Treatment of low-grade gliomas with mirdametinib

Abstract

The present disclosure relates to methods of treating a patient (e.g., a human patient) with low-grade glioma by administering (e.g., orally) mirdametinib, or a pharma- ceutically acceptable salt thereof, to the patient.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 321,042 (filed March 17, 2022), the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to methods of treating a patient (e.g., a human patient) with low-grade glioma by administering (e.g., orally) mirdametinib, or a pharma- ceutically acceptable salt thereof, to the patient. [Background technology]

[0003] Low-grade gliomas are brain tumors that arise from glial cells, which support and nourish neurons in the brain. Glial tumors (or gliomas) are divided into four grades depending on how the cells look under a microscope. Grades 1 and 2 gliomas are considered low-grade and account for about two-thirds of all childhood tumors.

[0004] The classification of low-grade gliomas is based on the location and type of glial cell (astrocyte, oligodendrocyte, or ependymal cell) in which they arise, in addition to grade.

[0005] Low-grade gliomas do not spread outside the brain, but grow within normal brain tissue, causing symptoms as the tumor grows locally. This can disrupt connections between normal brain cells and cause pressure on nearby brain tissue. When a tumor grows within the brain, the brain cannot expand because it is confined within the skull. As a result, even relatively small, slow-growing tumors can cause serious brain problems, especially if they are located in critical areas of the brain.

[0006] Low-grade gliomas are slow-growing tumors. As they grow, they press on surrounding healthy parts of the brain, affecting their function. Therefore, the symptoms of pediatric low-grade gliomas vary depending on the size of the tumor and its location in the brain. Some of the most common symptoms of pediatric low-grade gliomas include: ● Headaches (especially in the morning); • Severe or frequent vomiting without other signs of gastrointestinal illness; ● Vision problems (e.g. double vision, blurred vision, or loss of vision); ● Difficulty walking or balancing; ● Seizures; ● Weight gain or loss; ●Precocious puberty; ● Clumsy; Confusion; and ●Drowsiness.

[0007] In many people, seizures are the first sign of low-grade glioma. Seizures, which also occur as a result of other conditions, are caused by unregulated electrical activity in the brain. Seizures can cause loss of consciousness (fainting), involuntary movements (convulsions or seizures), and / or loss of muscle control throughout the body.

[0008] Robinson et al., Oncogene, 2011, 30(11):1341-1350, describe treatment of mouse and human glioma cells with the MEK inhibitor PD0325901.

[0009] There is a need for improved treatment of low-grade gliomas. Moreover, objective responses are lacking and disease recurrence after completion of treatment is common. Summary of the Invention

[0010] In one aspect, the present invention relates to a method of treating low-grade glioma in a patient (e.g., a human patient in need thereof), comprising administering (e.g., orally administering) mirdametinib or a pharma- ceutically acceptable salt thereof to the patient, hi one embodiment, the patient is a pediatric patient.

[0011] In another aspect, the present invention relates to a method for treating one or more symptoms of low-grade glioma in a patient (e.g., a human patient in need thereof), comprising administering (e.g., orally administering) mirdametinib or a pharma- ceutically acceptable salt thereof to the patient. In certain embodiments, the one or more symptoms associated with low-grade glioma include, but are not limited to, headache, vomiting, vision problems (e.g., double vision, blurred vision, or loss of vision), difficulty walking or balancing, seizures, weight gain or loss, precocious puberty, clumsiness, confusion, drowsiness, and any combination of the foregoing. In one embodiment, the patient is a pediatric patient.

[0012] In some embodiments of any of the methods described herein, the patient has one or more BRAF, MYB, RAF1, NF1, or FGFR1 mutations (e.g., somatic gene rearrangements of BRAF, MYB, RAF1, NF1, or FGFR1).

[0013] In some embodiments of any of the methods described herein, the patient has an NF1 germline mutation.

[0014] In some embodiments of any of the methods described herein, the patient has metastatic disease.

[0015] In some embodiments of any of the methods described herein, a therapeutically effective amount of mirdametinib or a pharma- ceutical acceptable salt thereof is administered. In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutical acceptable salt thereof is administered in an amount of about 1 mg / m per day based on mirdametinib free base. 2 ~about 10mg / m 2 is administered in an amount of

[0016] In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutical acceptable salt thereof is administered in an amount of about 0.1 mg / m based on mirdametinib free base. 2 ~about 10mg / m 2In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg to about 10 mg based on mirdametinib free base.

[0017] In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is administered once a day. In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is administered twice a day.

[0018] In one embodiment, 1 mg / m 2 is orally administered to the patient twice daily. In another embodiment, 2.0 mg / m 2 is orally administered to the patient twice daily. In yet another embodiment, 2.5 mg / m 2 is orally administered to the patient twice daily. In yet another embodiment, 3.0 mg / m 2 is administered orally to patients twice daily.

[0019] In one embodiment of any of the methods described herein, (a) Body surface area is 0.38 m 2 ~1.80m 2 For patients with 2 of mirdametinib administered orally twice daily (i.e., a total of 6 mg per day), (b) Body surface area is 0.44 m 2 ~2.22m 2 For patients with 2 of mirdametinib administered orally twice daily (i.e., a total of 4 mg per day), (c) Body surface area is 0.44 m 2 ~3.0m 2 For patients with 2 of mirdametinib will be administered orally twice daily (i.e., a total of 2 mg per day).

[0020] In one embodiment of any of the methods described herein, (a) Body surface area is 0.69 m 2 Patients will initially receive 1 mg of mirdametinib orally twice daily (i.e., a total of 2 mg per day) for the following patients: (b) Body surface area is 0.7 to 1.04 m 2 For patients with , patients were initially treated with 2 mg of mirdametinib orally twice daily (i.e., a total of 4 mg per day) (c) Body surface area is 1.05 to 1.49 m 2 For patients with , patients were initially treated with 3 mg mirdametinib orally twice daily (i.e., a total of 6 mg per day) (d) Body surface area is 1.5 m 2 For these patients, patients will initially receive 4 mg of mirdametinib orally twice daily (i.e., a total of 8 mg per day).

[0021] In another embodiment of any of the methods described herein, a human rat is aged 2 to 10 years and has a body surface area of ​​0.69 m 2 In another embodiment, the patient is initially administered 1 mg of mirdametinib orally twice daily (i.e., a total of 2 mg per day) for patients aged 2 to 8 years and with a body surface area of ​​0.69 m 2 In another embodiment, the patient is initially administered 1 mg of mirdametinib orally twice daily (i.e., a total of 2 mg per day) for patients aged 2-7 years and with a body surface area of ​​0.69 m 2 In another embodiment, the patient is initially administered 1 mg of mirdametinib orally twice daily (i.e., a total of 2 mg per day) for patients aged 2-6 years and with a body surface area of ​​0.69 m 2 In another embodiment, the patient is initially administered 1 mg of mirdametinib orally twice daily (i.e., a total of 2 mg per day) for patients aged 2-5 years and with a body surface area of ​​0.69 m 2 For the following patients, patients will initially receive 1 mg of mirdametinib orally twice daily (i.e., a total of 2 mg per day):

[0022] In another embodiment of any of the methods described herein, the administered dose is reduced due to an adverse event, and the dose is reduced as follows: (a) if the dose at the time of the event is 1 mg mirdametinib twice daily, the reduced daily dose is 1 mg mirdametinib administered only in the morning; (b) if the dose at the time of the event is 2 mg mirdametinib twice daily, the reduced daily dose is 2 mg mirdametinib administered in the morning and 1 mg mirdametinib administered in the afternoon or evening; (c) if the dose at the time of the event is 3 mg mirdametinib twice daily, the reduced daily dose is 2 mg mirdametinib administered twice daily; and (d) If the dose at the time of the event is 4 mg mirdametinib administered twice daily, the reduced daily dose is 3 mg mirdametinib administered twice daily.

[0023] In one embodiment, the adverse event leading to dose reduction is acneiform rash.

[0024] In another embodiment of any of the methods described herein, the method comprises orally administering 1 mg of mirdametinib twice daily (i.e., a total of 2 mg per day).

[0025] In another embodiment of any of the methods described herein, the maximum oral daily dose administered to the patient is 4 mg of mirdametinib twice daily (i.e., a total of 8 mg per day).

[0026] In one embodiment of any of the methods described herein, the 2 Patients will receive mirdametinib orally twice daily.

[0027] In one embodiment of any of the methods described herein, in each 4 week period, mirdametinib is administered for the first 3 weeks and discontinued for the last week.

[0028] In some embodiments of any of the methods described herein, mirdametinib, or a pharma- ceutically acceptable salt thereof, exhibits high blood-brain barrier permeability.

[0029] In some embodiments of any of the methods described herein, the patient is a human. In some embodiments of any of the methods described herein, the human is 2 years of age or older and less than 25 years of age.

[0030] In some embodiments of any of the methods described herein, the human has not been previously exposed to a MEK inhibitor.

[0031] In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is orally administered. In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is dispersible in a drinking liquid or orodispersible in the patient's saliva. In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is orally administered as a solid dosage form. In some embodiments of any of the methods described herein, the solid dosage form is a tablet or capsule. In some embodiments of any of the methods described herein, the solid dosage form is a capsule.

[0032] In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is administered as monotherapy to treat low-grade glioma or one or more symptoms associated therewith. In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat low-grade glioma or one or more symptoms associated therewith. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] I. Definition To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0034] Generally, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0035] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more" and "at least one," may be used interchangeably herein. In certain embodiments, the term "a" or "an" means "single." In other embodiments, the term "a" or "an" includes "two or more" or "multiple."

[0036] Furthermore, "and / or" as used herein should be interpreted as a specific disclosure of each of the two specified features or components, whether or not the other is present. Thus, the term "and / or" as used in phrases such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (single), and "B" (single). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0037] The term "mirdametinib" refers to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzamide. Mirdametinib is an allosteric small molecule compound that targets mitogen-activated protein kinase (MEK). The teachings throughout this specification regarding mirdametinib are equally applicable to pharma- ceutically acceptable salts of mirdametinib.

[0038] "mg / m 2 The term "body surface area" refers to the area per square meter of the patient's body surface area. 2 This refers to the dose in milligrams per unit.

[0039] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as, for example, a human subject.

[0040] The term "child" refers to a human subject who is under 21 years of age at the time of treatment. The term "child" can be further classified into various subpopulations, including neonates (birth to 28 days after birth), infants (29 days after birth to under 2 years of age), children (2 years to under 12 years of age), and adolescents (12 years to 21 years of age, up to but not including the 22nd birthday). See, e.g., Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some additional embodiments, the pediatric patient is between 2 and 21 years old, between 3 and 21 years old, between 2 and 16 years old, between 2 and 15 years old, between 2 and 8 years old, between 2 and 7 years old, between 2 and 6 years old, or between 2 and 5 years old. Younger pediatric patients, particularly (e.g., neonates, infants, and toddlers), may have difficulty swallowing capsules or tablets whole.

[0041] As used herein, the term "dispersible" refers to a composition (e.g., tablet, powder, granule, mini-tablet, or pellet) that disintegrates and / or dissolves when placed in the mouth of a subject, combined with water or other drinking liquid (e.g., beverage other than water), or the subject's own saliva, with or without stirring or temperature change. In some embodiments, a dispersible composition disintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after being combined with water or another drinking liquid. Such disintegration or dissolution does not need to be complete. For example, a dispersible tablet may be almost completely dissolved, but some undissolved particulates may remain.

[0042] The term "orodispersible" refers to a composition that, when administered orally, is capable of dissolving or disintegrating in a subject's oral cavity (i.e., dissolving or disintegrating in the subject's saliva) without the need to first dissolve or disintegrate in a separate container.

[0043] As used herein, the terms "treat", "treated" and "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Thus, those in need of treatment include those already diagnosed with a disorder or suspected of having a disorder. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; reduction in the extent of a condition, disorder, or disease; stabilization (i.e., not worsening) of a condition, disorder, or disease; delay in onset or slowing of progression of a condition, disorder, or disease; improvement or remission (partial or complete) of a condition, disorder, or disease state; improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or improvement or amelioration of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment. The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or clinician.

[0044] In certain embodiments, if a patient shows one or more of the following: reduction in tumor size; mitigation of one or more symptoms related to a particular tumor; reduction in tumor volume; improvement in quality of life; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), reduction in progression (PD), increase in time to progression (TTP), or any combination thereof, the subject is successfully "treated" with tumor according to the methods described herein.In some embodiments, the nationally or internationally accepted standard of treatment outcome in a given tumor can be used to determine whether the effective amount of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0045] In certain embodiments, if the patient shows one or more of the following: reduction in tumor size; mitigation of one or more symptoms associated with a particular tumor; reduction or complete absence of cancer cell count; mitigation of one or more symptoms associated with a particular cancer; reduction in morbidity and mortality; improvement in quality of life; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), reduction in progression (PD), increase in time to progression (TTP), or any combination thereof, the subject is "treated" successfully with cancer (e.g., low-grade glioma) according to the methods described herein. In some embodiments, the nationally or internationally accepted standard of therapeutic outcome in a given cancer can be used to determine whether the effective amount of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0046] The terms "pharmaceutical acceptable carrier", "pharmaceutical acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutical acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0047] The term "pharmaceutical acceptable salts" refers to inorganic and organic acid addition salts of mirdametinib that are relatively non-toxic. These salts can be prepared in situ during the administration vehicle or dosage form manufacturing process, or by separately reacting the purified compounds of the present invention in free base form with a suitable organic or inorganic acid and isolating the salt thus formed during subsequent purification. Representative salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. See, for example, Berge et al., "Pharmaceutical Salts", J.Pharm.Sci.66:1-19,1977.

[0048] Pharmaceutically acceptable salts of Mirdametinib also include conventional non-toxic salts or quaternary ammonium salts of compounds, for example, derived from non-toxic organic or inorganic acids.For example, such conventional non-toxic salts include, but are not limited to, salts derived from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid) and salts derived from organic acids (e.g., acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isothioic acid).

[0049] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which error depends, in part, on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0050] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are to be interpreted inclusively rather than exclusively, and are used with the express understanding that Applicant intends each of these terms to be so interpreted in interpreting this patent, including the claims which follow.

[0051] II. Treatment method Provided herein is a method for treating low-grade glioma, the method comprising administering mirdametinib, or a pharma- ceutical acceptable salt thereof, to a patient (e.g., a human patient in need thereof).

[0052] Provided herein is a method for treating one or more symptoms associated with low-grade glioma, the method comprising administering mirdametinib, or a pharma- ceutical acceptable salt thereof, to a patient (e.g., a patient in need thereof).

[0053] In some embodiments of any of the methods described herein, a therapeutically effective amount of mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered.

[0054] In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutical acceptable salt thereof is administered at a dose of about 1 mg / m per day based on mirdametinib free base. 2 ~about 10mg / m2 , approximately 1.5 mg / m per day based on mirdametinib free base 2 ~about 9.5mg / m 2 , approximately 2 mg / m per day based on mirdametinib free base 2 ~about 9mg / m 2 , approximately 2.5 mg / m per day based on mirdametinib free base 2 ~about 8.5mg / m 2 , approximately 3 mg / m per day based on mirdametinib free base 2 ~about 8mg / m 2 , approximately 3.5 mg / m per day based on mirdametinib free base 2 ~about 7.5mg / m 2 , approximately 4 mg / m per day based on mirdametinib free base 2 ~about 7mg / m 2 , approximately 4.5 mg / m per day based on mirdametinib free base 2 ~about 6.5mg / m 2 or approximately 5 mg / m per day based on mirdametinib free base 2 ~about 6mg / m 2 In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutical acceptable salt thereof is administered in an amount of about 1 mg / m per day based on mirdametinib free base. 2 , approximately 1.5 mg / m per day based on mirdametinib free base 2 , approximately 2 mg / m per day based on mirdametinib free base 2 , approximately 2.5 mg / m per day based on mirdametinib free base 2 , approximately 3 mg / m per day based on mirdametinib free base 2 , approximately 3.5 mg / m based on mirdametinib free base 2 , approximately 4 mg / m per day based on mirdametinib free base 2 , approximately 4.5 mg / m based on mirdametinib free base 2 , approximately 5 mg / m per day based on mirdametinib free base 2 , approximately 5.5 mg / m per day based on mirdametinib free base 2 , approximately 6 mg / m per day based on mirdametinib free base2 , approximately 6.5 mg / m per day based on mirdametinib free base 2 , approximately 7 mg / m per day based on mirdametinib free base 2 , approximately 7.5 mg / m based on mirdametinib free base 2 , approximately 8 mg / m per day based on mirdametinib free base 2 , approximately 8.5 mg / m per day based on mirdametinib free base 2 , approximately 9 mg / m per day based on mirdametinib free base 2 , approximately 9.5 mg / m per day based on mirdametinib free base 2 or approximately 10 mg / m per day based on mirdametinib free base 2 is administered in an amount of

[0055] In some embodiments of any of the methods described herein, mirdametinib, or a pharma- ceutical acceptable salt thereof, is administered at a dose of about 0.1 mg / m2 based on mirdametinib free base. 2 ~about 10mg / m 2 , approximately 0.5 mg / m based on mirdametinib free base 2 ~about 9.5mg / m 2 , approximately 1 mg / m based on mirdametinib free base 2 ~about 9mg / m 2 , approximately 1.5 mg / m based on mirdametinib free base 2 ~about 8.5mg / m 2 , approximately 2 mg / m based on mirdametinib free base 2 t~about 8mg / m 2 , approximately 2.5 mg / m based on mirdametinib free base 2 ~about 7.5mg / m 2 , approximately 3 mg / m based on mirdametinib free base 2 ~about 7mg / m 2 , approximately 3.5 mg / m based on mirdametinib free base 2 ~about 6.5mg / m 2 , approximately 4 mg / m based on mirdametinib free base 2 ~about 6mg / m 2 or about 4.5 mg / m based on mirdametinib free base 2~about 5.5mg / m 2 In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutical acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg / m2 based on mirdametinib free base. 2 , approximately 0.2 mg / m based on mirdametinib free base 2 , approximately 0.3 mg / m based on mirdametinib free base 2 , approximately 0.4 mg / m based on mirdametinib free base 2 , approximately 0.5 mg / m based on mirdametinib free base 2 , approximately 1 mg / m based on mirdametinib free base 2 , approximately 1.5 mg / m based on mirdametinib free base 2 , approximately 2 mg / m based on mirdametinib free base 2 , approximately 2.5 mg / m based on mirdametinib free base 2 , approximately 3 mg / m based on mirdametinib free base 2 , approximately 3.5 mg / m based on mirdametinib free base 2 , approximately 4 mg / m based on mirdametinib free base 2 , approximately 4.5 mg / m based on mirdametinib free base 2 , approximately 5 mg / m based on mirdametinib free base 2 , approximately 5.5 mg / m based on mirdametinib free base 2 , approximately 6 mg / m based on mirdametinib free base 2 , approximately 6.5 mg / m based on mirdametinib free base 2 , approximately 7 mg / m based on mirdametinib free base 2 , approximately 7.5 mg / m based on mirdametinib free base 2 , approximately 8 mg / m based on mirdametinib free base 2 , approximately 8.5 mg / m based on mirdametinib free base 2 , approximately 9 mg / m based on mirdametinib free base 2 , approximately 9.5 mg / m based on mirdametinib free base 2 or about 10 mg / m based on mirdametinib free base 2 The compound is administered in a single dosage form comprising:

[0056] In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is administered once, twice, three times, or four times a day.In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is administered once a day.In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is administered twice a day.

[0057] In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutical acceptable salt thereof is administered twice daily at a dose of about 0.5 mg / m2 based on mirdametinib free base. 2 ~about 10mg / m 2 , approximately 1 mg / m based on mirdametinib free base 2 ~about 9.5mg / m 2 , approximately 1.5 mg / m based on mirdametinib free base 2 ~about 9mg / m 2 , approximately 2 mg / m based on mirdametinib free base 2 ~about 8.5mg / m 2 , approximately 2.5 mg / m based on mirdametinib free base 2 ~about 8mg / m 2 , approximately 3 mg / m based on mirdametinib free base 2 ~about 7.5mg / m 2 , approximately 3.5 mg / m based on mirdametinib free base 2 ~about 7mg / m 2 , approximately 4 mg / m based on mirdametinib free base 2 ~about 6.5mg / m 2 , approximately 4.5 mg / m based on mirdametinib free base 2 ~about 6mg / m 2 or approximately 5 mg / m based on mirdametinib free base 2 ~about 6mg / m 2 In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutical acceptable salt thereof is administered twice daily in an amount of about 0.5 mg / m2 based on mirdametinib free base. 2, approximately 1 mg / m based on mirdametinib free base 2 , approximately 1.5 mg / m based on mirdametinib free base 2 , approximately 2 mg / m based on mirdametinib free base 2 , approximately 2.5 mg / m based on mirdametinib free base 2 , approximately 3 mg / m based on mirdametinib free base 2 , approximately 3.5 mg / m based on mirdametinib free base 2 , approximately 4 mg / m based on mirdametinib free base 2 , approximately 4.5 mg / m based on mirdametinib free base 2 , approximately 5 mg / m based on mirdametinib free base 2 , approximately 5.5 mg / m based on mirdametinib free base 2 , approximately 6 mg / m based on mirdametinib free base 2 , approximately 6.5 mg / m based on mirdametinib free base 2 , approximately 7 mg / m based on mirdametinib free base 2 , approximately 7.5 mg / m based on mirdametinib free base 2 , approximately 8 mg / m based on mirdametinib free base 2 , approximately 8.5 mg / m based on mirdametinib free base 2 , approximately 9 mg / m based on mirdametinib free base 2 , approximately 9.5 mg / m based on mirdametinib free base 2 or about 10 mg / m based on mirdametinib free base 2 is administered in an amount of

[0058] In some embodiments of any of the methods described herein, mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered as mirdametinib free base.

[0059] In one embodiment, the present invention relates to a method for treating low-grade glioma in a patient (e.g., a patient in need thereof), comprising administering mirdametinib free radical to the patient.

[0060] In some embodiments of any of the methods described herein, a therapeutically effective amount of mirdametinib free base is administered.

[0061] In some embodiments of any of the methods described herein, the mirdametinib free base is administered in an amount of about 1 mg / m 2 ~about 10mg / m 2 , approximately 1.5 mg / m per day 2 ~about 9.5mg / m 2 , approximately 2 mg / m per day 2 ~about 9mg / m 2 , approximately 2.5 mg / m per day 2 ~about 8.5mg / m 2 , approximately 3 mg / m per day 2 ~about 8mg / m 2 , approximately 3.5 mg / m per day 2 ~about 7.5mg / m 2 , approximately 4 mg / m per day 2 ~about 7mg / m 2 , approximately 4.5 mg / m per day 2 ~about 6.5mg / m 2 , or about 5 mg / m per day. 2 ~about 6mg / m 2 In some embodiments of any of the methods described herein, mirdametinib free base is administered in an amount of about 1 mg / m per day. 2 , approximately 1.5 mg / m per day 2 , approximately 2 mg / m per day 2 , approximately 2.5 mg / m per day 2 , approximately 3 mg / m per day 2 , approximately 3.5 mg / m per day 2 , approximately 4 mg / m per day 2 , approximately 4.5 mg / m per day 2 , approximately 5 mg / m per day 2 , approximately 5.5 mg / m per day 2 , approximately 6 mg / m per day 2 , approximately 6.5 mg / m per day 2 , approximately 7 mg / m per day 2 , approximately 7.5 mg / m per day 2 , approximately 8 mg / m per day 2, approximately 8.5 mg / m per day 2 , approximately 9 mg / m per day 2 , approximately 9.5 mg / m per day 2 , or about 10 mg / m per day. 2 is administered in an amount of

[0062] In some embodiments of any of the methods described herein, the mirdametinib free base is administered at a concentration of about 0.1 mg / m 2 ~about 10mg / m 2 , about 0.5mg / m 2 ~about 9.5mg / m 2 , about 1mg / m 2 ~about 9mg / m 2 , about 1.5mg / m 2 ~about 8.5mg / m 2 , about 2mg / m 2 ~about 8mg / m 2 , about 2.5mg / m 2 ~about 7.5mg / m 2 , about 3mg / m 2 ~about 7mg / m 2 , about 3.5mg / m 2 ~about 6.5mg / m 2 , about 4mg / m 2 ~about 6mg / m 2 , or about 4.5 mg / m 2 ~about 5.5mg / m 2 In some embodiments of any of the methods described herein, mirdametinib free base is administered in a single dosage form comprising about 0.1 mg / m 2 , about 0.2mg / m 2 , about 0.3mg / m 2 , about 0.4mg / m 2 , about 0.5mg / m 2 , about 1mg / m 2 , about 1.5mg / m 2 , about 2mg / m 2 , about 2.5mg / m 2 , about 3mg / m 2 , about 3.5mg / m 2 , about 4mg / m 2 , about 4.5mg / m 2 , about 5mg / m 2 , about 5.5mg / m 2, about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2 , about 8.5mg / m 2 , about 9mg / m 2 , about 9.5mg / m 2 , or about 10 mg / m 2 The compound is administered in a single dosage form comprising:

[0063] In some embodiments of any of the methods described herein, mirdametinib free base is administered once, twice, three times, or four times a day.In some embodiments of any of the methods described herein, mirdametinib free base is administered once a day.In some embodiments of any of the methods described herein, mirdametinib free base is administered twice a day.

[0064] In some embodiments of any of the methods described herein, mirdametinib free base is administered at about 0.5 mg / m twice daily. 2 ~about 10mg / m 2 , about 1mg / m 2 ~about 9.5mg / m 2 , about 1.5mg / m 2 ~about 9mg / m 2 , about 2mg / m 2 ~about 8.5mg / m 2 , about 2.5mg / m 2 ~about 8mg / m 2 , about 3mg / m 2 ~about 7.5mg / m 2 , about 3.5mg / m 2 ~about 7mg / m 2 , about 4mg / m 2 ~about 6.5mg / m 2 , about 4.5mg / m 2 ~about 6mg / m 2 , or about 5 mg / m 2 ~about 6mg / m 2 In some embodiments of any of the methods described herein, mirdametinib free base is administered twice daily in an amount of about 0.5 mg / m2 , about 1mg / m 2 , about 1.5mg / m 2 , about 2mg / m 2 , about 2.5mg / m 2 , about 3mg / m 2 , about 3.5mg / m 2 , about 4mg / m 2 , about 4.5mg / m 2 , about 5mg / m 2 , about 5.5mg / m 2 , about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2 , about 8.5mg / m 2 , about 9mg / m 2 , about 9.5mg / m 2 , or about 10 mg / m 2 is administered in an amount of

[0065] In some embodiments of any of the methods described herein, mirdametinib, or a pharma- ceutically acceptable salt thereof, exhibits high blood-brain barrier permeability.

[0066] In some embodiments of any of the methods described herein, the patient is a human.

[0067] In some embodiments of any of the methods described herein, the human is at least 2 years old and less than 25 years old.

[0068] In some embodiments of any of the methods described herein, the human has not been previously exposed to a MEK inhibitor. In some embodiments of any of the methods described herein, the human has not responded to previous treatment with one or more MEK inhibitors.

[0069] In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is orally administered. In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is orally administered as a solid dosage form. In some embodiments of any of the methods described herein, the solid dosage form is a tablet or capsule. In some aspects, the solid dosage form is a capsule. In some embodiments of any of the methods described herein, mirdametinib or a pharma- ceutically acceptable salt thereof is dispersible in a drinking liquid or orally dispersible in the patient's saliva.

[0070] In some embodiments of any of the methods described herein, mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered as monotherapy to treat low-grade glioma or a symptom thereof.

[0071] In some embodiments of any of the methods described herein, mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered in combination with another active ingredient and / or surgery to treat low-grade glioma or a symptom thereof. EXAMPLES

[0072] Example 1: Phase I / II Evaluation of Single Agent Mirdametinib, a Brain-Penetrant MEK1 / 2 Inhibitor, for the Treatment of Children, Adolescents, and Young Adults with Low-Grade Gliomas (LGG) Mirdametinib is currently undergoing a multiarm Phase I / II study in patients aged 2 years or older and younger than 25 years with LGG. The Phase I study requires participants who have not been exposed to MEK inhibitors and have recurrent / progressive disease with biopsy-proven evidence of MAPK pathway activation. Using a rolling-6 design, the study will include three escalating dose steps (2 mg / m twice daily). 2 / dose, 2.5mg / m twice a day 2 / dose, and 3 mg / m twice daily 2 / dose) is planned.

[0073] The median age of enrollees was 10 years (range, 3-21 years). Ten patients had somatic gene rearrangements (7 BRAF, 1 MYB, 1 RAF1, 1 FGFR1), one patient had a germline NF1 mutation, and three patients had metastatic disease. 2 ), no dose-limiting toxicity occurred, but 2 ) data are pending. Only grade 1 and 2 treatment-related adverse events have been observed. No MEK-related retinopathy or cardiomyopathy has been observed. Four of six patients who completed at least one follow-up disease assessment have had a minor response (>25% <50% reduction). No disease progression occurred.

[0074] Of the 11 patients with somatic gene rearrangements or NF1, 4 with BRAF and 1 with FGFR1 received 2 mg / m 2 The remaining 11 patients (3 BRAF, 1 MYB, 1 NF1, and 1 RAF1) received 2.5 mg / m 2 The results at specific cutoff dates are shown in Table 1 below. [Table 1]

[0075] PR = 50-75% reduction in tumor size, MR = 25-50% reduction, SD = stable or up to 25% reduction in tumor size.

[0076] To date, mirdametinib has been well tolerated and shown clinical promise when administered continuously in patients with recurrent / progressive pediatric LGG (pLGG).

[0077] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that a term in this application is found to be defined differently in a document incorporated herein by reference, the definition provided herein shall serve as the definition of that term.

[0078] While the invention has been described in conjunction with specific embodiments thereof, it will be understood that it is capable of further modifications, and that this application is intended to cover any variations, uses, or adaptations of the present disclosure, including departures from the present disclosure that may be applied to the essential features set forth above, which generally follow the principles and come within known or customary practice in the art to which the invention pertains, and which comply with the scope of the claims.

Claims

1. 1. A method of treating low-grade glioma in a subject in need thereof, comprising administering mirdametinib or a pharma- ceutical acceptable salt thereof to the patient.

2. 2. The method of claim 1, wherein the patient has one or more BRAF, MYB, RAF1, or FGFR1 mutations.

3. The method according to claim 1 or 2, wherein a therapeutically effective amount of mirdametinib or a pharma- ceutically acceptable salt thereof is administered.

4. The mirdametinib or a pharma- ceutical acceptable salt thereof is administered at a dose of about 1 mg / m per day based on the mirdametinib free base. ２ ~Approx. 10mg / m ２ The method of claim 1 , wherein the compound is orally administered in an amount of

5. The mirdametinib or a pharma- ceutical acceptable salt thereof is administered at a dose of about 4 mg / m per day based on the mirdametinib free base. ２ The method according to any one of claims 1 to 3, wherein the compound is orally administered in an amount of

6. The mirdametinib or a pharma- ceutical acceptable salt thereof is administered at a dose of about 5 mg / m per day based on the mirdametinib free base. ２ The method according to any one of claims 1 to 3, wherein the compound is orally administered in an amount of

7. The mirdametinib or a pharma- ceutical acceptable salt thereof is administered at a dose of about 6 mg / m per day based on the mirdametinib free base. ２ The method according to any one of claims 1 to 3, wherein the compound is orally administered in an amount of

8. The method of any one of claims 1 to 7, wherein the mirdametinib or a pharma- ceutically acceptable salt thereof is administered orally once daily.

9. The method of any one of claims 1 to 7, wherein the mirdametinib or a pharma- ceutically acceptable salt thereof is administered orally twice daily.

10. The mirdametinib or a pharma- ceutical acceptable salt thereof is administered in an amount of about 2 mg / m2 based on the mirdametinib free base. ２ The method according to any one of claims 1 to 3, wherein the compound is orally administered twice daily in an amount of

11. The mirdametinib or a pharma- ceutical acceptable salt thereof is administered at a dose of about 2.5 mg / m2 based on the mirdametinib free base. ２ The method according to any one of claims 1 to 3, wherein the compound is orally administered twice daily in an amount of

12. The mirdametinib or a pharma- ceutical acceptable salt thereof is administered in an amount of about 3 mg / m2 based on the mirdametinib free base. ２ The method according to any one of claims 1 to 3, wherein the compound is orally administered twice daily in an amount of

13. (a) Body surface area is 0.69 m ２ The patient is initially administered 1 mg of mirdametinib orally twice daily, (b) Body surface area is 0.7 to 1.04 m ２ said patient initially receiving 2 mg of mirdametinib orally twice daily; (c) Body surface area is 1.05 to 1.49 m ２ said patient initially receiving 3 mg of mirdametinib orally twice daily; (d) Body surface area is 1.5 m ２ For the above patients, the patient is initially administered 4 mg of mirdametinib orally twice daily. The method according to any one of claims 1 to 3.

14. (a) Body surface area is 0.38 m ２ ~1.80m ２ For a patient, the patient is initially administered 3.0 mg / m ２ Mirdametinib was administered orally twice daily. (b) Body surface area is 0.44 m ２ ~2.22m ２ For a patient, the patient is initially administered 2.0 mg / m ２ Mirdametinib was administered orally twice daily. (c) Body surface area is 0.44 m ２ ~3.0m ２ For a patient, the patient is initially administered 1.0 mg / m ２ of mirdametinib administered orally twice daily. The method according to any one of claims 1 to 3.

15. 13. The method of any one of the preceding claims, wherein the administered dose is reduced due to an adverse event, and wherein the dose is reduced as follows: (a) if the dose at the time of the event is 1 mg of mirdametinib twice daily, then the reduced daily dose is 1 mg of mirdametinib administered orally in the morning only; (b) if the dose at the time of the event is 2 mg of mirdametinib twice daily, the reduced daily dose is 2 mg of mirdametinib administered orally in the morning and 1 mg of mirdametinib administered in the afternoon or evening; (c) if the dose at the time of the event is 3 mg of mirdametinib twice daily, the reduced daily dose is 2 mg of mirdametinib administered orally twice daily; and (d) if the dose at the time of the event is 4 mg mirdametinib twice daily, then the reduced daily dose is 3 mg mirdametinib administered orally twice daily.

16. 16. The method of claim 15, wherein the adverse event leading to the dose reduction is an acneiform rash.

17. 2. The method of any one of the preceding claims, wherein in each four week period, the mirdametinib is administered for the first three weeks and discontinued for the last week.

18. 2. The method of any one of the preceding claims, wherein the patient is aged 2 to less than 25 years.

19. The method of any one of claims 1 to 17, wherein the patient is between 2 and 21 years old.

20. The method of any one of claims 1 to 17, wherein the patient is a pediatric patient.

21. The method of any one of claims 1 to 17, wherein the patient is aged between 2 and 15 years.

22. 2. The method of any one of the preceding claims, wherein the human has not previously been exposed to a MEK inhibitor.

23. 2. The method of any one of the preceding claims, wherein the mirdametinib or a pharma- ceutically acceptable salt thereof is administered as monotherapy to treat the low-grade glioma.

24. The method according to any one of claims 1 to 22, wherein the mirdametinib or a pharma- ceutically acceptable salt thereof is administered in combination with other active ingredients and / or surgery to treat the low-grade glioma.

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