PLGG carrying a BRAF fusion or rearrangement or a BRAF V600 mutation.

10. The method according to any one of claims 1 to 9, wherein the subject has previously received MAP kinase inhibitor treatment.

11. A method for treating pediatric low-grade glioma (pLGG) in a subject of need, the method comprising selecting a subject who has previously received MAP kinase inhibitor therapy and administering a type II pan-RAF inhibitor to the subject.

12. The method of claim 10 or 11, wherein the subject does not experience progression of pLGG while receiving treatment with the MAP kinase inhibitor.

13. The method of claim 10 or 11, wherein the subject has radiographic progression of the pLGG while receiving treatment with the MAP kinase inhibitor.

14. The method according to any one of claims 10 to 13, wherein the subject has relapsed / refractory pLGG after treatment with a MAP kinase inhibitor.

15. The method according to any one of claims 10 to 14, wherein the MAP kinase inhibitor treatment is the most recent treatment administered to the subject.

16. The method according to any one of claims 10 to 14, wherein the MAP kinase inhibitor treatment is not a recent treatment administered to the subject.

17. The method of claim 16, wherein the most recent treatment applied to the subject is selected from chemotherapy, radiotherapy, and surgery.

18. The method of any one of claims 1 to 17, wherein the subject has previously received one or more additional therapeutic treatments, including chemotherapy, radiation therapy, and surgery.

19. The method according to any one of claims 11 to 18, wherein the type II panRAF inhibitor is tovorafenib or a salt thereof.

20. The method according to any one of claims 10 to 19, wherein the MAP kinase inhibitor treatment comprises trametinib or a salt thereof.

21. A method for treating pediatric low-grade glioma (pLGG) in a subject of need, the method comprising administering a type II pan-RAF inhibitor to the subject for 2 months or longer, wherein the pLGG shows radiographic progression after the initial month of administration.

22. The method of claim 21, wherein the pLGG shows radiographic progress two months after application.

23. The method according to claim 21 or 22, wherein the type II pan-RAF inhibitor is administered to the subject for 3 months or longer, 4 months or longer, or 5 months or longer.

24. The method according to any one of claims 21 to 23, wherein the type II panRAF inhibitor is tovorafenib or a salt thereof.

25. A method for treating recurrent or refractory pediatric low-grade glioma (pLGG) in a subject of need, the method comprising administering tovorafenib or a salt thereof to the subject. The age of the subject is 6 months or older; and in, (i) When the object has a diameter of 0.30-0.89 m 2 When the body surface area (BSA) is measured, it is taken once a week (e.g., at approximately 380 mg / m²). 2 The tovorafenib or its salt is administered as an oral liquid formulation (e.g., a liquid suspension) in an amount that is appropriate for oral administration. (ii) When the object has a diameter of 0.90-1.12 m 2 When BSA is present, tovorafenib or its salts are administered once weekly in an oral liquid or solid dosage form at a dose of approximately 400 mg. (iii) When the object has a diameter of 1.13-1.39 m 2 When BSA is present, tovorafenib or its salts are administered once weekly in an oral liquid or solid dosage form at a dose of approximately 500 mg. (iv) When the object has at least 1.40 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly in an oral liquid or solid dosage form at a dose of approximately 600 mg.

26. The method of claim 25, wherein the pediatric low-grade glioma (pLGG) carries a BRAF fusion or rearrangement or a BRAF V600 mutation.

27. The method according to any one of claims 1 to 10, 25 or 26, wherein the method comprises confirming the presence of BRAF fusions or rearrangements or BRAFV600 mutations prior to initiating treatment with the tovorafenib or a salt thereof.

28. The method according to any one of claims 1 to 10, 25 or 26, wherein the method comprises selecting a subject suffering from PLGG carrying a BRAF fusion or rearrangement or a BRAF V600 mutation.

29. The method according to any one of claims 25 to 28, wherein the tovorafenib or a salt thereof is tovorafenib (i.e., in the free base form).

30. The method according to any one of claims 25 to 29, wherein about 380 mg / m 2 The amount of tovorafenib or its salt is applied.

31. The method according to any one of claims 25 to 29, wherein the concentration is about 380 mg / m³ 2 The initial dose of the tovorafenib or its salt is administered.

32. The method according to any one of claims 25 to 29, wherein when the object has a diameter of 0.90-1.12 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly in a solid dosage form at a dose of approximately 400 mg.

33. The method according to any one of claims 25 to 29, wherein when the object has a diameter of 1.13-1.39 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly in a solid dosage form at a dose of approximately 500 mg.

34. The method according to any one of claims 25 to 29, wherein when the object has at least 1.40 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly in a solid dosage form at a dose of approximately 600 mg.

35. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.30-0.35 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 125 mg.

36. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.30-0.35 m 2 When BSA is administered, the tovorafenib or its salt is given once weekly in an amount of approximately 125 mg as an oral liquid formulation (e.g., a liquid suspension).

37. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.30-0.35 m 2 When administering BSA, the tovorafenib or its salt is given as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 5 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

38. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.36-0.42 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 150 mg.

39. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.36-0.42 m 2 When BSA is used, the tovorafenib or its salt is administered once weekly in an amount of approximately 150 mg as an oral liquid formulation (e.g., a liquid suspension).

40. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.36-0.42 m 2 When administering BSA, the tovorafenib or its salt is given in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 6 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

41. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.43-0.48 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 175 mg.

42. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.43-0.48 m 2 When BSA is administered, the tovorafenib or its salt is given once weekly in an amount of approximately 175 mg as an oral liquid formulation (e.g., a liquid suspension).

43. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.43-0.48 m 2 When administering BSA, the tovorafenib or its salt is given in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 7 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

44. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.49-0.54 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 200 mg.

45. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.49-0.54 m 2 When BSA is used, the tovorafenib or its salt is administered once weekly in an amount of approximately 200 mg as an oral liquid formulation (e.g., a liquid suspension).

46. ​​The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.49-0.54 m 2 When administering BSA, the tovorafenib or its salt is given as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 8 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

47. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.55-0.63 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 225 mg.

48. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.55-0.63 m 2 When BSA is administered, the tovorafenib or its salt is given once weekly in an amount of approximately 225 mg as an oral liquid formulation (e.g., a liquid suspension).

49. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.55-0.63 m 2 When administering BSA, the tovorafenib or its salt is given in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 9 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

50. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.64-0.77 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 275 mg.

51. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.64-0.77 m 2 When BSA is administered, the tovorafenib or its salt is given once weekly in an oral liquid formulation (e.g., a liquid suspension) at a dose of approximately 275 mg.

52. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.64-0.77 m 2 When administering BSA, the tovorafenib or its salt is given as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 11 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

53. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.78-0.83 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 300 mg.

54. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.78-0.83 m 2 When BSA is used, the tovorafenib or its salt is administered once weekly in an amount of approximately 300 mg as an oral liquid formulation (e.g., a liquid suspension).

55. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.78-0.83 m 2 When administering BSA, the tovorafenib or its salt is given as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 12 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

56. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.84-0.89 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 350 mg.

57. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.84-0.89 m 2 When BSA is administered, the tovorafenib or its salt is given once weekly in an oral liquid formulation (e.g., a liquid suspension) at a dose of approximately 350 mg.

58. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.84-0.89 m 2 When administering BSA, the tovorafenib or its salt is given in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 14 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

59. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.90-1.05 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 375 mg.

60. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.90-1.05 m 2 When BSA is administered, the tovorafenib or its salt is given once weekly in an oral liquid formulation (e.g., a liquid suspension) at a dose of approximately 375 mg.

61. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 0.90-1.05 m 2 When administering BSA, the tovorafenib or its salt is given as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 15 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

62. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 1.06-1.25 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 450 mg.

63. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 1.06-1.25 m 2 When BSA is used, the tovorafenib or its salt is administered once weekly in an amount of approximately 450 mg as an oral liquid formulation (e.g., a liquid suspension).

64. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 1.06-1.25 m 2 When administering BSA, the tovorafenib or its salt is given as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 18 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

65. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 1.26-1.39 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 525 mg.

66. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 1.26-1.39 m 2 When BSA is administered, the tovorafenib or its salt is given once weekly in an amount of approximately 525 mg as an oral liquid formulation (e.g., a liquid suspension).

67. The method according to any one of claims 25 to 29, wherein when the object has a diameter of about 1.26-1.39 m 2 When administering BSA, the tovorafenib or its salt is given as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 21 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

68. The method according to any one of claims 25 to 29, wherein when the object has ≥1.40 m 2 When BSA is present, the tovorafenib or its salt is administered once weekly at a dose of approximately 600 mg.

69. The method according to any one of claims 25 to 29, wherein when the object has ≥1.40 m 2 When BSA is used, the tovorafenib or its salt is administered once weekly in an amount of approximately 600 mg as an oral liquid formulation (e.g., a liquid suspension).

70. The method according to any one of claims 25 to 29, wherein when the object has ≥1.40 m 2 When administering BSA, the tovorafenib or its salt is given as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 24 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

71. The method according to any one of claims 25 to 29, wherein the tovorafenib or a salt thereof is applied in an amount according to Table A or Table B.

72. The method according to any one of claims 25 to 71, wherein the method comprises dose reduction of tovorafenib or a salt thereof.

73. The method of claim 72, wherein the dose reduction comprises administering tovorafenib or a salt thereof in an amount that is about 5% to 30% less than the dose prior to the dose reduction.

74. The method of claim 72, wherein the dose reduction comprises administering tovorafenib or a salt thereof in an amount approximately 10% to 20% less than the dose prior to the dose reduction.

75. The method of claim 72, wherein the dose reduction comprises administering tovorafenib or a salt thereof in an amount that is about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% less than the dose prior to the dose reduction.

76. The method according to any one of claims 72 to 75, wherein the dose reduction comprises administering tovorafenib or a salt thereof to the subject according to Table C or Table D.

77. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 1.13-1.39 m 2 When BSA is present, the dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 400 mg.

78. The method according to any one of claims 72 to 75, wherein when the object has ≥1.40 m 2 When BSA is present, the dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 500 mg.

79. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.30-0.35 m 2 When BSA is present, the dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 100 mg.

80. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.30-0.35 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 100 mg.

81. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.30-0.35 m 2 When BSA is administered, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 4 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

82. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.36-0.42 m 2 When BSA is used, the dose reduction includes administering tovorafenib or a salt thereof once a week at a dose of about 125 mg.

83. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.36-0.42 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 125 mg.

84. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.36-0.42 m 2 When BSA is administered, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 5 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

85. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.43-0.48 m 2 When BSA is used, the dose reduction includes administering tovorafenib or its salt once a week at a dose of about 150 mg.

86. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.43-0.48 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 150 mg.

87. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.43-0.48 m 2 When BSA is administered, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 6 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

88. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.49-0.54 m 2 When BSA is used, the dose reduction includes administering tovorafenib or its salt once a week at a dose of about 175 mg.

89. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.49-0.54 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 175 mg.

90. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.49-0.54 m 2 When BSA is administered, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 7 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

91. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.55-0.63 m 2 When BSA is present, the dose reduction includes administering tovorafenib or its salt once weekly at a dose of approximately 200 mg.

92. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.55-0.63 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 200 mg.

93. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.55-0.63 m 2 When administering BSA, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 8 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

94. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.64-0.77 m 2 When BSA is used, the dose reduction includes administering tovorafenib or a salt thereof once a week at a dose of about 225 mg.

95. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.64-0.77 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 225 mg.

96. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.64-0.77 m 2 When BSA is administered, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 9 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

97. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.78-0.83 m 2 When BSA is used, the dose reduction includes administering tovorafenib or its salt once a week at a dose of about 250 mg.

98. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.78-0.83 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 250 mg.

99. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.78-0.83 m 2 When BSA is administered, the dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 10 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

100. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.84-0.89 m 2 When BSA is present, the dose reduction includes administering tovorafenib or its salt once weekly at a dose of approximately 300 mg.

101. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.84-0.89 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 300 mg.

102. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.84-0.89 m 2 When BSA is administered, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 12 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

103. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.90-1.05 m 2 When BSA is used, the dose reduction includes administering tovorafenib or its salt once a week at a dose of about 325 mg.

104. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.90-1.05 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 325 mg.

105. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 0.90-1.05 m 2 When administering BSA, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 13 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

106. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 1.06-1.25 m 2 When BSA is used, the dose reduction includes administering tovorafenib or its salt once a week at a dose of approximately 375 mg.

107. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 1.06-1.25 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 375 mg.

108. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 1.06-1.25 m 2 When BSA is administered, the dose reduction includes administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 15 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

109. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 1.26-1.39 m 2 When BSA is present, the dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 450 mg.

110. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 1.26-1.39 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 450 mg.

111. The method according to any one of claims 72 to 75, wherein when the object has a diameter of 1.26-1.39 m 2 When administering BSA, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 18 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

112. The method according to any one of claims 72 to 75, wherein when the object has ≥1.40 m 2 When BSA is present, the dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 500 mg.

113. The method according to any one of claims 72 to 75, wherein when the object has ≥1.40 m 2 When BSA is used, the dose reduction includes administration of tovorafenib or its salt in an oral liquid formulation (e.g., liquid suspension) once weekly at a dose of about 500 mg.

114. The method according to any one of claims 72 to 75, wherein when the object has ≥1.40 m 2 When BSA is administered, the dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 20 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

115. The method according to any one of claims 25 to 114, wherein the method comprises a second dose reduction of tovorafenib or a salt thereof.

116. The method of claim 115, wherein the second dose reduction comprises administering tovorafenib or a salt thereof in an amount approximately 5% to 30% less than the dose prior to the dose reduction.

117. The method of claim 115, wherein the second dose reduction comprises administering tovorafenib or a salt thereof in an amount approximately 10% to 20% less than the dose prior to the dose reduction.

118. The method of claim 115, wherein the second dose reduction comprises administering tovorafenib or a salt thereof in an amount approximately 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% less than the dose prior to the dose reduction.

119. The method according to any one of claims 115 to 118, wherein the second dose reduction comprises administering tovorafenib or a salt thereof to the subject according to Table C or Table D.

120. The method according to any one of claims 115 to 118, wherein when the object has ≥1.40 m 2 When BSA is present, the second dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 400 mg.

121. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.30-0.35 m 2 When BSA is present, the second dose reduction includes administration of tovorafenib or its salt once weekly at a dose of approximately 75 mg.

122. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.30-0.35 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) once weekly at a dose of approximately 75 mg.

123. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.30-0.35 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 3 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

124. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.36-0.42 m 2 When BSA is present, the second dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 100 mg.

125. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.36-0.42 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 100 mg as an oral liquid formulation (e.g., a liquid suspension).

126. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.36-0.42 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 4 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

127. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.43-0.48 m 2 When BSA is present, the second dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 125 mg.

128. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.43-0.48 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 125 mg as an oral liquid formulation (e.g., a liquid suspension).

129. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.43-0.48 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof in an oral liquid formulation (e.g., a liquid suspension) in an amount of about 5 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

130. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.49-0.54 m 2 When BSA is present, the second dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 150 mg.

131. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.49-0.54 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 150 mg as an oral liquid formulation (e.g., a liquid suspension).

132. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.49-0.54 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 6 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

133. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.55-0.63 m 2 When BSA is present, the second dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 150 mg.

134. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.55-0.63 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 150 mg as an oral liquid formulation (e.g., a liquid suspension).

135. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.55-0.63 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 6 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

136. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.64-0.77 m 2 When BSA is present, the second dose reduction includes administration of tovorafenib or its salt once a week at a dose of approximately 200 mg.

137. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.64-0.77 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 200 mg as an oral liquid formulation (e.g., a liquid suspension).

138. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.64-0.77 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 8 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

139. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.78-0.83 m 2 When BSA is present, the second dose reduction includes administration of tovorafenib or its salt once a week at a dose of approximately 200 mg.

140. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.78-0.83 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 200 mg as an oral liquid formulation (e.g., a liquid suspension).

141. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.78-0.83 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 8 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

142. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.84-0.89 m 2 When BSA is present, the second dose reduction includes administering tovorafenib or its salt once weekly at a dose of approximately 250 mg.

143. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.84-0.89 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 250 mg as an oral liquid formulation (e.g., a liquid suspension).

144. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.84-0.89 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 10 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

145. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.90-1.05 m 2 When BSA is present, the second dose reduction includes administration of tovorafenib or its salt once weekly at a dose of approximately 275 mg.

146. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.90-1.05 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 275 mg as an oral liquid formulation (e.g., a liquid suspension).

147. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 0.90-1.05 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 11 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

148. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 1.06-1.25 m 2 When BSA is present, the second dose reduction includes administration of tovorafenib or its salt once weekly at a dose of approximately 325 mg.

149. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 1.06-1.25 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 325 mg as an oral liquid formulation (e.g., a liquid suspension).

150. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 1.06-1.25 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 13 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

151. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 1.26-1.39 m 2 When BSA is present, the second dose reduction includes administration of tovorafenib or its salt once weekly at a dose of approximately 375 mg.

152. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 1.26-1.39 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an oral liquid formulation (e.g., a liquid suspension) at a dose of approximately 375 mg.

153. The method according to any one of claims 115 to 118, wherein when the object has a diameter of 1.26-1.39 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 15 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

154. The method according to any one of claims 115 to 118, wherein when the object has ≥1.40 m 2 When BSA is present, the second dose reduction includes administering tovorafenib or a salt thereof once weekly at a dose of approximately 400 mg.

155. The method according to any one of claims 115 to 118, wherein when the object has ≥1.40 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof once weekly in an amount of approximately 400 mg as an oral liquid formulation (e.g., a liquid suspension).

156. The method according to any one of claims 115 to 118, wherein when the object has ≥1.40 m 2 When BSA is administered, the second dose reduction comprises administering tovorafenib or a salt thereof as an oral liquid formulation (e.g., a liquid suspension) in an amount of about 16 mL, wherein the tovorafenib is present in the oral liquid formulation at about 25 mg / mL.

157. The method according to any one of claims 1 to 156, wherein each dose of the tovorafenib or a salt thereof is administered to the subject at least four-day intervals.

158. The method according to any one of the preceding claims, wherein the pLGG has a BRAF mutation.

159. The method of claim 158, wherein the BRAF mutation is a V600E mutation.

160. The method of claim 158, wherein the BRAF mutation is a mutation other than the V600E mutation.

161. The method according to any one of claims 1 to 157, wherein the pLGG carries BRAF fusion or rearrangement.

162. The method according to any one of the preceding claims, wherein the subject is selected from subjects who have previously received MAP kinase inhibitor treatment.

163. The method according to any one of claims 11-24, wherein about 350 mg / m² is orally administered to the subject weekly. 2 Approximately 400 mg / m 2 Tovorafenib or its salts.

164. The method of claim 163, wherein approximately 380 mg / m² is orally administered to the subject weekly. 2 Tovorafenib or its salts.

165. The method according to any one of the preceding claims, wherein tovorafenib or a salt thereof is administered to the subject for 10 weeks or longer.

166. The method of claim 165, wherein tovorafenib or a salt thereof is administered to the subject for 16 weeks or longer.

167. The method according to any one of the preceding claims, wherein tovorafenib or a salt thereof is administered as a tablet or liquid formulation.

168. The method according to any one of claims 1 to 167, wherein tovorafenib or its salt is administered with food.

169. The method according to any one of claims 1 to 167, wherein tovorafenib or its salt is not administered with food.

170. The method according to any one of claims 1 to 169, further comprising assessing the liver function of the subject (e.g., ALT, AST, and / or bilirubin).

171. The method according to any one of the preceding claims, wherein the subject has previously received tovorafenib or a salt thereof and is on a drug vacation.

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