Mirdametinib treatment

Abstract

The present disclosure relates to a method of treating certain types of tumors or cancers, e.g., plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), by orally administering to a patient an effective amount of mirdametinib, the amount of mirdametinib being such that, on the first day of treatment, (i) an AUC 0-tau , (ii) C of 40 ng / mL or less max or (iii) both.

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 by reference in its entirety herein.

[0002] The present disclosure relates to a method of treating certain types of tumors or cancers, e.g., plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), by orally administering to a patient an effective amount of mirdametinib, the amount of mirdametinib being such that, on the first day of treatment, (i) an AUC 0-tau , (ii) C of 40 ng / mL or less max or (iii) administered to provide both. [Background technology]

[0003] Mirdametinib is an allosteric small molecule compound that targets mitogen-activated protein kinase (MEK).

[0004] Weiss describes a phase II clinical trial of mirdametinib in subjects with neurofibromatosis type 1 with plexiform neurofibromas (Weiss et al., J. Clin. Oncol., 29, 797-806, 2021).

[0005] There is a continuing need for improved treatments for tumors and cancers, including NF1-PN. Summary of the Invention

[0006] One aspect of the invention relates to a method of treating a patient (e.g., a human patient) aged 2 years or older having inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib being an AUC 0-tauThe present inventors have discovered that lower doses of mirdametinib can be administered to effectively treat patients with tumors or cancers (e.g., NF1-PN) with reduced toxicity. In one embodiment, patients receive an AUC of less than 400 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide. In one embodiment, the patient has symptomatic inoperable plexiform neurofibromas.

[0007] Another embodiment is a method of treating a human patient 2 years of age or older with NF1-associated PN that is progressing or causing significant morbidity by orally administering to the patient an effective amount of mirdametinib, wherein the amount of mirdametinib is an AUC 0-tau In one embodiment, the patient has an AUC of less than 400 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide

[0008] Yet another embodiment provides for the treatment of human patients 2 years of age or older with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), comprising administering 1 mg mirdametinib twice daily with an AUC of less than 400 ng·h / mL on the first day of treatment. 0-tau This method is carried out by orally administering the compound to a patient so as to achieve the above-mentioned objective.

[0009] Yet another embodiment is a method of treating a human patient 2 years of age or older with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), comprising administering 1 mg mirdametinib twice daily at a C of 40 ng / mL or less on the first day of treatment. max orally administering to a patient such that the

[0010] Yet another embodiment is a method of treating a human patient, 8 years of age or older, having inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib being such that, on the first day of treatment, (i) an AUC 0-tau , (ii) C of 40 ng / mL or less max or (iii) both, during which the patient is suffering from an acneiform rash and is treated (or administered) topically with clindamycin. In one embodiment, the patient is suffering from a pustular rash. In one embodiment, the patient is administered an AUC 0-tau Mirdametinib is administered continuously to provide Yet another embodiment is a method of treating a tumor or cancer in a patient (e.g., a human patient) by orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib having, on the first day of treatment, (i) an AUC 0-tau , (ii) C of 40 ng / mL or less max In one embodiment, the patient is administered to provide (i) an AUC of less than 400 ng·h / mL, or (iii) both. 0-tau , (ii) C of 40 ng / mL or less maxor (iii) mirdametinib is administered continuously to provide both. In one embodiment, the tumor or cancer is selected from the group consisting of plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), high-grade glioma (HGG), low-grade ovarian cancer, Langerhans cell histiocytosis (LCH), brain tumor, and cancer metastasized to the patient's brain. In one embodiment, the tumor or cancer is a plexiform neurofibroma. In another embodiment, the tumor or cancer is a plexiform neurofibroma associated with neurofibromatosis type 1. In yet another embodiment, the tumor or cancer is a high-grade glioma. In yet another embodiment, the high-grade glioma is a primary cancer. In yet another embodiment, the high-grade glioma is a metastatic cancer. In yet another embodiment, the tumor or cancer is a low-grade ovarian cancer. In yet another embodiment, the tumor or cancer is a Langerhans cell histiocytosis. In yet another embodiment, the tumor or cancer is a brain tumor. In yet another embodiment, the tumor or cancer is a cancer (including lung cancer, breast cancer, and melanoma) that has metastasized to the patient's brain.

[0011] In yet another embodiment, there is provided a method of treating a human patient, age 2 or older, having inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), by orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib being an effective amount of mirdametinib having a C of 40 ng / mL or less on the first day of treatment. max is administered to achieve

[0012] Yet another embodiment is a method of treating a human patient, age 2 or older, with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) that are progressing or causing significant morbidity, by orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib being in an amount that is equal to or less than 40 ng / mL C on the first day of treatment. max In one embodiment, the amount of mirdametinib is administered to provide a C of 32 ng / mL or less on the first day of treatment. maxIn another embodiment, the amount of mirdametinib is administered to provide a C of 30 ng / mL or less on the first day of treatment. max is administered to provide

[0013] Yet another embodiment is a method of treating a human patient at least 2 years of age having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising: (a) selecting mirdametinib as a treatment for a 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; (b) if mirdametinib is selected as the treatment, administering an effective amount of mirdametinib orally to the patient. In one embodiment, in step (a), 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%.

[0014] In one embodiment of any of the methods described herein, the amount of mirdametinib has an AUC 0-tau In one embodiment, the patient has an AUC of less than 200 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide

[0015] In one embodiment of any of the methods described herein, the amount of mirdametinib has an AUC 0-tau In one embodiment, the patient has an AUC of less than 100 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide

[0016] In one embodiment of any of the methods described herein, the patient has symptomatic inoperable plexiform neurofibroma (PN).

[0017] In one embodiment of any of the methods described herein, the patient has advanced PN.

[0018] In one embodiment of any of the methods described herein, the patient has PN that causes significant morbidity.

[0019] In one embodiment of any of the methods described herein, the patient (e.g., NF1-PN patient) has a head and neck lesion that damages the airway or large blood vessels, a brachial or lumbar plexus lesion that causes nerve compression and loss of function, a lesion that causes significant disfigurement or significant disfigurement, a limb lesion that causes limb enlargement or loss of function, or a painful lesion. In one embodiment, the lesion that causes significant disfigurement or significant disfigurement is a tumor in the head and neck, or a tumor in another body site that cannot be hidden by standard clothing. In one embodiment of any of the methods described herein, the patient has a paraspinal lesion.

[0020] In one embodiment of any of the methods described herein, the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and one or more of the following: (a) 6 or more cafe au lait spots, each greater than 5 mm in diameter in prepubertal individuals and greater than 15 mm in diameter in postpubertal individuals; (b) Ephelidean pigmentation in the axillary or inguinal area, (c) optic glioma, (d) 2 or more Lisch nodules; (e) characteristic bone lesions (dysplasia of the sphenoid bone or thinning dysplasia of the long bone cortex), and (f) A first-degree relative with NF1.

[0021] In one embodiment of any of the methods described herein, the patient has a constitutional NF1 mutation documented by a Clinical Laboratory Improvement Amendments / College of American Pathologists accredited laboratory.

[0022] In one embodiment of any of the methods described herein, the patient (a) has a parent diagnosed with NF1 and one or more criteria of (1)-(7), or (b) does not have a parent diagnosed with NF1 but has two or more criteria of (1)-(7): (1) Six or more cafe au lait spots, each greater than 5 mm in maximum diameter in prepubertal individuals and greater than 15 mm in maximum diameter in postpubertal individuals; (2) Ephelidean pigmentation in the axillary or inguinal area, (3) Two or more neurofibromas of any type, or one plexiform neurofibroma, (4) Optic pathway glioma (5) 2 or more iris-Lish nodules identified by slit-lamp examination or 2 or more choroidal abnormalities (defined as distinct patchy nodules by optical coherence tomography (OCT) / near-infrared reflectance (NIR) imaging); (6) characteristic bone lesions (e.g., sphenoid dysplasia, anterolateral varus of the tibia, or nonunion of a long bone), and (7) Heterozygous pathogenic NF1 variants with a 50% proportion of variant alleles in apparently normal tissues (e.g., white blood cells).

[0023] In one embodiment of any of the methods described herein, (a) Body surface area is 0.69 m 2Patients will initially receive 1 mg mirdametinib twice daily 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 twice daily. (c) Body surface area is 1.05 to 1.49 m 2 For patients with , patients initially received 3 mg of mirdametinib twice daily, (d) Body surface area is 1.5 m 2 For these patients, patients will initially receive 4 mg of mirdametinib twice daily.

[0024] In one embodiment of any of the methods described herein, the initial dosing regimen is continued unless, for example, a serious adverse event occurs that requires a reduction in the dosage regimen.

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

[0026] 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.

[0027] In one embodiment of any of the methods described herein, the patient experiences at least a 20% reduction in plexiform neurofibroma volume as quantified by volumetric magnetic resonance imaging after treatment with mirdametinib.

[0028] In one embodiment of any of the methods described herein, treatment results in a decrease in pain intensity.

[0029] In one embodiment of any of the methods described herein, treatment results in a decrease in pain interference.

[0030] In one embodiment of any of the methods described herein, the dose administered 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 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 administered in the morning and 1 mg 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 administered 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 administered twice daily. In one embodiment, the adverse event leading to the dose reduction is acneiform.

[0031] In one embodiment of any of the methods described herein, during treatment the patient is administered topical clindamycin to treat acne.

[0032] In one embodiment of any of the methods described herein, the patient is at least 2 years old. In one embodiment, the patient is at least 2 years old and less than 25 years old. In yet another embodiment of any of the methods described herein, the patient is between 2 and 15 years old.

[0033] In one embodiment of any of the methods described herein, the method further comprises, prior to treatment, (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient based at least in part on its objective response rate, the objective response rate being 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%.

[0034] In some embodiments, a therapeutically effective amount of mirdametinib or a pharma- ceutical acceptable salt thereof is administered. In some embodiments, 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 In some embodiments, mirdametinib or a pharma- ceutical acceptable salt thereof is administered in an amount of about 1 mg to about 10 mg per day based on mirdametinib free base.

[0035] In some embodiments, 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 2In some embodiments, mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered in a single dosage form comprising about 0.1 mg to about 10 mg of mirdametinib free base.

[0036] In some embodiments, mirdametinib or a pharma- ceutically acceptable salt thereof is administered once a day.In some embodiments, mirdametinib or a pharma- ceutically acceptable salt thereof is administered twice a day.

[0037] In some embodiments, mirdametinib, or a pharma- ceutically acceptable salt thereof, exhibits high blood-brain barrier permeability.

[0038] In one embodiment of any of the methods described herein, the human patient has not been previously exposed to a MEK inhibitor.

[0039] In one embodiment of any of the methods described herein, mirdametinib or its pharma- ceutically acceptable salt is orally administered.In some embodiments, mirdametinib or its pharma- ceutically acceptable salt is dispersible in drinking liquid or orodispersible in patient's saliva.In some embodiments, mirdametinib or its pharma- ceutically 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.

[0040] In one embodiment of any of the methods described herein, mirdametinib or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat tumors or cancer. In some embodiments, mirdametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat tumors or cancer.

[0041] In one embodiment of any of the methods described herein, the mirdametinib is mirdametinib free base.

[0042] Yet another embodiment is an oral pharmaceutical composition comprising 1 mg of mirdametinib, the composition having an AUC of less than 400 ng·h / mL upon initial oral administration to a human subject who has just begun treatment with mirdametinib. 0-tau In one embodiment, the composition has an AUC of less than 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, or 100 ng·h / mL upon initial oral administration to a human subject who has just begun treatment with mirdametinib. 0-tau to provide.

[0043] Yet another embodiment is an oral pharmaceutical composition comprising 1 mg of mirdametinib, the composition having a C of 40 ng / mL or less upon initial oral administration to a human subject who has just begun treatment with mirdametinib. max In one embodiment, the composition provides a C of 38, 36, 34, 32, 30, or 28 ng / mL or less upon initial oral administration to a human subject who has just begun treatment with mirdametinib. max to provide.

[0044] In one embodiment of any of the compositions described herein, the mirdametinib is mirdametinib free base. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] I. Definition To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0046] 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.

[0047] 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."

[0048] 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).

[0049] The term "mirdametinib" refers to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The teachings on mirdametinib throughout this specification are equally applicable to pharmaceutically acceptable salts of mirdametinib. For example, the present disclosure of a method for treating inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) using mirdametinib also means that pharmaceutically acceptable salts of mirdametinib can be administered to treat inoperable PN associated with NF1.

[0050] "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.

[0051] 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 with reference to a mammalian subject, such as, for example, a human subject. A patient may be a pediatric patient.

[0052] 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 divided into various subpopulations, including neonates (birth to 28 days after birth), infants (29 days to 2 years), children (2 to 12 years), and adolescents (12 to 21 years (up to but not including their 22nd birthday)). See, for example, 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. Young pediatric patients, especially (eg, neonates, infants, and young children), may have difficulty swallowing capsules or tablets whole.

[0053] "AUC 0-tau The term "area under the plasma concentration-time curve from time 0 to the end of the dosing interval. For twice-daily drugs, the dosing interval is 0 to 12 hours.

[0054] "C max " refers to peak plasma concentration.

[0055] 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.

[0056] 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.

[0057] 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 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.

[0058] In certain embodiments, a subject is successfully "treated" with tumor according to the methods described herein if the patient shows one or more of the following: reduction in tumor size; improvement in quality of life; increase in 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), decrease in progression (PD), increase in time to progression (TTP), or any combination thereof.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).

[0059] In certain embodiments, if a patient shows one or more of the following: 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., ovarian cancer) 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).

[0060] 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).

[0061] 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 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. (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19.

[0062] Pharmaceutically acceptable salts of the subject compounds include, for example, conventional non-toxic salts or quaternary ammonium salts from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid) and 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).

[0063] 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.

[0064] 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.

[0065] II. Treatment method One aspect of the invention relates to a method of treating a patient (e.g., a human patient) aged 2 years or older having inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib being an AUC 0-tau In one embodiment, the patient has an AUC of less than 400 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide. In one embodiment, the patient has symptomatic inoperable plexiform neurofibromas.

[0066] Another embodiment is a method of treating a human patient 2 years of age or older with NF1-associated PN that is progressing or causing significant morbidity by orally administering to the patient an effective amount of mirdametinib, wherein the amount of mirdametinib is an AUC 0-tauIn one embodiment, the patient has an AUC of less than 400 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide

[0067] Yet another embodiment provides for the treatment of human patients 2 years of age or older with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), comprising administering 1 mg mirdametinib twice daily with an AUC of less than 400 ng·h / mL on the first day of treatment. 0-tau This method is carried out by orally administering the compound to a patient so as to achieve the above-mentioned objective.

[0068] Yet another embodiment is a method of treating a human patient 2 years of age or older with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), comprising administering 1 mg mirdametinib twice daily at a C of 40 ng / mL or less on the first day of treatment. max orally administering to a patient such that the

[0069] Yet another embodiment is a method of treating a human patient, 8 years of age or older, having inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib being such that, on the first day of treatment, (i) an AUC 0-tau , (ii) C of 40 ng / mL or less max or (iii) both, during which the patient is suffering from an acneiform rash and is treated (or administered) topically with clindamycin. In one embodiment, the patient is suffering from a pustular rash. In one embodiment, the patient is administered an AUC 0-tau Mirdametinib is administered continuously to provide Yet another embodiment is a method of treating a tumor or cancer in a patient (e.g., a human patient) by orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib having, on the first day of treatment, (i) an AUC 0-tau , (ii) C of 40 ng / mL or lessmax In one embodiment, the patient is administered to provide (i) an AUC of less than 400 ng·h / mL, or (iii) both. 0-tau , (ii) C of 40 ng / mL or less max or (iii) mirdametinib is administered continuously to provide both. In one embodiment, the tumor or cancer is selected from the group consisting of plexiform neurofibroma (PN), plexiform neurofibroma associated with neurofibromatosis type 1 (NF1-PN), high-grade glioma (HGG), low-grade ovarian cancer, Langerhans cell histiocytosis (LCH), brain tumor, and cancer metastasized to the patient's brain. In one embodiment, the tumor or cancer is a plexiform neurofibroma. In another embodiment, the tumor or cancer is a plexiform neurofibroma associated with neurofibromatosis type 1. In yet another embodiment, the tumor or cancer is a high-grade glioma. In yet another embodiment, the high-grade glioma is a primary cancer. In yet another embodiment, the high-grade glioma is a metastatic cancer. In yet another embodiment, the tumor or cancer is a low-grade ovarian cancer. In yet another embodiment, the tumor or cancer is a Langerhans cell histiocytosis. In yet another embodiment, the tumor or cancer is a brain tumor. In yet another embodiment, the tumor or cancer is a cancer (including lung cancer, breast cancer, and melanoma) that has metastasized to the patient's brain.

[0070] In yet another embodiment, there is provided a method of treating a human patient, age 2 or older, having inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), by orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib being an effective amount of mirdametinib having a C of 40 ng / mL or less on the first day of treatment. max is administered to achieve

[0071] Yet another embodiment is a method of treating a human patient, age 2 or older, with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) that are progressing or causing significant morbidity, by orally administering to the patient an effective amount of mirdametinib, the amount of mirdametinib being in an amount that is equal to or less than 40 ng / mL C on the first day of treatment.max In one embodiment, the amount of mirdametinib is administered to provide a C of 32 ng / mL or less on the first day of treatment. max In another embodiment, the amount of mirdametinib is administered to provide a C of 30 ng / mL or less on the first day of treatment. max is administered to provide

[0072] Yet another embodiment is a method of treating a human patient at least 2 years of age having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising: (a) selecting mirdametinib as a treatment for a 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; (b) if mirdametinib is selected as the treatment, administering an effective amount of mirdametinib orally to the patient. In one embodiment, in step (a), 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%.

[0073] In one embodiment of any of the methods described herein, the amount of mirdametinib has an AUC 0-tauIn one embodiment, the patient receives an AUC of less than 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, or 100 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide

[0074] In one embodiment of any of the methods described herein, the amount of mirdametinib has an AUC 0-tau In one embodiment, the patient has an AUC of less than 200 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide

[0075] In one embodiment of any of the methods described herein, the amount of mirdametinib has an AUC 0-tau In one embodiment, the patient has an AUC of less than 100 ng·h / mL. 0-tau Mirdametinib is administered continuously to provide

[0076] In one embodiment of any of the methods described herein, the amount of mirdametinib is a C of 38, 36, 34, 32, 30, or 28 ng / mL or less on the first day of treatment. max In another embodiment of any of the methods described herein, the amount of mirdametinib is administered to provide a C of 32 ng / mL or less on the first day of treatment. max In yet another embodiment, the amount of mirdametinib is administered to provide a C of 30 ng / mL or less on the first day of treatment. max is administered to provide

[0077] In one embodiment of any of the methods described herein, the patient has symptomatic inoperable plexiform neurofibroma (PN).

[0078] In one embodiment of any of the methods described herein, the patient has advanced PN.

[0079] In one embodiment of any of the methods described herein, the patient has PN that causes significant morbidity.

[0080] In one embodiment of any of the methods described herein, the patient (e.g., NF1-PN patient) has a head and neck lesion that damages the airway or large blood vessels, a brachial or lumbar plexus lesion that causes nerve compression and loss of function, a lesion that causes significant disfigurement or significant disfigurement, a limb lesion that causes limb enlargement or loss of function, or a painful lesion. In one embodiment, the lesion that causes significant disfigurement or significant disfigurement is a tumor in the head and neck, or a tumor in another body site that cannot be hidden by standard clothing. In one embodiment of any of the methods described herein, the patient has a paraspinal lesion.

[0081] In one embodiment of any of the methods described herein, the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and one or more of the following: (a) 6 or more cafe au lait spots, each greater than 5 mm in diameter in prepubertal individuals and greater than 15 mm in diameter in postpubertal individuals; (b) Ephelidean pigmentation in the axillary or inguinal area, (c) optic glioma, (d) 2 or more Lisch nodules; (e) characteristic bone lesions (dysplasia of the sphenoid bone or thinning dysplasia of the long bone cortex), and (f) A first-degree relative with NF1.

[0082] In one embodiment of any of the methods described herein, the patient has a constitutional NF1 mutation documented by a Clinical Laboratory Improvement Amendments / College of American Pathologists accredited laboratory.

[0083] In one embodiment of any of the methods described herein, the patient (a) has a parent diagnosed with NF1 and one or more criteria of (1)-(7), or (b) does not have a parent diagnosed with NF1 but has two or more criteria of (1)-(7): (1) Six or more cafe au lait spots, each greater than 5 mm in maximum diameter in prepubertal individuals and greater than 15 mm in maximum diameter in postpubertal individuals; (2) Ephelidean pigmentation in the axillary or inguinal area, (3) Two or more neurofibromas of any type, or one plexiform neurofibroma, (4) Optic pathway glioma (5) 2 or more iris-Lish nodules identified by slit-lamp examination or 2 or more choroidal abnormalities (defined as distinct patchy nodules by optical coherence tomography (OCT) / near-infrared reflectance (NIR) imaging); (6) characteristic bone lesions (e.g., sphenoid dysplasia, anterolateral varus of the tibia, or nonunion of a long bone), and (7) Heterozygous pathogenic NF1 variants with a 50% proportion of variant alleles in apparently normal tissues (e.g., white blood cells).

[0084] 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 mirdametinib twice daily 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 twice daily. (c) Body surface area is 1.05 to 1.49 m 2 For patients with , patients initially received 3 mg of mirdametinib twice daily, (d) Body surface area is 1.5 m 2 For these patients, patients will initially receive 4 mg of mirdametinib twice daily.

[0085] In one embodiment of any of the methods described herein, the initial dosing regimen is continued unless, for example, a serious adverse event occurs that requires a reduction in the dosage regimen.

[0086] In one embodiment of any of the methods described herein, the maximum daily dose is 4 mg of mirdametinib twice daily.

[0087] 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.

[0088] In one embodiment of any of the methods described herein, the patient experiences at least a 20% reduction in plexiform neurofibroma volume as quantified by volumetric magnetic resonance imaging after treatment with mirdametinib.

[0089] In one embodiment of any of the methods described herein, treatment results in a decrease in pain intensity.

[0090] In one embodiment of any of the methods described herein, treatment results in a decrease in pain interference.

[0091] In one embodiment of any of the methods described herein, the dose administered 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 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 administered in the morning and 1 mg 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 administered 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 administered twice daily. In one embodiment, the adverse event leading to the dose reduction is an acneiform rash.

[0092] In one embodiment of any of the methods described herein, during treatment the patient is administered topical clindamycin to treat acne.

[0093] In one embodiment of any of the methods described herein, the human patient is at least 2 years old. In one embodiment, the human patient is at least 2 years old and less than 25 years old. In another embodiment of any of the methods described herein, the human patient is between 2 and 15 years old. In another embodiment of any of the methods described herein, the human patient is between 2 and 18 years old.

[0094] In one embodiment of any of the methods described herein, the method further comprises, prior to treatment, (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient based at least in part on its objective response rate, the objective response rate being 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%.

[0095] In some embodiments, a therapeutically effective amount of mirdametinib or a pharma- ceutical acceptable salt thereof is administered. In some embodiments, 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 In some embodiments, mirdametinib or a pharma- ceutical acceptable salt thereof is administered in an amount of about 1 mg to about 10 mg per day based on mirdametinib free base.

[0096] In some embodiments, 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 In some embodiments, mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered in a single dosage form comprising about 0.1 mg to about 10 mg of mirdametinib free base.

[0097] In some embodiments, mirdametinib or a pharma- ceutically acceptable salt thereof is administered once a day.In some embodiments, mirdametinib or a pharma- ceutically acceptable salt thereof is administered twice a day.

[0098] In some embodiments, mirdametinib, or a pharma- ceutically acceptable salt thereof, exhibits high blood-brain barrier permeability.

[0099] In one embodiment of any of the methods described herein, the human patient has not been previously exposed to a MEK inhibitor.

[0100] In one embodiment of any of the methods described herein, mirdametinib or its pharma- ceutically acceptable salt is orally administered.In some embodiments, mirdametinib or its pharma- ceutically acceptable salt is dispersible in drinking liquid or orodispersible in patient's saliva.In some embodiments, mirdametinib or its pharma- ceutically 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.

[0101] In one embodiment of any of the methods described herein, mirdametinib or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat tumors or cancer. In some embodiments, mirdametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat tumors or cancer.

[0102] In one embodiment of any of the methods described herein, the mirdametinib is mirdametinib free base.

[0103] In some embodiments, a therapeutically effective amount of mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered.

[0104] In some embodiments, 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 / 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 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 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 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

[0105] In some embodiments, mirdametinib or a pharma- ceutically acceptable salt thereof is administered in an amount of about 1 mg to about 10 mg per day based on mirdametinib free base, about 1.5 mg to about 9.5 mg per day based on mirdametinib free base, about 2 mg to about 9 mg per day based on mirdametinib free base, about 2.5 mg to about 8.5 mg per day based on mirdametinib free base, about 3 mg to about 8 mg per day based on mirdametinib free base, about 3.5 mg to about 7.5 mg per day based on mirdametinib free base, about 4 mg to about 7 mg per day based on mirdametinib free base, about 4.5 mg to about 6.5 mg per day based on mirdametinib free base, or about 5 mg to about 6 mg per day based on mirdametinib free base. In some embodiments, mirdametinib or a pharma- ceutical 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, about 6 mg per day based on mirdametinib free base, about 7 mg per day based on mirdametinib free base, about 8 mg per day based on mirdametinib free base, about 9 mg per day based on mirdametinib free base, about 10 mg per day based on mirdametinib free base, about 11 mg per day based on mirdametinib free base, about 12 mg per day based on mirdametinib free base, about 13 mg per day based on mirdametinib free base, about 14 mg per day based on mirdametinib free base, about 15 mg per day based on mirdametinib free base, about 16 mg per day based on mirdametinib free base, about 17 mg per day based on mirdametinib free base, about 18 mg per day based on mirdametinib free base, about 19 mg per day based on mirdametinib free base, about 20 mg per day based on mirdametinib free base, about 21 mg per day based on mirdametinib free base, about 22 mg per day based on mirdametinib free base, about 23 mg per day based on mirdametinib free base, about 24 mg per day based on mirdametinib free base, about 25 mg per day based on mirdametin The drug is administered in an amount of about 5.5 mg per day based on mirdametinib free base, about 6 mg per day based on mirdametinib free base, about 6.5 mg per day based on mirdametinib free base, about 7 mg per day based on mirdametinib free base, about 7.5 mg per day based on mirdametinib free base, about 8 mg per day based on mirdametinib free base, about 8.5 mg per day based on mirdametinib free base, about 9 mg per day based on mirdametinib free base, about 9.5 mg per day based on mirdametinib free base, or about 10 mg per day based on mirdametinib free base.

[0106] In some embodiments, 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 / m2 , 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, 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:

[0107] In some embodiments, mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered in a unitary dosage form comprising from 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 pharma- ceutical acceptable salt thereof, is administered in an amount of about 0.1 mg based on mirdametinib free base, about 0.2 mg based on mirdametinib free base, about 0.3 mg based on mirdametinib free base, about 0.4 mg based on mirdametinib free base, 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 ... The compound is administered in a single dosage form containing about 4 mg based on the base, about 4.5 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.

[0108] In some embodiments, mirdametinib or its pharmaceutically acceptable salt is administered once, twice, three times or four times a day.In some embodiments, mirdametinib or its pharmaceutically acceptable salt is administered once a day.In some embodiments, mirdametinib or its pharmaceutically acceptable salt is administered twice a day.

[0109] In some embodiments, 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, 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

[0110] In some embodiments, mirdametinib or a pharma- ceutically 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 pharma- ceutical acceptable salt thereof is administered twice daily at 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. The compound is administered in an amount of 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.

[0111] In some embodiments, mirdametinib or a pharma- ceutical 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 base 2 , approximately 8.5 mg / m based on mirdametinib free base2 , 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 should not exceed 10 mg / kg.

[0112] In some embodiments, mirdametinib or a pharma- ceutical 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, about 8 mg based on mirdametinib free base, about 8 mg based on mirdametinib free base, about 9 mg based on mirdametinib free base, about 10 ... The drug is administered in 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.

[0113] In some embodiments, mirdametinib or a pharma- ceutically acceptable salt thereof is administered as mirdametinib free base.

[0114] In some embodiments, the mirdametinib free base is 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 / m2 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 about 10 mg / m per day. 2 is administered in an amount of

[0115] 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.

[0116] 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 / m2 , 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:

[0117] 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, or about 4.5 mg to about 5.5 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.

[0118] In some embodiments, mirdametinib free base is administered once, twice, three times, or four times a day.In some embodiments, mirdametinib free base is administered once a day.In some embodiments, mirdametinib free base is administered twice a day.

[0119] In some embodiments, 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, mirdametinib free base is administered in an amount of about 0.5 mg / m twice daily. 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 is administered in an amount of

[0120] In some embodiments, mirdametinib free base is administered twice daily in an amount of about 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.

[0121] In some embodiments, the mirdametinib free base is at 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 should not exceed 10 mg / kg.

[0122] In some embodiments, mirdametinib free base is administered at a total daily dose not exceeding about 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.

[0123] In some embodiments, mirdametinib, or a pharma- ceutically acceptable salt thereof, exhibits high blood-brain barrier permeability.

[0124] In some embodiments, the human patient has not been exposed to a MEK inhibitor. In some embodiments, the human patient has not responded to previous treatment with one or more MEK inhibitors.

[0125] In some embodiments, mirdametinib or its pharma- ceutically acceptable salt is orally administered. In some embodiments, mirdametinib or its pharma- ceutically 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 pharma- ceutically acceptable salt is dispersible in drinking liquid or orally dispersible in patient's saliva. In one embodiment, mirdametinib or its pharma- ceutically acceptable salt is administered as a dispersible formulation (e.g., 0.5 mg or 1 mg mirdametinib dispersible tablet) as described in U.S. Pat. No. 11,571,402 (incorporated herein by reference).

[0126] In some embodiments, mirdametinib, or a pharma- ceutically acceptable salt thereof, is administered as a monotherapy to treat a tumor or cancer.

[0127] In some embodiments, mirdametinib or a pharma- ceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat tumors or cancer.

[0128] III. Pharmaceutical Compositions Yet another embodiment is an oral pharmaceutical composition comprising 1.0 mg of mirdametinib, the composition having an AUC of less than 400 ng·h / mL upon initial oral administration to a human subject who has just begun treatment with mirdametinib. 0-tau In one embodiment, the composition has an AUC of less than 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, or 100 ng·h / mL upon initial oral administration to a human subject who has just begun treatment with mirdametinib. 0-tau to provide.

[0129] Yet another embodiment is an oral pharmaceutical composition comprising 1.0 mg of mirdametinib, the composition having a C of 40 ng / mL or less upon initial oral administration to a human subject who has just begun treatment with mirdametinib. max In one embodiment, the composition provides a C of 38, 36, 34, 32, 30, or 28 ng / mL or less upon initial oral administration to a human subject who has just begun treatment with mirdametinib. max to provide.

[0130] The oral pharmaceutical compositions described herein may include one or more pharma- ceutical acceptable excipients. The oral pharmaceutical compositions may include one or more diluents, disintegrants, lubricants, or any combination of the foregoing. In one embodiment, the oral dosage form includes (a) about 0.1 w / w% to about 5 w / w% mirdametinib, (b) about 50 w / w% to about 98 w / w% of one or more diluents, (c) about 1 w / w% to about 10 w / w% of one or more disintegrants, and (d) up to about 5 w / w% of one or more lubricants.

[0131] Suitable diluents include, but are not limited to, microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate, calcium dihydrogen phosphate, and combinations of any of the foregoing. In one embodiment, the oral dosage form comprises the diluent microcrystalline cellulose.

[0132] Suitable disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, alginic acid, and combinations of any of the foregoing. In one embodiment, the oral dosage form comprises the disintegrant croscarmellose sodium.

[0133] Suitable lubricants include, but are not limited to, magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oils, sodium stearyl fumarate, glycerol dibehenate, talc, and combinations of any of the foregoing. In one embodiment, the oral dosage form includes the lubricant magnesium stearate.

[0134] Oral pharmaceutical compositions may be capsules, such as hard gelatin capsules, or tablets. EXAMPLES

[0135] Example 1: Phase I / II Evaluation of Mirdametinib, a Single Agent, Brain-Penetrant MEK1 / 2 Inhibitor, for the Treatment of Children, Adolescents, and Young Adults with Brain Tumors A multiarm Phase I / II study of mirdametinib will be conducted in patients aged 2 years or older and younger than 25 years with brain tumors. The Phase I study will require participants who have not been exposed to MEK inhibitors and have recurrent / progressive disease with biopsy-proven evidence of MAPK pathway activation. A rolling-6 design will be used with 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.

[0136] The median age at enrollment was 10 years (range, 3-21 years). No dose-limiting toxicities occurred across all three dose levels. No MEK-related retinopathy or cardiomyopathy was observed. No disease progression occurred. Thus far, mirdametinib has been well tolerated and clinically promising when administered continuously in patients with brain tumors.

[0137] Example 2: Phase 2b study of mirdametinib in adult and pediatric patients with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) that are progressing or causing significant morbidity. The objective of this study is to evaluate the efficacy, safety, and tolerability of mirdametinib in participants aged 2 years and older with inoperable NF1-associated plexiform neurofibromas (PN) that are progressing and / or causing significant morbidity.

[0138] Approximately 120 participants will be screened (assessed for eligibility as described below) to achieve study drug allocation for approximately 100 participants. Of these participants, approximately 50 will be aged 18 years or older and approximately 50 will be aged 2-17 years.

[0139] Participants will be screened up to 28 days prior to their first dose of the investigational drug mirdametinib. The investigational drug will be administered orally twice daily (BID) at the doses specified in the table below. Dosing will be in 28-day cycles (4-week courses) on a 3-week-on / 1-week-off schedule. Treatment will last up to 24 cycles, followed by a 30-day safety follow-up period. [Table 1]

[0140] Partial response is defined as a 20% or greater reduction in PN compared to baseline using centrally read MRI volumetric analysis.

[0141] Selection Criteria Patients can be included in the study only if they meet all of the following criteria: 1. Participants must be 2 years of age or older at the time of signing the informed consent / assent form. 2. Participants must have a clinical diagnosis of NF1 using the National Institutes of Health (NIH) Consensus Conference criteria, in addition to the presence of PN, at least one other diagnostic criterion (inclusion criteria 2.1–2.6, see below), or a documented constitutional NF1 mutation in a Clinical Laboratory Improvement Amendments / College of American Pathologists-accredited laboratory. 2.1 6 or more cafe au lait spots, each greater than 5 mm in diameter for prepubertal individuals and 15 mm in diameter for postpubertal individuals; 2.2 Ephelidean pigmentation in the axillary or inguinal area, 2.3 Optic glioma, 2.4 2 or more Richmond nodules, 2.5 Characteristic bone lesions (dysplasia of the sphenoid bone or thinning of the cortical long bones), 2.6 First-degree relative with NF1. 3. Participants' PN must be progressive (Inclusion Criterion 3.1) or causing significant morbidity (e.g., but not limited to, head and neck lesions damaging the airway or great vessels, brachial or lumbar plexus lesions causing nerve compression and loss of function, lesions causing significant deformity or significant disfigurement (Inclusion Criterion 3.2), limb lesions causing limb enlargement or loss of function, and painful lesions). Participants with paraspinal PN are eligible for the study. Histological confirmation of the tumor is not required if there is consistency of clinical and radiographic findings, but will be considered if there is clinical suspicion of malignant degeneration of the PN. 3.1 For participants enrolled with regard to tumor progression, progression will be defined as follows: 3.1.1 Measurable increase in PN size (≥20% volume increase) documented by comparison of two MRI scans during the 12-month period prior to the first dose of investigational drug (mirdametinib). 3.2 For participants enrolling with "severely disfiguring" or "markedly disfiguring" tumors, eligible tumors will be limited to tumors of the head and neck, or tumors in other body sites that cannot be concealed by standard clothing. 4. Participants have PN that is deemed inoperable (defined as PN that cannot be completely removed surgically without significant risk of morbidity due to inclusion or proximity of critical structures, invasiveness or high vascularity of the PN, or participant refusal of surgery). Participants who have previously undergone surgery for PN will be eligible to participate in the study after surgery if the PN is incompletely resected and evaluable by volumetric analysis. 5. Participants must have target PN, defined as the most clinically significant PN, amenable to MRI volumetric analysis. The target PN must be observed in at least 3 contiguous MRI slices in the study, with the entire tumor included in the field of view. The target PN must be determined by central radiological review to be analyzable by volumetric measurement, have a volume of at least 5 mL, and be classified as "typical PN," "nodular PN," or "isolated nodular PN" prior to the first dose of study drug. 6. Participants aged 18 years or older must have a PN amenable to percutaneous biopsy and be willing to undergo pre- and intra-treatment tumor biopsies to provide fresh tumor tissue. There should be no contraindications for serial biopsies. Patients aged 2-17 years will not undergo biopsy unless there is a clinical indication to obtain fresh tumor tissue. 7. Participants aged 16 and over must have a Karnofsky performance level of 60% or greater; participants under 16 must have a Lansky performance level of 60% or greater. 8. Participant has adequate organ and bone marrow function as defined by the following screening laboratory values: 8.1 Absolute neutrophil count ≥1500 cells / μL, 8.2 Platelets ≥ 100 × 10 3 / μL, 8.3 Hemoglobin ≥ 9.5 g / dL; 8.4 Serum albumin ≥ 2.8 g / dL; Calculated creatinine clearance ≥ 60 mL / min (Cockcroft-8.5 Gault formula) at screening or normal serum creatinine based on age as per the table below. [Table 2] 9. Participants may swallow the capsule whole. 10. Participants are willing and able to comply with all aspects of the Protocol. 11. Participants must weigh at least 10 kg at the time of signing the informed consent / assent form. 12. Participants must have a body surface area (BSA) of at least 0.4 m2 (inclusive) calculated using the Du Bois formula (BSA = 0.007184 x W0.425 x H0.725). 13. 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 sperm And one of the following: Agree to abstain (long-term and sustained) from heterosexual intercourse and remain abstinent as a preferred and normal lifestyle. or • If you have sexual intercourse with a woman of childbearing potential (WOCBP), you must agree to use a male condom. b.Female participants: Female participants were eligible to participate if they were not pregnant or breastfeeding and met at least one of the following criteria: Not a woman of childbearing age Or - Are WOCBP and agree to use a highly effective (failure rate less than 1% per year) and preferably low user-dependent method of contraception during treatment and for at least 30 days after the last dose of investigational drug, and to not donate eggs (eggs, oocytes) for reproductive purposes during the study and for the 90-day period. WOCBP must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result at baseline prior to the first dose of study drug.

[0142] Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria: 1. Participant's screening alanine transaminase (ALT) level is >2.0x the upper limit of normal (ULN). 2. Participant has a total bilirubin level >1.5xULN at screening (separate bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%). 3.Participant has a history of hypercalcemia associated with malignancy. 4. Participant has active parathyroid disorder, hyperphosphatemia (serum phosphorus >1 x ULN) at screening, and / or serum calcium (mg / dL) x serum phosphorus (mg / dL) product >70 at screening. 5. Any active or known clinically significant liver disease or known liver or bile duct abnormality (except Gilbert's syndrome or asymptomatic gallstones). 5.1 Test for hepatitis serology and viral load at screening. Patients with positive hepatitis B surface antigen (HBsAg) or positive hepatitis C virus (HCV) antibody at screening should not be enrolled until further confirmatory testing of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) titer <500 IU / mL or a negative HCV ribonucleic acid (RNA) polymerase chain reaction test is obtained. 6. Lymphoma, leukemia, or any malignancy within the past 5 years, including malignant glioma or malignant peripheral nerve sheath tumor (MPNST), except for basal cell or squamous cell carcinoma of the skin that has been resected and has had no evidence of metastatic disease for 3 years. 7. Breast cancer within the past 10 years. 8. 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. Ophthalmological findings secondary to long-standing optic pathway glioma (e.g., vision loss, optic nerve pallor, or strabismus) or ophthalmological findings secondary to long-standing orbitotemporal PN (e.g., vision loss, strabismus) are not considered significant abnormalities in this study. 9. The participant's QT interval corrected by the Fridericia formula after electrolyte correction (triplicate ECG readings taken 2-3 minutes apart and averaged) at screening is abnormal (>450 msec for male participants, >470 msec for female participants, or >480 msec for participants with bundle branch block). 10. Participant has experienced any of the following within 6 months (24 weeks) of signing the informed consent / assent form: clinically significant cardiac disease, myocardial infarction, severe / unstable angina, coronary / peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism. 11.Participant has had a documented left ventricular ejection fraction (LVEF) of less than 55% as assessed by echocardiogram or has a history of congestive heart failure. 12. Participants have a history of, or have evidence of retinal pathology on ophthalmologic 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 are currently known to have any of the following risk factors for RVO: 12.1 Intraocular pressure ≥ 21 mmHg, 12.2 Serum cholesterol >300 mg / dL, 12.3 Serum triglycerides >300 mg / dL, 12.4 Hyperglycemia (fasting blood glucose >125 mg / dL or random blood glucose >200 mg / dL), 12.5 Age-specific Hypertension i. Participants aged 13 years or older with blood pressure over 140 / 90mmHg ii. Participants aged 12 years or younger with blood pressure greater than the 95th percentile for age + 12 mmHg (Section 10.11) 13.Participant has a history of glaucoma. 14.Participant has a history of positive human immunodeficiency virus (HIV) antibody test. 15. 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 procedures). Delivery of mirdametinib via a nasogastric tube or gastrostomy is not permitted. 16. Participant has received NF1 PN targeted therapy (e.g., MEK inhibitor, farnesyltransferase inhibitor, kinase inhibitor, etc.) within 28 days (or 5.5 half-lives, whichever is longer) of the first dose of investigational drug. If a participant enrolls with progression and no associated morbidity, they must not have received NF1 targeted therapy after progression is observed (Inclusion Criterion 3.1.1). All toxicities from prior therapy must be grade 1 or less or have resolved to baseline. 17.Participant has previously received or is currently receiving treatment with mirdametinib. 18. Participant has received systemic or ocular glucocorticoid therapy within 14 days prior to the first dose of study drug (with the exception of participants with endocrine insufficiency, who may receive physiologic or stress doses of steroids if necessary). 19. Participant has received radiation therapy within 6 months prior to signing the informed consent / assent form. Participants who have received orbital radiation at any time will be excluded. 20. Currently participating in or have participated in any other clinical trial (observational studies excluded) within 28 days of signing the informed consent / assent form. 21. Participant cannot tolerate MRI or has contraindications for MRI. 22. The tumor cannot be reliably assessed by MRI dose analysis. 23. Sensitivity to the investigational drug or any of its components, or any drug or other allergy that the Investigator or Medical Monitor determines to contraindicate study participation. 24. Participant with active bacterial, fungal, or viral infection at screening (including but not limited to use of antibiotic, antifungal, or antiviral medications). 25. Underlying medical conditions, clinical laboratory abnormalities, or alcohol or drug abuse or dependence that the investigator determines is unfavorable to administration of the investigational product or that affects the interpretation of drug toxicity or adverse events, or if the investigator determines that compliance during the study is inadequate. 26. The participant has experienced any other serious acute or chronic medical or psychiatric condition (including recent (within 1 year of signing the informed consent / assent form)), or active suicidal thoughts or behavior, or laboratory abnormalities which, in the opinion of the Investigator, may increase the risks associated with study participation or administration of the investigational product, or may interfere with the interpretation of the study results, making the participant unsuitable for participation in the study.

[0143] Supportive care Dermatological adverse events:

[0144] The use of medications for supportive care of the rash is permitted. Early initiation of treatment of the rash is strongly recommended to minimize the duration and severity of adverse events.

[0145] Acne-like rash: Pustular rash can be treated with twice-daily application of clindamycin gel or lotion. In severe cases, semisynthetic oral tetracyclines such as doxycycline or minocycline may also be useful in older children, adolescents, and adults, but should be avoided in children under 8 years of age due to risks to developing teeth.

[0146] Eczema / Xeroderma: Eczema / dry skin rashes and other macular (non-acne-like) rashes should be treated with moisturizers such as Cerave or Eucerin, or another equivalent product. Less potent steroids (e.g., betamethasone valerate lotion (0.05%), desonide cream (0.05%), fluocinolone acetonide solution (0.01%), dexamethasone sodium phosphate cream (0.1%), hydrocortisone acetate cream (1%), methylprednisolone acetate cream (0.25%) or equivalent) may also be used if symptomatic.

[0147] For rashes involving the scalp, ketoconazole shampoo should be used.

[0148] Paronychia: Acute, non-surgical (i.e., no fluctuations suggestive of an abscess) paronychia may resolve with warm baths applied only 3-4 times per day. If there is widespread redness suggestive of cellulitis, or if non-surgical paronychia is present but the participant is diabetic or immunocompromised, oral antibiotics with Staphylococcus aureus coverage will be initiated. Antibiotic choices include penicillin / clindamycin / first generation cephalosporin / Augmentin (amoxicillin and clavunate) with Staphylococcus aureus coverage.

[0149] If an abscess develops, it will be treated surgically by incision and drainage with or without debridement. Any infectious organisms identified will be treated accordingly. If the participant has diabetes or is immunocompromised, oral antibiotics (see above) ensuring coverage for Staphylococcus aureus will be initiated prior to culture and sensitivity reports. Once culture reports are obtained, antibiotic therapy will be adjusted accordingly.

[0150] Prohibited or restricted concomitant medications / treatments Prior use of mirdametinib is prohibited. Alternative therapies for the treatment of PN (e.g., MEK inhibitors, farnesyltransferase inhibitors, kinase inhibitors, etc.) are prohibited within 28 days (or 5.5 half-lives, whichever is longer) of the first dose of investigational drug and throughout the treatment period. If a participant is enrolled with progression and no associated morbidity, NF1 targeted therapy should not be administered after progression is observed (Inclusion Criterion 3.1.1). Medical treatment (e.g., chemotherapy, biologic therapy, radiation therapy) for NF1-associated tumors (e.g., optic pathway gliomas) is prohibited throughout the treatment period. ● Prohibit the use of chronic systemic or ocular glucocorticoid therapy within 14 days prior to the first dose of study drug and throughout the treatment period (with the exception of endocrine-compromised participants, who may receive physiologic or stress doses of steroids if necessary). In addition, corticosteroids are acceptable as premedication for blood product transfusions or for the treatment of acute allergic reactions or bronchospasm.

[0151] 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 any term in this application is found to have a different definition in a document incorporated herein by reference, the definition set forth in this specification shall serve as the definition of such term.

[0152] 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. A pharmaceutical composition for use in a method of treating a human patient aged 2 years or older having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising mildametinib, wherein the method comprises orally administering an effective amount of mildametinib to the patient, the amount of mildametinib being less than 300 ng·h / mL on the first day of treatment (AUC). ０－ｔａｕ The pharmaceutical composition, which is administered to provide.

2. The pharmaceutical composition according to claim 1, wherein the patient has a symptomatic, inoperable plexiform neurofibroma.

3. A pharmaceutical composition for use in a method of treating a human patient aged 2 years or older having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1) that is progressing or causing a significant pathological condition, wherein the method comprises orally administering an effective amount of mildametinib to the patient, the amount of mildametinib being less than 300 ng·h / mL on the first day of treatment (AUC). ０－ｔａｕ The pharmaceutical composition, which is administered to provide.

4. The AUC of mildametinib dose is less than 200 ng·h / mL on the first day of treatment. ０－ｔａｕ The pharmaceutical composition according to claim 1, which is administered to provide.

5. The AUC of mildametinib dose is less than 100 ng·h / mL on the first day of treatment. ０－ｔａｕ The pharmaceutical composition according to claim 1, which is administered to provide.

6. The pharmaceutical composition according to claim 1, wherein the patient has progressive PN.

7. The pharmaceutical composition according to claim 1, wherein the patient has a PN that causes a significant pathological condition.

8. The pharmaceutical composition according to claim 1, wherein the patient has a head and neck lesion causing damage to the airway or major blood vessels, a brachial or lumbar plexus lesion causing nerve compression and loss of function, a lesion causing significant deformity or disfigurement, a limb lesion causing limb hypertrophy or loss of function, or a painful lesion.

9. The pharmaceutical composition according to claim 8, wherein the lesion causing significant deformation or significantly impairing appearance is a tumor of the head and neck, or a tumor of another body part that cannot be concealed by standard clothing.

10. The pharmaceutical composition according to claim 1, wherein the patient has a paravertebral lesion.

11. The pharmaceutical composition according to claim 1, wherein the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and 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, or more than 15 mm in diameter in post-pubescent individuals. (b) Freckle-like pigmented spots in the axillary or groin region, (c) optic glioma, (d) Two or more Riche nodes, (e) Characteristic bone lesions (sphenoid dysplasia or dysplasia of thinning of the long bone cortex), and (f) A first-degree relative who has NF1.

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

13. The pharmaceutical composition according to claim 1, wherein the patient (a) has a parent diagnosed with NF1 and one or more of criteria (1) to (7), or (b) does not have a parent diagnosed with NF1 but has two or more of criteria (1) to (7): (1) Six or more café au lait spots with a maximum diameter of more than 5 mm in pre-pubescent individuals, and more than 15 mm in maximum diameter in post-pubescent individuals. (2) Freckle-like pigmented spots in the axillary or groin area, (3) Two or more neurofibromas of any type, or one plexiform neurofibroma, (4) Scleral tract glioma, (5) Two or more iris-Rich nodules, or two or more choroidal abnormalities identified by slit-lamp examination (defined as clear patchy nodules by optical coherence tomography (OCT) / near-infrared reflection (NIR) imaging), (6) Characteristic bone lesions (e.g., sphenoid dysplasia, anterolateral varus of the tibia, or pseudoarthrosis of long bones), and (7) A heterozygous pathogenic NF1 variant in which the proportion of the variant allele in an apparent normal tissue (e.g., leukocytes) is 50%.

14. (a) Body surface area of ​​0.69 m ２ In the case of the following patients, the patient is initially administered 1 mg of mildametinib twice daily. (b) Body surface area of ​​0.7 to 1.04 m ２ In the case of the patient, the patient was initially administered 2 mg of mildametinib twice daily. (c) Body surface area of ​​1.05 to 1.49 m² ２ In the case of the patient, the patient was initially administered 3 mg of mildametinib twice daily. (d) Body surface area of ​​1.5 m ２ In the case of the above patients, the patient will initially be administered 4 mg of mildametinib twice daily. The pharmaceutical composition according to claim 1.

15. The pharmaceutical composition according to claim 1, wherein the maximum daily dose is 4 mg of mildametinib, administered twice daily.

16. The pharmaceutical composition according to claim 13, wherein in each four-week period, mildametinib is administered for the first three weeks and discontinued for the last week.

17. The pharmaceutical composition according to claim 1, wherein, after treatment with mildametinib, the volume of plexiform neurofibromas quantified by volume magnetic resonance imaging is reduced by at least 20% in the patient.

18. The pharmaceutical composition according to claim 1, wherein the pain intensity is reduced as a result of the aforementioned treatment.

19. The pharmaceutical composition according to claim 1, wherein pain interference is reduced as a result of the aforementioned treatment.

20. The pharmaceutical composition according to claim 13, wherein the dose administered 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 of mildametinib twice daily, the reduced daily dose is 1 mg 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 administered in the morning and 1 mg administered 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 administered 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 administered twice daily.

21. The method according to claim 20, wherein the adverse event resulting in the dose reduction is an acne-like rash.

22. The pharmaceutical composition according to claim 21, wherein during treatment, the patient is administered clindamycin topically to treat an acne-like rash.

23. The pharmaceutical composition according to claim 1, wherein the patient is between 2 and 15 years of age. A pharmaceutical composition for use in a method of treating a human patient two years of age or older having inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising midostaurin, wherein the method comprises orally administering 1 mg of midostaurin twice daily to the patient on the first day of treatment to achieve an AUC ０－ｔａｕ less than 300 ng·h / mL, said pharmaceutical composition.

25. The pharmaceutical composition according to claim 1, wherein the method further comprises, before treatment, (i) determining whether to select mildametinib as a treatment for the patient, and (ii) selecting mildametinib as a treatment for the patient, at least in part based on its objective response rate, wherein the objective response rate is defined as a reduction of at least 20% of tumor size using centrally read MRI volume analysis.

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

27. ​​A pharmaceutical composition for use in a method of treating a human patient aged 2 years or older having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising mildametinib, wherein the method comprises orally administering an effective amount of mildametinib to the patient, the amount of mildametinib being 40 ng / mL or less on the first day of treatment. ｍａｘ The pharmaceutical composition, administered to achieve the objective.

28. A pharmaceutical composition for use in a method of treating a human patient aged 2 years or older having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1) that is progressing or causing a significant pathological condition, wherein the method comprises orally administering an effective amount of mildametinib to the patient, the amount of mildametinib being 40 ng / mL or less on the first day of treatment. ０ｍａｘ The method described above, administered to provide.

29. If the dose of mildametinib is 32 ng / mL or less on the first day of treatment, ｍａｘ The pharmaceutical composition according to claim 27, which is administered to provide.

30. The dose of mildametinib is less than 30 ng / mL on the first day of treatment. ｍａｘ The pharmaceutical composition according to claim 27, which is administered to provide.

31. The pharmaceutical composition according to claim 27, wherein the patient has a symptomatic, inoperable plexiform neurofibroma.

32. The pharmaceutical composition according to claim 27, wherein the patient has progressive PN.

33. The pharmaceutical composition according to claim 27, wherein the patient has a PN that causes a significant pathological condition.

34. The pharmaceutical composition according to claim 27, wherein the patient has a head and neck lesion causing damage to the airway or major blood vessels, a brachial or lumbar plexus lesion causing nerve compression and loss of function, a lesion causing significant deformity or disfigurement, a limb lesion causing limb hypertrophy or loss of function, or a painful lesion.

35. The pharmaceutical composition according to claim 34, wherein the lesion causing significant deformation or significantly impairing appearance is a tumor of the head and neck, or a tumor of another body part that cannot be concealed by standard clothing.

36. The pharmaceutical composition according to claim 27, wherein the patient has a paravertebral lesion.

37. The pharmaceutical composition according to claim 27, wherein the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and 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, or more than 15 mm in diameter in post-pubescent individuals. (b) Freckle-like pigmented spots in the axillary or groin region, (c) optic glioma, (d) Two or more Riche nodes, (e) Characteristic bone lesions (sphenoid dysplasia or dysplasia of thinning of the long bone cortex), and (f) A first-degree relative who has NF1.

38. The pharmaceutical composition according to claim 27, wherein the patient has a constitutional NF1 mutation documented at a Clinical Laboratory Improvement Amendments / College of American Pathologists accredited laboratory.

39. The pharmaceutical composition according to claim 27, wherein the patient (a) has a parent diagnosed with NF1 and one or more of criteria (1) to (7), or (b) does not have a parent diagnosed with NF1 but has two or more of criteria (1) to (7): (1) Six or more café au lait spots with a maximum diameter of more than 5 mm in pre-pubescent individuals, and more than 15 mm in maximum diameter in post-pubescent individuals. (2) Freckle-like pigmented spots in the axillary or groin area, (3) Two or more neurofibromas of any type, or one plexiform neurofibroma, (4) Scleral tract glioma, (5) Two or more iris-Rich nodules, or two or more choroidal abnormalities identified by slit-lamp examination (defined as clear patchy nodules by optical coherence tomography (OCT) / near-infrared reflection (NIR) imaging), (6) Characteristic bone lesions (e.g., sphenoid dysplasia, anterolateral varus of the tibia, or pseudoarthrosis of long bones), and (7) A heterozygous pathogenic NF1 variant in which the proportion of the variant allele in an apparent normal tissue (e.g., leukocytes) is 50%.

40. (a) Body surface area of ​​0.69 m ２ In the case of the following patients, the patient is initially administered 1 mg of mildametinib twice daily. (b) Body surface area of ​​0.7 to 1.04 m ２ In the case of the patient, the patient was initially administered 2 mg of mildametinib twice daily. (c) Body surface area of ​​1.05 to 1.49 m² ２ In the case of the patient, the patient was initially administered 3 mg of mildametinib twice daily. (d) Body surface area of ​​1.5 m ２ The pharmaceutical composition according to claim 27, wherein, in the case of the above patient, the patient is initially administered 4 mg of mildametinib twice daily.

41. The pharmaceutical composition according to claim 27, wherein the maximum daily dose is 4 mg of mildametinib twice daily.

42. The pharmaceutical composition according to claim 27, wherein in each 28-week period, mildametinib is administered for the first three weeks and discontinued for the last week.

43. The pharmaceutical composition according to claim 27, wherein, after treatment with mildametinib, the volume of plexiform neurofibromas quantified by volume magnetic resonance imaging is reduced by at least 20% in the patient.

44. The pharmaceutical composition according to claim 27, wherein the pain intensity is reduced as a result of the aforementioned treatment.

45. The pharmaceutical composition according to claim 27, wherein pain interference is reduced as a result of the aforementioned treatment.

46. The pharmaceutical composition according to claim 27, wherein the dose administered 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 of mildametinib twice daily, the reduced daily dose is 1 mg 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 administered in the morning and 1 mg administered 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 administered 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 administered twice daily.

47. The pharmaceutical composition according to claim 46, wherein the adverse event resulting in the dose reduction is acne-like rash.

48. The pharmaceutical composition according to claim 47, wherein during treatment, the patient is administered clindamycin topically to treat the acne-like rash.

49. The pharmaceutical composition according to claim 27, wherein the patient is between 2 and 15 years of age.

50. A pharmaceutical composition for use in a method of treating a human patient aged 2 years or older having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), wherein the method involves administering 1 mg of mildametinib twice daily on the first day of treatment, with a concentration of 40 ng / mL or less. ｍａｘ The pharmaceutical composition comprising being administered orally to the patient to provide the patient.

51. The pharmaceutical composition according to claim 27, wherein the method further comprises, before treatment, (i) determining whether to select mildametinib as a treatment for the patient, and (ii) selecting mildametinib as a treatment for the patient, at least in part based on its objective response rate, wherein the objective response rate is defined as a reduction of at least 20% of tumor size using centrally read MRI volume analysis.

52. The pharmaceutical composition according to claim 51, wherein in step (i), mildametinib is selected based on an at least 70% response rate.

53. A pharmaceutical composition for use in a method of treating a human patient aged 8 years or older having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising mildametinib, wherein the method comprises orally administering an effective amount of mildametinib to the patient, wherein the amount of mildametinib is (i) less than 400 ng·h / mL on the first day of treatment. ０－ｔａｕ (ii) C 40 ng / mL or less ｍａｘ The pharmaceutical composition is administered to provide (iii) both, and during treatment, the patient is suffering from an acne-like rash.

54. The pharmaceutical composition according to claim 53, wherein the patient is suffering from a pustular rash.