Treatment of cutaneous neurofibromas with mirdametinib

Abstract

The present disclosure relates to a method for treating cutaneous neurofibroma (cNF), the method comprising administering to a patient in need thereof mirdametinib, or a pharma- ceutically acceptable salt thereof.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 321,036, filed March 17, 2022, and U.S. Provisional Application No. 63 / 321,046, filed March 17, 2022, each of which is incorporated herein by reference.

[0002] Mirdametinib is an allosteric small molecule that targets mitogen-activated protein kinase kinase (MEK).

[0003] Weiss described a phase II clinical trial of mirdametinib in subjects with neurofibromatosis type 1 who had plexiform neurofibromas (Weiss et al., J. Clin. Oncol., 29, 797-806, 2021).

[0004] The present disclosure relates to a method for treating cutaneous neurofibromas (cNFs), the method comprising administering to a patient in need thereof mirdametinib, or a pharmaceutically acceptable salt thereof. [Background technology]

[0005] There are many clinical features associated with the neuropathic condition neurofibromatosis type 1 (NF1). However, it is the development of cutaneous neurofibromas (cNF) that affects the majority of NF1 patients. Neurofibromas are defined as histologically benign (WHO grade I) tumors composed of multiple cell types, including Schwann cells, fibroblasts, immune cells (such as mast cells and macrophages), and other neural elements. Regardless of their location, all neurofibromas share certain histological and cytological characteristics.

[0006] The most common and prominent site for neurofibromas is the skin (including the epidermis and dermis). Individual lesions are often referred to as cutaneous or cutaneous neurofibromas. cNFs are benign and have no known malignant potential.

[0007] Although not life-threatening, cNFs have a major impact on the quality of life of most patients with NF1 due to their prevalence and disfigurement. Furthermore, the number of cNFs increases with age after adolescence and throughout the patient's life. Despite the documented high prevalence of cNFs in patients with NF1 and their impact on quality of life, current treatment is limited to surgical removal or physical destruction.

[0008] There is a need for improved treatments for cutaneous neurofibromas. Summary of the Invention

[0009] One aspect of the present invention is a method of treating cutaneous neurofibroma (cNF) in a human patient, the method comprising administering to the patient mirdametinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient in need thereof further has neurofibromatosis 1 ("NF1").

[0010] In some embodiments, a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, mirdametinib, or a pharmaceutically 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 In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg to about 10 mg per day based on mirdametinib free base.

[0011] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.1 mg / m based on mirdametinib free base. 2 ~about 10mg / m 2 In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in a single dosage form containing about 0.1 mg to about 10 mg of mirdametinib free base.

[0012] In some embodiments, Mirdametinib, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0013] In one embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg / m per day based on mirdametinib free base. 2 ~about 10mg / m 2 It is administered orally in the amount of

[0014] In another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 1 mg to about 10 mg per day based on mirdametinib free base.

[0015] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 2 mg / m per day based on mirdametinib free base. 2 It is administered orally in the amount of

[0016] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 2 mg per day based on mirdametinib free base.

[0017] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 4 mg per day based on mirdametinib free base.

[0018] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 6 mg per day based on mirdametinib free base.

[0019] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 8 mg per day based on mirdametinib free base.

[0020] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally twice daily in an amount of about 1 mg based on mirdametinib free base.

[0021] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally twice daily in an amount of about 2 mg based on mirdametinib free base.

[0022] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally twice daily in an amount of about 3 mg based on mirdametinib free base.

[0023] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally twice daily in an amount of about 4 mg based on mirdametinib free base.

[0024] 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 if: (b) Body surface area is 0.7 to 1.04 m 2 For patients with , patients will initially receive 2 mg of mirdametinib orally twice daily. (c) Body surface area is 1.05 to 1.49 m 2 For patients with , the patient will initially receive 3 mg of mirdametinib orally twice daily, and (d) a body surface area of ​​at least 1.5 m 2 For patients with , patients will initially receive 4 mg of mirdametinib orally twice daily.

[0025] In one embodiment, the maximum daily dose is 4 mg of mirdametinib twice daily.

[0026] In one embodiment, over each 4-week period, mirdametinib is administered for the first 3 weeks and discontinued for the last week.

[0027] In another embodiment, mirdametinib is administered every day without interruption.

[0028] In one 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 orally in the morning only; (b) if the dose at the time of the event is 2 mg mirdametinib twice daily, the reduced daily dose is 2 mg orally in the morning and 1 mg 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 orally twice daily; and (d) If the dose at the time of the event is 4 mg mirdametinib twice daily, the reduced daily dose is 3 mg orally twice daily.

[0029] In one embodiment, the adverse event leading to a dose reduction is acne-like.

[0030] In one embodiment of any of the methods described herein, the method further comprises, prior to treatment, (i) determining whether to select mirdametinib as treatment for the patient, and (ii) selecting mirdametinib as treatment for the patient based at least in part on its objective response rate, where the objective response rate is defined as at least a 20% reduction in tumor size using centrally read MRI volumetric analysis. In one embodiment, in step (i), mirdametinib is selected based on a response rate of at least 70%. In another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 75%. In yet another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 80%. In yet another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 85%. In yet another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 90%. In yet another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 95%.

[0031] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, exhibits high blood-brain barrier permeability.

[0032] In one embodiment, the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and has one or more of the following: (a) 6 or more cafe au lait spots, diameter >5 mm in prepubertal individuals and >15 mm in postpubertal individuals; (b) pigmented macules in the axillary or inguinal region; (c) optic glioma, (d) two or more Lisch nodules; (e) specific bony lesions (sphenoid dysplasia or thinning of the long bone cortex), and (f) first-degree relative with NF1.

[0033] In another embodiment, the patient has a constitutional NF1 mutation documented by a Clinical Laboratory Improvement Amendments / College of American Pathologists certified laboratory.

[0034] In one embodiment of any of the methods described herein, the patient is a human. In one embodiment, the human is an adult. In another embodiment, the patient is between 2 and 15 years of age.

[0035] In one embodiment of any of the methods described herein, the human has not had prior exposure to a MEK inhibitor.

[0036] In one embodiment of any of the methods described herein, Mirdametinib or its pharmaceutically acceptable salt is orally administered.In some aspects, Mirdametinib or its pharmaceutically acceptable salt is dispersible in drinking liquid or dispersible in patient's saliva.In some aspects, Mirdametinib or its pharmaceutically acceptable salt is orally administered as a solid dosage form.In some aspects, the solid dosage form is a tablet or capsule.In some aspects, the solid dosage form is a capsule.

[0037] In one embodiment of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered as monotherapy for cNF. In one embodiment of any of the methods described herein, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in combination with another active ingredient and / or surgery to treat cNF. DETAILED DESCRIPTION OF THE INVENTION

[0038] I. Definition To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0039] 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.

[0040] As used in this specification and 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 aspects, the terms "a" or "an" mean "single." In other aspects, the terms "a" or "an" include "two or more" or "multiple."

[0041] 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" used in phrases such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" 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 (alone); B (alone); and C (alone).

[0042] The term "mirdametinib" refers to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (free base form). The teachings throughout this specification regarding mirdametinib also apply to pharmaceutically acceptable salts of mirdametinib.

[0043] 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, referring to a mammalian subject, such as, for example, a human subject. A patient may be a pediatric patient.

[0044] "mg / m 2 The term "body surface area" refers to the area of ​​the patient's body that is covered by 1 m 2 refers to the dose in milligrams per tablet.

[0045] The term "child" refers to a human subject under the age of 21 at the time of treatment. The term "child" can be further divided into various subpopulations, including neonates (birth to 28 days after birth), infants (29 days to under 2 years of age), children (2 to under 12 years of age), and adolescents (12 to 21 years of age (up to but excluding their 22nd birthday)). See, e.g., Berhman RE, Kliegman R, Arvin AM, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In particular, young pediatric patients, such as neonates, infants, and toddlers, may have difficulty swallowing whole capsules or tablets.

[0046] The term "dispersible" as used herein refers to a composition (e.g., a tablet, powder, granules, minitablets, or pellets) that disintegrates and / or dissolves when combined with water or another drinking liquid (e.g., a non-aqueous beverage), or the subject's own saliva when placed in the mouth of the subject, with or without stirring or temperature change. In some embodiments, the dispersible composition disintegrates or dissolves within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute after being combined with water or another drinking liquid. Such disintegration or dissolution need not be complete. For example, a dispersible tablet may dissolve almost completely, although some undissolved particulate matter may remain. Dispersible formulations of mirdametinib suitable for the methods described herein include those described in U.S. Pat. No. 11,571,402, which is incorporated herein by reference.

[0047] The term "orodispersible" refers to a composition that, when orally administered, can dissolve or disintegrate in a subject's mouth (i.e., dissolve or disintegrate in the subject's saliva) without first having to be dissolved or disintegrated in a separate container.

[0048] 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 result. Thus, those in need of treatment include those already diagnosed with a disorder or those suspected of having a disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; a decrease in the extent of the condition, disorder, or disease; a stabilized (i.e., non-worsening) state of the condition, disorder, or disease; a delay in the onset or slowing of the progression of the condition, disorder, or disease; an improvement or remission (partial or complete) of the condition, disorder, or disease state; an improvement in at least one measurable physical parameter not necessarily discernible by the patient; or an enhancement or amelioration of the 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 if not receiving 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 that amount of a compound that is 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.

[0049] In certain embodiments, if a patient shows one or more of the following: tumor size reduction; quality of life improvement; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS) increase, 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, according to the methods described herein, the subject is "treated" successfully for tumor. In some embodiments, the nationally or internationally accepted criteria for treatment outcome for a given tumor can be used to determine whether an effective amount of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0050] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, 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).

[0051] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of Compound A or Compound B. These salts can be prepared in situ during the manufacturing process of an administration vehicle or dosage form, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid and then isolating the salt formed during purification. Representative salts include 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 lauryl sulfate. See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.

[0052] Pharmaceutically acceptable salts of the subject compounds include the conventional non-toxic salts or quaternary ammonium salts of the compounds, derived, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as 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.

[0053] The term "about" or "approximately" refers to the tolerance of error for a particular value, as determined by one of ordinary skill in the art, which 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.

[0054] 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 that follow.

[0055] II. Treatment Methods Provided herein are methods for treating patients with cutaneous neurofibromas ("cNF"), comprising administering mirdametinib, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In some embodiments, the patient in need thereof further has neurofibromatosis 1 ("NF1").

[0056] In some embodiments, a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof, is administered.

[0057] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg / m per day based on mirdametinib free base. 2 ~about 10mg / m 2 , 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 , approximately 5 mg / m per day based on mirdametinib free base 2 ~about 6mg / m 2 In some embodiments, mirdametinib, or a pharmaceutically 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 per day based on mirdametinib free base 2 , approximately 4 mg / m per day based on mirdametinib free base 2 , approximately 4.5 mg / m per day 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 base 2 , 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 per day based on mirdametinib free base2 , 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

[0058] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg per day based on mirdametinib free base, about 1.5 mg per day based on mirdametinib free base, about 2 mg per day based on mirdametinib free base, about 2.5 mg per day based on mirdametinib free base, about 3 mg per day based on mirdametinib free base, about 3.5 mg per day based on mirdametinib free base, about 4 mg per day based on mirdametinib free base, about 4.5 mg per day based on mirdametinib free base, about 5 mg per day based on mirdametinib free base, The mirdametinib free base is administered in an amount of about 5.5 mg per day based on the mirdametinib free base, about 6 mg per day based on the mirdametinib free base, about 6.5 mg per day based on the mirdametinib free base, about 7 mg per day based on the mirdametinib free base, about 7.5 mg per day based on the mirdametinib free base, about 8 mg per day based on the mirdametinib free base, about 8.5 mg per day based on the mirdametinib free base, about 9 mg per day based on the mirdametinib free base, about 9.5 mg per day based on the mirdametinib free base, or about 10 mg per day based on the mirdametinib free base.

[0059] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.1 mg / m 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 approximately 4.5 mg / m based on mirdametinib free base 2 ~about 5.5mg / m 2 In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in a single dosage form comprising about 0.1 mg / m 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:

[0060] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in a single dosage form comprising about 0.1 mg to about 10 mg based on mirdametinib free base, 0.5 mg to about 9.5 mg based on mirdametinib free base, 1 mg to about 9 mg based on mirdametinib free base, 1.5 mg to about 8.5 mg based on mirdametinib free base, 2 mg to about 8 mg based on mirdametinib free base, 2.5 mg to about 7.5 mg based on mirdametinib free base, 3 mg to about 7 mg based on mirdametinib free base, 3.5 mg to about 6.5 mg based on mirdametinib free base, 4 mg to about 6 mg based on mirdametinib free base, or 4.5 mg to about 5.5 mg based on mirdametinib free base. In some embodiments, Mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.1 mg based on the mirdametinib free base, about 0.2 mg based on the mirdametinib free base, about 0.3 mg based on the mirdametinib free base, about 0.4 mg based on the mirdametinib free base, about 0.5 mg based on the mirdametinib free base, about 1 mg based on the mirdametinib free base, about 1.5 mg based on the mirdametinib free base, about 2 mg based on the mirdametinib free base, about 2.5 mg based on the mirdametinib free base, about 3 mg based on the mirdametinib free base, about 3.5 mg based on the mirdametinib free base, or about 4 mg based on the mirdametinib free base. The drug is administered in a single dosage form containing about 4 mg based on the mirdametinib free base, about 4.5 mg based on the mirdametinib free base, about 5 mg based on the mirdametinib free base, about 5.5 mg based on the mirdametinib free base, about 6 mg based on the mirdametinib free base, about 6.5 mg based on the mirdametinib free base, about 7 mg based on the mirdametinib free base, about 7.5 mg based on the mirdametinib free base, about 8 mg based on the mirdametinib free base, about 8.5 mg based on the mirdametinib free base, about 9 mg based on the mirdametinib free base, about 9.5 mg based on the mirdametinib free base, or about 10 mg based on the mirdametinib free base.

[0061] In some embodiments, Mirdametinib or its pharmaceutically acceptable salt is administered once, twice, three times or four times per day.In some embodiments, Mirdametinib or its pharmaceutically acceptable salt is administered once per day.In some embodiments, Mirdametinib or its pharmaceutically acceptable salt is administered twice per day.

[0062] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.5 mg / m 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, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily in an amount of about 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 It is administered twice daily in the amount of

[0063] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily in an amount of about 0.5 mg to about 10 mg based on mirdametinib free base, about 1 mg to about 9.5 mg based on mirdametinib free base, about 1.5 mg to about 9 mg based on mirdametinib free base, about 2 mg to about 8.5 mg based on mirdametinib free base, about 2.5 mg to about 8 mg based on mirdametinib free base, about 3 mg to about 7.5 mg based on mirdametinib free base, about 3.5 mg to about 7 mg based on mirdametinib free base, about 4 mg to about 6.5 mg based on mirdametinib free base, about 4.5 mg to about 6 mg based on mirdametinib free base, or about 5 mg to about 6 mg based on mirdametinib free base. In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg based on mirdametinib free base, about 1 mg based on mirdametinib free base, about 1.5 mg based on mirdametinib free base, about 2 mg based on mirdametinib free base, about 2.5 mg based on mirdametinib free base, about 3 mg based on mirdametinib free base, about 3.5 mg based on mirdametinib free base, about 4 mg based on mirdametinib free base, about 4.5 mg based on mirdametinib free base, or about 5 mg based on mirdametinib free base. about 5 mg based on mirdametinib free base, about 5.5 mg based on mirdametinib free base, about 6 mg based on mirdametinib free base, about 6.5 mg based on mirdametinib free base, about 7 mg based on mirdametinib free base, about 7.5 mg based on mirdametinib free base, about 8 mg based on mirdametinib free base, about 8.5 mg based on mirdametinib free base, about 9 mg based on mirdametinib free base, about 9.5 mg based on mirdametinib free base, or about 10 mg based on mirdametinib free base twice daily.

[0064] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg / m based on mirdametinib free base. 2 , approximately 9.5 mg / m based on mirdametinib free base 2 , approximately 9 mg / m based on mirdametinib free base2 , approximately 8.5 mg / m based on mirdametinib free base 2 , approximately 8 mg / m based on mirdametinib free base 2 , approximately 7.5 mg / m based on mirdametinib free base 2 , approximately 7 mg / m based on mirdametinib free base 2 , approximately 6.5 mg / m based on mirdametinib free base 2 , approximately 6 mg / m based on mirdametinib free base 2 , approximately 5.5 mg / m based on mirdametinib free base 2 , approximately 5 mg / m based on mirdametinib free base 2 , approximately 4.5 mg / m based on mirdametinib free base 2 , approximately 4 mg / m based on mirdametinib free base 2 , approximately 3.5 mg / m based on mirdametinib free base 2 , approximately 3 mg / m based on mirdametinib free base 2 , approximately 2.5 mg / m based on mirdametinib free base 2 , approximately 2 mg / m based on mirdametinib free base 2 , or 1.5 mg / m based on mirdametinib free base 2 The total daily dose is not to exceed 100 mg / kg.

[0065] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 10 mg based on mirdametinib free base, about 9.5 mg based on mirdametinib free base, about 9 mg based on mirdametinib free base, about 8.5 mg based on mirdametinib free base, about 8 mg based on mirdametinib free base, about 7.5 mg based on mirdametinib free base, about 7 mg based on mirdametinib free base, about 6.5 mg based on mirdametinib free base, The dose is administered at a total daily dose not to exceed about 6 mg based on mirdametinib free base, about 5.5 mg based on mirdametinib free base, about 5 mg based on mirdametinib free base, about 4.5 mg based on mirdametinib free base, about 4 mg based on mirdametinib free base, about 3.5 mg based on mirdametinib free base, about 3 mg based on mirdametinib free base, about 2.5 mg based on mirdametinib free base, about 2 mg based on mirdametinib free base, or about 1.5 mg based on mirdametinib free base.

[0066] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered as mirdametinib free base.

[0067] Provided herein are methods for treating patients with cutaneous neurofibromas ("cNF"), comprising administering mirdametinib free base to a patient in need thereof. In some embodiments, the patient further has neurofibromatosis 1 ("NF1").

[0068] In some embodiments, a therapeutically effective amount of mirdametinib free base is administered.

[0069] In some embodiments, mirdametinib free base is administered at a dose of about 1 mg / m per day. 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 approximately 5 mg / m per day 2 ~about 6mg / m 2 In some embodiments, 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 approximately 10 mg / m per day 2 is administered in an amount of

[0070] In some embodiments, mirdametinib free base is administered in an amount of about 1 mg to about 10 mg per day, about 1.5 mg to about 9.5 mg per day, about 2 mg to about 9 mg per day, about 2.5 mg to about 8.5 mg per day, about 3 mg to about 8 mg per day, about 3.5 mg to about 7.5 mg per day, about 4 mg to about 7 mg per day, about 4.5 mg to about 6.5 mg per day, or about 5 mg to about 6 mg per day. In some embodiments, mirdametinib free base is administered in an amount of about 1 mg per day, about 1.5 mg per day, about 2 mg per day, about 2.5 mg per day, about 3 mg per day, about 3.5 mg per day, about 4 mg per day, about 4.5 mg per day, about 5 mg per day, about 5.5 mg per day, about 6 mg per day, about 6.5 mg per day, about 7 mg per day, about 7.5 mg per day, about 8 mg per day, about 8.5 mg per day, about 9 mg per day, about 9.5 mg per day, or about 10 mg per day.

[0071] In some embodiments, the mirdametinib free base is 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, the 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 approximately 10 mg / m 2 The compound is administered in a single dosage form comprising:

[0072] In some embodiments, mirdametinib free base is administered in a single dosage form containing about 0.1 mg to about 10 mg, about 0.5 mg to about 9.5 mg, about 1 mg to about 9 mg, about 1.5 mg to about 8.5 mg, about 2 mg to about 8 mg, about 2.5 mg to about 7.5 mg, about 3 mg to about 7 mg, about 3.5 mg to about 6.5 mg, about 4 mg to about 6 mg, about 4.5 mg to about 5.5 mg, or about 5 mg to about 6 mg. In some embodiments, mirdametinib free base is administered in a single dosage form comprising about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0073] In some embodiments, mirdametinib free base is administered once, twice, three times, or four times per day. In some embodiments, mirdametinib free base is administered once per day. In some embodiments, mirdametinib free base is administered twice per day.

[0074] In some embodiments, the mirdametinib free base is about 0.5 mg / m 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 approximately 5 mg / m 2 ~about 6mg / m 2 In some embodiments, the mirdametinib free base is administered twice daily in an amount of about 0.5 mg / 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 / m2 , about 9.5mg / m 2 , or approximately 10 mg / m 2 It is administered twice daily in the amount of

[0075] In some embodiments, mirdametinib free base is administered twice daily in an amount of 0.5 mg to about 10 mg, about 1 mg to about 9.5 mg, about 1.5 mg to about 9 mg, about 2 mg to about 8.5 mg, about 2.5 mg to about 8 mg, about 3 mg to about 7.5 mg, about 3.5 mg to about 7 mg, about 4 mg to about 6.5 mg, about 4.5 mg to about 6 mg, or about 5 mg to about 6 mg. In some embodiments, mirdametinib free base is administered twice daily in an amount of about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0076] In some embodiments, the mirdametinib free base is administered at a dose of about 10 mg / m 2 , about 9.5mg / m 2 , about 9mg / m 2 , about 8.5mg / m 2 , about 8mg / m 2 , about 7.5mg / m 2 , about 7mg / m 2 , about 6.5mg / m 2 , about 6mg / m 2 , about 5.5mg / m 2 , about 5mg / m 2 , about 4.5mg / m 2 , about 4mg / m 2 , about 3.5mg / m 2 , about 3mg / m 2 , about 2.5mg / m 2 , about 2mg / m 2 , or about 1.5 mg / m 2 The total daily dose is not to exceed 100 mg / kg.

[0077] In some embodiments, mirdametinib free base is administered at a total daily dose not exceeding about 10.5 mg, 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, or about 1.5 mg.

[0078] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 2 mg / m per day based on mirdametinib free base. 2 It is administered orally in the amount of

[0079] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 2 mg per day based on mirdametinib free base.

[0080] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 4 mg per day based on mirdametinib free base.

[0081] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 6 mg per day based on mirdametinib free base.

[0082] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally in an amount of about 8 mg per day based on mirdametinib free base.

[0083] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally twice daily in an amount of about 1 mg based on mirdametinib free base.

[0084] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally twice daily in an amount of about 2 mg based on mirdametinib free base.

[0085] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally twice daily in an amount of about 3 mg based on mirdametinib free base.

[0086] In yet another embodiment, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered orally twice daily in an amount of about 4 mg based on mirdametinib free base.

[0087] 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 if: (b) Body surface area is 0.7 to 1.04 m 2 For patients with , patients will initially receive 2 mg of mirdametinib orally twice daily. (c) Body surface area is 1.05 to 1.49 m 2 For patients with , the patient will initially receive 3 mg of mirdametinib orally twice daily, and (d) a body surface area of ​​at least 1.5 m 2 For patients with , patients will initially receive 4 mg of mirdametinib orally twice daily.

[0088] In one embodiment, the maximum daily dose is 4 mg of mirdametinib twice daily.

[0089] In one embodiment, over each 4-week period, mirdametinib is administered for the first 3 weeks and discontinued for the last week.

[0090] In another embodiment, mirdametinib is administered every day without interruption.

[0091] In one 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 orally in the morning only; (b) if the dose at the time of the event is 2 mg mirdametinib twice daily, the reduced daily dose is 2 mg orally in the morning and 1 mg 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 orally twice daily; and (d) If the dose at the time of the event is 4 mg mirdametinib twice daily, the reduced daily dose is 3 mg orally twice daily.

[0092] In one embodiment, the adverse event leading to a dose reduction is acne-like.

[0093] In one embodiment of any of the methods described herein, the method further comprises, prior to treatment, (i) determining whether to select mirdametinib as treatment for the patient, and (ii) selecting mirdametinib as treatment for the patient based at least in part on its objective response rate, where the objective response rate is defined as at least a 20% reduction in tumor size using centrally read MRI volumetric analysis. In one embodiment, in step (i), mirdametinib is selected based on a response rate of at least 70%. In another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 75%. In yet another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 80%. In yet another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 85%. In yet another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 90%. In yet another embodiment, in step (i), mirdametinib is selected based on a response rate of at least 95%.

[0094] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, exhibits high blood-brain barrier permeability.

[0095] In one embodiment, the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and has one or more of the following: (a) 6 or more cafe au lait spots, diameter >5 mm in prepubertal individuals and >15 mm in postpubertal individuals; (b) pigmented macules in the axillary or inguinal region; (c) optic glioma, (d) two or more Lisch nodules; (e) specific bony lesions (sphenoid dysplasia or thinning of the long bone cortex), and (f) first-degree relative with NF1.

[0096] In another embodiment, the patient has a constitutional NF1 mutation documented by a Clinical Laboratory Improvement Amendments / College of American Pathologists certified laboratory.

[0097] In one embodiment of any of the methods described herein, the patient is a human. In one embodiment, the human is an adult. In another embodiment, the patient is between 2 and 15 years of age. In some aspects, the human is between 2 and 18 years of age.

[0098] In some embodiments, the human has no prior exposure to a MEK inhibitor. In some embodiments, the human has not responded to prior treatment with one or more MEK inhibitors.

[0099] In some embodiments, Mirdametinib or its pharmaceutically acceptable salt is orally administered. In some embodiments, Mirdametinib or its pharmaceutically acceptable salt is orally administered as a solid dosage form. In some embodiments, the solid dosage form is a tablet or capsule. In some embodiments, the solid dosage form is a capsule. In some embodiments, Mirdametinib or its pharmaceutically acceptable salt is dispersible in drinking liquid or dispersible in the patient's saliva.

[0100] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered as monotherapy to treat cutaneous neurofibromas (“cNFs”).

[0101] In some embodiments, mirdametinib, or a pharmaceutically acceptable salt thereof, is administered in combination with another active ingredient and / or surgery to treat cutaneous neurofibromas ("cNF"). [Example]

[0102] Example 1: An open-label, multicenter, dose-ranging study to evaluate the safety, tolerability, and antitumor activity of mirdametinib monotherapy in adult patients with neurofibromatosis 1 (NF1) and cutaneous neurofibromas (cNF) A Phase 1 / 2a, Open-Label, Multicenter, Dose-Finding Study to Evaluate the Safety, Tolerability, and Antitumor Activity of Mirdametinib Monotherapy in Adult Patients with Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF)

[0103] Phase 1 Study Objectives: The primary study objective is to evaluate the safety and tolerability of mirdametinib monotherapy in adult patients with NF1 and cNF and to determine the RP2D (recommended Phase 2 dose). Secondary study objectives are to evaluate the antitumor activity of mirdametinib monotherapy in adult patients with NF1 and cNF. The exploratory study objectives are to evaluate the on-treatment effect of mirdametinib on target inhibition (pERK, markers of apoptosis, markers of mitosis, and measures of extracellular matrix proteins) in cutaneous neurofibroma(s) in adult patients with cutaneous neurofibromas (cNF) and NF1.

[0104] Phase 2A (POC) Study Objectives: The primary study objective is to evaluate the safety of mirdametinib monotherapy in adult patients with NF1 and cNF. Secondary study objectives are to evaluate the efficacy of mirdametinib monotherapy in adult patients with NF1 and cNF. Exploratory study objectives are (1) to evaluate the quality of life impact of mirdametinib monotherapy in adult patients with NF1 and cNF, and (2) to evaluate the on-treatment effect of mirdametinib on target inhibition (pERK, markers of apoptosis, markers of mitosis, and measures of extracellular matrix proteins) in cutaneous neurofibromas (cNF) and cutaneous neurofibromas(e) in adult patients with NF1.

[0105] Test Plan: The trial will be conducted in two phases: 1) Phase 1 will test the safety and tolerability of multiple dose cohorts of mirdametinib and identify up to two doses for Phase 2a; 2) Phase 2a of the trial will test the efficacy and safety of up to two different doses in participants with NF1 and cNF.

[0106] In both phases of the study, participation in the study will consist of three periods: screening, treatment, and post-study safety follow-up.

[0107] 1. Screening Period (Phase 1 and Phase 2a) Participants will be screened for up to 28 days before receiving their first dose of study treatment. Participants' disease diagnoses will be confirmed using clinical and pathology reports available to participants at the start of screening, and written informed consent, clinical examinations, and laboratory tests will be conducted to establish the participant's eligibility for the study.

[0108] Cardiac, ophthalmologic, and laboratory tests (including serum / urine pregnancy tests) will be performed.

[0109] Two target areas are selected (7 cm x 7 cm, with a minimum of six cutaneous neurofibromas ≥0.5 cm); 2D photographs of the target areas are taken to ensure tracking of the same lesions.

[0110] This is a routine visit where routine clinical tests are performed. Eligibility is determined based on the screening visit.

[0111] The following patient-reported outcome measures will be administered: Skindex26; Neurofibromatosis Burden Assessment Tool; and Pruritus Visual Analogue Scale.

[0112] For participants who do not register, a brief reason will be entered.

[0113] Eligible participants will receive their first dose of study treatment after all pre-dose assessments on Day 1 of Cycle 1. All participants will remain in the treatment phase of the study until disease progression, the participant discontinues study treatment for other reasons, the study is terminated by the sponsor for any reason, or the participant completes the study through Cycle 12 of Phase 1 or Cycle 12 of Phase 2a.

[0114] 2. Treatment period Phase 1 trial: Participants completed screening before receiving their first dose of study treatment (mirdametinib). There are four dose groups with a sample size of six participants each. 1. Study treatment will be administered orally at doses of 1 mg BID, 2 mg BID, 3 mg BID, or 4 mg BID for each of the four dose groups. 2. Dosing will be administered in 28-day cycles (4-week courses) on a continuous dosing schedule. The treatment phase will last a maximum of 12 cycles, followed by a 30-day safety follow-up period (safety follow-up visits are required only for participants not continuing into Phase 2a). 3. Study visits and participant evaluations will be similar to the activity schedule.

[0115] Phase 2a Study: Participants previously enrolled in the selected RP2D arm of Phase 1 will be enrolled in the Phase 2 study. 1. Newly enrolled participants in Phase 2 will be screened for up to 28 days before their first dose of study treatment (mirdametinib). Participants who meet the enrollment criteria will be randomly assigned to one of two active treatment arms or placebo. 2. Each group will include 12 participants, for a total of up to 36 participants. The study treatment will be administered orally at a dose to be determined after Phase 1. Medication will be administered in 28-day cycles (4-week courses) on a continuous dosing schedule. The treatment phase will last for up to 12 cycles, followed by a 30-day safety follow-up period. 3. Endpoint and PRO assessments will be conducted every 3 months (pre-treatment baseline, M3, M6, M9, M12). 4. Subjects will complete a daily diary to record adverse events and compliance with treatment.

[0116] Safety Follow-up Period (Phase 1 and Phase 2a): A post-study follow-up (FU) visit will be conducted 30 days (± 3 days) after the last dose of study drug, excluding subjects who died, withdrew consent, and opposed further data collection, received new treatment with a MEK inhibitor, or were lost to follow-up.

[0117] FU assessment can be performed in person (preferred) or by phone (if the subject is unable to come in).

[0118] Phase 1 (dose determination) In this phase, four different dose options of mirdametinib will be tested in up to 24 participants to identify two doses that will be used to advance to Phase 2. These two doses will be selected based on tolerability and efficacy signals. Each study arm will be enrolled and treated simultaneously, except for dose arm 4, which will not begin until the 3 mg BID dose is deemed to be tolerable.

[0119] Cohort management during dose determination The dose groups will proceed in parallel. The actual number of dose groups will be four. Each group will include six participants, for a total of 24 participants in this phase of the study. [Table 1]

[0120] Each dose group will begin with a continuous dosing approach. If two participants (33%) in a dose group experience a DLT (defined below), the dose group will be tapered to an intermittent (3 weeks / 1 week off) approach. If the DLT persists or if an additional 33% (N=2) of participants experience a DLT on the intermittent dosing approach, the dose group will be terminated.

[0121] The first management decision will be made after at least 25% of participants (N=6) have completed C1 or experienced a DLT.

[0122] Definition of Dose-Limiting Toxicity (DLT) DLT is defined as one or more of the following events occurring during the 28-day DLT period in Cycle 1, excluding toxicity clearly related to disease progression or intercurrent illness: DLT severity will be graded according to CTCAE v5.0: Hematology: Grade 4 or higher anemia. Hematologic toxicity as defined by: Grade 4 neutropenia lasting more than 5 days. Grade 3 febrile neutropenia (1000 / mm 3 (defined by an absolute neutrophil count [ANC] of > 38.3°C (> 101°F), a single temperature reading of > 38°C (> 100.4°F) or a temperature of > 38°C (> 100.4°F) sustained for > 1 hour). Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with clinically significant bleeding. Non-hematological: Grade 3 or greater ocular toxicity resulting in decreased vision limiting activities of daily living (ADL), including but not limited to glaucoma, retinal detachment, or retinal vascular disease. · Symptomatic reduction in left ventricular ejection fraction (LVEF) or other signs or symptoms of congestive heart failure (CHF). Events that meet the criteria of Hy's Law (all three characteristics): Aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) >3 × upper limit of normal (ULN) Concurrent elevation of total bilirubin >2×ULN without early evidence of bile stasis (elevated serum alkaline phosphatase) No alternative etiology identified Grade 3 or greater significant neurological toxicity (e.g., seizures, hallucinations, confusion, or delirium) Grade 3 or greater generalized muscle weakness. Grade 3 or greater increase in CK, confirmed by electrophoretic fractionation and associated with a significant increase in skeletal muscle isoenzyme (CK-MM) after excluding factors unrelated to the study drug (e.g., physical exercise, trauma, inflammatory comorbidities). Grade 3 or greater skin rash that has not begun to resolve within 7 days of initiating optimal medical and supportive care. Grade 3 or greater non-hematologic toxicity (excluding alopecia) not listed above that resolved to Grade 1 or less within 3 days of initiating optimal medical and supportive care.

[0123] Additionally, any clinically significant or persistent toxicity not included above may also be considered a DLT after review and discussion between CMC and the sponsor.

[0124] The following toxicities may not be considered DLTs at the investigator's discretion after consultation with the medical monitor: Isolated Grade 3 or Grade 4 laboratory abnormality not listed above (e.g., elevated lactose dehydrogenase) without clinical correlation that resolves to Grade 1 or less within 3 days of initiating optimal medical and supportive therapy. Grade 3 or greater nausea, vomiting, or diarrhea that resolves in 3 days or less in the absence of optimal medical therapy. · Grade 3 or greater fatigue that resolves in 5 days or less. Asymptomatic elevation of lipase or amylase levels of Grade 3 or greater without pancreatitis lasting 3 days or less.

[0125] Phase 2a (safety and efficacy POC) The objective of this phase is to generate proof-of-concept data on the safety and antitumor efficacy of mirdametinib in the treatment of cNF. Additionally, PK / PD will be evaluated.

[0126] This phase will begin after two doses from Phase 1 are selected for further testing. Participants who complete Phase 1 at either of the two recommended Phase 2 doses will continue in Phase 2, with cohorts expanded to 12 participants each.

[0127] Tracking cNF lesions To ensure that the same lesions are measured over time during the study, "target area" and "target cNF" lesions will be identified and marked at baseline before treatment.

[0128] Define two "target areas" (7 cm x 7 cm, with a minimum of six cutaneous neurofibroma "target cNF" lesions ≥ 0.5 cm in longest diameter). Use 2D photography to document the "target cNF" lesions in relation to skin landmarks in combination with a permanent map of the "target area" created by marking the location of each cNF on a plastic sheet template placed on the participant's relevant body area.

[0129] Measurement of cNF lesions This study will use a handheld 3D camera and digital calipers as measurement tools for cNF lesions.

[0130] At screening, the size of the cNF lesions will be assessed for eligibility using 3D photography or digital calipers (as locally recommended).

[0131] Phase 1 will assess tumor response using both 3D photography and digital calipers.

[0132] In Phase 2a, the primary efficacy assessment will be based on a 3D camera, and digital calipers will be used as a secondary endpoint.

[0133] To minimize variability in measurements, the same technician / staff member will be used throughout the study to obtain 3D images or caliper measurements. A blinded central examiner will be used for 3D image analysis. All photographs at each time point should be taken from the same distance, using similar lighting and camera settings.

[0134] Study population Eligible patients were adult patients (male and / or non-pregnant female), aged 18 years or older, with confirmed NF1 and a minimum of 12 measurable cutaneous neurofibromas (defined as non-schizophrenic, surrounded by normal skin, and not adjacent to another cNF lesion), each ≥0.5 cm in longest diameter and ≥0.5 cm in height, in communication with two "target areas" (defined as any two of the following body regions: head and neck, upper extremities, anterior chest wall, posterior chest wall, anterior abdominal wall, lower back, pelvic / gluteal region, or lower extremities).

[0135] Eligibility for inclusion Inclusion criteria Participants must meet all of the following criteria to be eligible for the study: 1. Participants must have either a clinical diagnosis of NF1 using the National Institutes of Health (NIH) Consensus Conference criteria, in addition to the presence of plexiform neurofibromas (PN), along with at least one other diagnostic criterion (Inclusions 2.1-2.6, see below), or a constitutional NF1 mutation documented in a Clinical Laboratory Improvement Amendments / College of American Pathologists-certified laboratory. Additional criteria are as follows: 2. 1. 6 or more cafe au lait spots, each greater than 5 mm in diameter in prepubertal individuals and greater than 15 mm in postpubertal individuals; 2.2. Pigmented spots in the axillary or inguinal area, 2.3. Optic glioma, 2.4. Two or more Lisch nodules, 2.5. Specific bony lesions (dysplasia of the sphenoid bone or dysplasia of the cortical thinning of long bones), 2.6. A first-degree relative with NF1, 3. Participants must have a Karnofsky performance level of 80% or greater. 4. Participant has adequate organ and bone marrow function as defined by the following screening laboratory values: 4.1. Absolute neutrophil count ≥ 1500 cells / μL; 4.2. Platelets are 100 x 10 3 / μL or more, 4.3. Hemoglobin level is 9.5 g / dL or higher, 4.4. Serum albumin ≥ 2.8 g / dL 4.5. Calculated creatinine clearance ≥ 60 mL / min (Cockcroft-Gault formula) at screening or normal serum creatinine. 5. Participants have the ability to swallow capsules whole if a capsule dosage form is being utilized. This criterion does not apply if participants are utilizing a dispersible tablet (Pediatric Dosage formulation) as the dosage form of the study treatment. 6. Participants are willing and able to comply with all aspects of the Protocol. contraception 7. Male or female Contraceptive use by men or women should be consistent with local regulations regarding contraceptive methods for clinical trial participants. a.Male participant: Male participants were eligible to participate if they agreed to the following during the treatment period and for at least 90 days after the last dose of study treatment: Refrain from donating semen Plus one of the following: Abstaining from heterosexual intercourse (long-term, sustained abstinence) as a desirable and normal lifestyle and agreeing to maintain abstinence or · If you have sex with a woman of childbearing potential (WOCBP), you must agree to use a male condom. b.Female participants: Female participants may participate if they are not pregnant or breastfeeding and at least one of the following conditions applies: Women of childbearing potential or You are a WOCBP and are using a highly effective (less than 1 year failure rate), preferably a method of contraception with low user dependency, during the treatment period and for at least 30 days after the last dose of study treatment, and agree not to donate eggs (eggs, egg cells) for reproductive purposes during the study period and for 90 days after the last dose of study treatment. The investigator will need to assess the effectiveness of the contraceptive method in relation to the first dose of study treatment. WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test at the baseline visit before the first dose of study treatment. The investigator is responsible for ascertaining medical history, menstrual history, and recent sexual activity to reduce the risk of including women with early undetected pregnancy.

[0136] Informed consent / assent The investigator or investigator's designee will obtain written informed consent and participant assent from each study participant, or the participant's legally acceptable representative, parent(s), or legal guardian, if applicable, prior to all study-specific activities. The investigator will retain the original signed consent / assent document for each participant.

[0137] Exclusion criteria: Participants who meet any of the following criteria are not eligible for the study:

[0138] health status Participants' screening alanine transaminase (ALT) levels >2.0 × upper limit of normal (ULN).

[0139] Participants had a total bilirubin level of >1.5 × ULN at screening (separate bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).

[0140] Participants had a history of malignancy-associated hypercalcemia.

[0141] Participants had active parathyroid disorder, hyperphosphatemia (serum phosphorus >1 × ULN) at screening, or a serum calcium (mg / dL) × serum phosphorus (mg / dL) product >70 at screening.

[0142] any history of clinically significant active or known liver disease or known liver or biliary tract abnormality (excluding Gilbert's syndrome or asymptomatic gallstones); Test hepatitis serology and viral load at screening. Patients who are hepatitis B surface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody positive at screening should not be enrolled until they have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) titer of less than 500 IU / mL or a negative HCV ribonucleic acid (RNA) polymerase chain reaction test.

[0143] Lymphoma, leukemia, or any malignancy (including malignant glioma or MPNST) within the past 5 years, except for excised basal cell carcinoma or squamous cell carcinoma of the skin with no evidence of metastatic disease for 3 years.

[0144] Breast cancer within the past 10 years.

[0145] Participants with evidence of active optic nerve glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy. Participants not requiring treatment are eligible. Ophthalmologic findings secondary to long-standing optic nerve glioma (such as vision loss, optic nerve palsy, or strabismus) or long-standing orbitotemporal PN (such as vision loss, strabismus) are not considered significant abnormalities for the purposes of the study.

[0146] Participants had an abnormal QT interval (>450 ms for male participants, >470 ms for female participants, or >480 ms for participants with bundle branch block) corrected by the Fridericia formula at screening (three ECG readings taken approximately 2–3 min apart and averaged).

[0147] Participants had experienced any of the following within 6 months (24 weeks) of signing the informed consent / assent: clinically significant cardiac disease, myocardial infarction, severe / unstable angina, coronary / peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism.

[0148] Participants had a documented LVEF of less than 55% or a history of congestive heart failure at screening or within 3 years of signing the informed consent / assent.

[0149] Participants will have a history or evidence of retinal pathology on eye examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration. Participants will be excluded from the study if they have any of the following risk factors for RVO at screening: Intraocular pressure > 21 mmHg, b. Serum cholesterol > 300 mg / dL; c. Serum triglycerides >300 mg / dL, d. Hyperglycemia (fasting blood glucose >125 mg / dL or random blood glucose >200 mg / dL), e. Age-related hypertension i. Participants aged 13 years or older with blood pressure ≥ 140 / 90mmHg ii. Participants aged 12 years or younger with blood pressure ≥ 95th percentile for age + 12 mmHg.

[0150] Participants had a history of glaucoma.

[0151] Participants had a history of positive human immunodeficiency virus (HIV) antibody testing.

[0152] Participant has a known malabsorption syndrome or a pre-existing gastrointestinal condition that may impair the absorption of mirdametinib (e.g., gastric bypass, lap-band, or other gastric procedure). Delivery of mirdametinib via a nasogastric or gastrostomy tube is prohibited.

[0153] Upfront / concomitant therapy Participants had previously received or were currently receiving treatment with mirdametinib.

[0154] Participants had received systemic or ocular glucocorticoid therapy within 14 days prior to the first dose of study treatment (except for participants with endocrine deficiencies who were permitted to receive physiological or stress doses of steroids as needed).

[0155] Participants must have received radiation therapy within 6 months prior to signing the informed consent / assent. Participants who have received radiation at any time during their orbit will be excluded.

[0156] Experience in prior / concurrent clinical trials Current enrollment or previous participation in other clinical trials (excluding observational studies) within 28 days of signing the informed consent / assent.

[0157] Other Exclusions Sensitivity to the study treatment or any component thereof, or to any drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

[0158] Participants with an active bacterial, fungal, or viral infection at screening, including but not limited to the use of antibiotics, antifungals, or antivirals.

[0159] underlying disease, clinical laboratory abnormalities, or alcohol or drug abuse or dependence that in the investigator's opinion is unfavorable to the administration of study treatment or affects the explanation for drug toxicity or adverse events, or poor compliance during the study according to the investigator, or

[0160] Participant is experiencing any other severe acute or chronic medical or psychiatric condition, including recent (within 1 year of signing / asserting informed consent) or current suicidal ideation or behavior, or laboratory abnormalities, that may increase the risks associated with study participation or study treatment administration or that may interfere with the interpretation of study results and that, in the investigator's judgment, would make the participant unsuitable for participation in this study.

[0161] All publications, patents, and patent applications mentioned in this specification are herein incorporated 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 control for that term.

[0162] While the invention has been described in relation to particular embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is generally intended to cover any variations, uses, or adaptations in accordance with the principles of the present disclosure, including such departures from the present disclosure as are within known or customary practice in the art to which this invention pertains, as may be applied to the essential features described above and as fall within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising mildametinib or a pharmaceutically acceptable salt thereof for the treatment of cutaneous neurofibroma (cNF) in a human patient in need thereof.

2. The pharmaceutical composition according to claim 1, wherein the patient further has neurofibromatosis 1 (NF1).

3. The pharmaceutical composition according to claim 1, wherein the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and has one or more of the following: (a) Six or more café au lait spots, with a diameter of more than 5 mm in pre-pubescent individuals and more than 15 mm in post-pubescent individuals. (b) Pigmented lesions in the axillary or groin area, (c) optic glioma, (d) Two or more Riche nodes, (e) specific bony lesions (malformations of the sphenoid bone, or malformations of thinning of the long bone cortex), and (f) A first-degree relative who has NF1.

4. The pharmaceutical composition according to claim 1, wherein the patient has a constitutional NF1 mutation documented by a Clinical Laboratory Improvement Amendments / College of American Pathologists certified laboratory.

5. A pharmaceutical composition according to any one of claims 1 to 4, comprising a therapeutically effective amount of mildametinib or a pharmaceutically acceptable salt thereof.

6. The mildametinib, or a pharmaceutically acceptable salt thereof, is administered at a rate of approximately 1 mg / m² per day based on the free base of mildametinib. ２ ~Approx. 10mg / m ２ A pharmaceutical composition according to any one of claims 1 to 4, for oral administration in an amount.

7. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 1 mg to about 10 mg per day based on mildametinib free base.

8. A pharmaceutical composition according to any one of claims 1 to 4, for administering mildametinib or a pharmaceutically acceptable salt thereof once daily.

9. A pharmaceutical composition according to any one of claims 1 to 4, for administering mildametinib or a pharmaceutically acceptable salt thereof twice daily.

10. The mildametinib, or a pharmaceutically acceptable salt thereof, is administered at a rate of approximately 2 mg / m² per day based on the free base of mildametinib. ２ A pharmaceutical composition according to any one of claims 1 to 4, for oral administration in an amount.

11. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 2 mg per day based on mildametinib free base.

12. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 4 mg per day based on mildametinib free base.

13. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 6 mg per day based on mildametinib free base.

14. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 8 mg per day based on mildametinib free base.

15. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 1 mg based on mildametinib free base twice daily.

16. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 2 mg based on mildametinib free base twice daily.

17. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 3 mg based on mildametinib free base twice daily.

18. A pharmaceutical composition according to any one of claims 1 to 4, for orally administering mildametinib or a pharmaceutically acceptable salt thereof in an amount of about 4 mg based on mildametinib free base twice daily.

19. (a) Body surface area of ​​0.69 m ２ In the case of the following patients, the patient will initially be given 1 mg of mildametinib orally twice daily. (b) Body surface area of ​​0.7 to 1.04 m ２ In the case of such a patient, the patient is initially given 2 mg of mildametinib orally twice daily. (c) Body surface area of ​​1.05 to 1.49 m² ２ In the case of the patient, the patient is initially given 3 mg of mildametinib orally twice daily, and (d) Body surface area of ​​at least 1.5 m ２ In the case of a patient, the patient is initially administered 4 mg of mildametinib orally twice daily, according to any one of claims 1 to 4.

20. The pharmaceutical composition according to any one of claims 1 to 4, wherein the maximum daily dose is 4 mg of mildametinib twice daily.

21. The pharmaceutical composition according to any one of claims 1 to 4, wherein mildametinib is administered for the first three weeks and discontinued for the last week over a period of four weeks.

22. The dose administered may be reduced due to adverse events, and the dose may be reduced as follows: (a) If the dose at the time of the event is 1 mg of mildametinib twice daily, the reduced daily dose is 1 mg orally administered only in the morning. (b) If the dose at the time of the event is 2 mg of mildametinib twice daily, the reduced daily dose is 2 mg orally in the morning and 1 mg in the afternoon or evening. (c) If the dose at the time of the event is 3 mg of mildametinib twice daily, the reduced daily dose is 2 mg orally twice daily, and (d) If the dose at the time of the event is 4 mg of mildametinib twice daily, the reduced daily dose is 3 mg orally twice daily, according to any one of claims 1 to 21.

23. The pharmaceutical composition according to claim 22, wherein the adverse event resulting from the reduction in the dose is acne-like.

24. The pharmaceutical composition according to any one of claims 1 to 4, wherein the treatment further comprises, before treatment, (i) determining whether or not to select mirdametinib as the treatment for the patient, and (ii) selecting mirdametinib as the treatment for the patient based at least in part on its objective response rate, wherein the objective response rate is defined as a reduction of at least 20% in tumor size using centrally interpreted MRI volume analysis.

25. The pharmaceutical composition according to claim 24, wherein in step (i), mildametinib is selected based on an at least 70% response rate.

26. The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient is between 2 and 15 years of age.

27. The pharmaceutical composition according to any one of claims 1 to 4, wherein the human is an adult.

28. The pharmaceutical composition according to any one of claims 1 to 4, wherein the human patient has not been previously exposed to a MEK inhibitor.

29. The pharmaceutical composition according to any one of claims 1 to 4, wherein the mildametinib or a pharmaceutically acceptable salt thereof is administered as monotherapy.

30. The pharmaceutical composition according to any one of claims 1 to 4, wherein the mildametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery.