Treatment of neurofibromatosis type 1 (nf1) related plexus neurofibromatosis (PN) in pediatric patients using midametinib

Abstract

The present disclosure relates to methods for treating plexus neurofibroma (NF1-PN) associated with neurofibromatosis type 1, comprising administering midametinib, or a pharmaceutically acceptable salt thereof, to a pediatric patient in need thereof (e.g., 2 to 15 years old).

Description

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

[0002] The present disclosure relates to methods of treating pediatric patients (eg, 2 to 15 years old) with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering to the patient an effective amount of mirdametinib. Background Art

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

[0004] Weiss described a phase II clinical trial of mirdametinib in subjects at least 16 years old with plexiform neurofibromas and neurofibromatosis type 1 (Weiss et al., J. Clin. Oncol., 29, 797-806, 2021).

[0005] Prior to the present invention, the safety and efficacy of mirdametinib in pediatric patients 15 years of age and younger with inoperable plexiform neurofibromas (PNs) associated with neurofibromatosis type 1 (NF1), such as those with progressive PN, was unknown.

[0006] However, because objective responses are rarely complete and disease recurrence after completion of treatment is common in various tumors and cancers, there is a need to find better treatments. Summary of the invention

[0007] One aspect of the invention is a method of treating a pediatric human patient (e.g., 2 to 15 years old) with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering an effective amount of mirdametinib to the patient. In one embodiment, the patient has symptomatic, inoperable plexiform neurofibromas.

[0008] Another aspect is a method of treating a pediatric human patient aged 2 to 15 years with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) that are progressing or causing significant morbidity, comprising orally administering to the patient an effective amount of mirdametinib.

[0009] In one embodiment of any of the methods described herein, the patient has progressive PN (demonstrated by a 20% increase in PN volume as determined by comparison of two MRI scans within a period of 12 months or less prior to the first dose of mirdametinib).

[0010] In one embodiment of any of the methods described herein, the patient suffers from PN that results in significant morbidity.

[0011] In one embodiment of any of the methods described herein, the patient has a lesion of the head and neck that compromises the airway or great blood vessels, a lesion of the brachial or lumbar plexus that causes nerve compression and loss of function, a lesion that causes severe deformity or significant disfigurement, a limb lesion that causes limb hypertrophy or loss of function, or a painful lesion. In one embodiment, the lesion that causes severe deformity or significant disfigurement is a tumor of the head and neck or a tumor elsewhere on the body that cannot be concealed by standard clothing.

[0012] In one embodiment of any of the methods described herein, the patient suffers from a paraspinal lesion.

[0013] In one embodiment of any of the methods described herein, the patient has a Lansky performance level of at least 60%.

[0014] In one embodiment of any of the methods described herein, the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and meets one or more of the following:

[0015] (a) Individuals have six or more café-au-lait macules that are >5 mm in diameter before puberty and >15 mm after puberty;

[0016] (b) freckles in the armpits or groin area;

[0017] (c) optic nerve glioma;

[0018] (d) two or more Lisch nodules;

[0019] (e) characteristic bone lesions (sphenoid dysplasia or dysplastic thinning of the long bone cortex); and

[0020] (f) and first-degree relatives 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 certified laboratory.

[0022] In one embodiment of any of the methods described herein, the patient either (a) has a parent diagnosed with NF1 and meets one or more of the criteria of (1) to (7) or (b) has a parent not diagnosed with NF1 but meets two or more of the criteria of (1) to (7):

[0023] (1) The individual has six or more café-au-lait macules with a maximum diameter greater than 5 mm before puberty and a maximum diameter greater than 15 mm after puberty;

[0024] (2) Freckles in the armpits or groin area;

[0025] (3) two or more neurofibromas of any type or one plexiform neurofibroma;

[0026] (4) glioma of the optic pathway;

[0027] (5) two or more iris Lisch nodules or two or more choroidal abnormalities (defined as bright, plaque-like nodules imaged by optical coherence tomography (OCT) / near-infrared reflectance (NIR) imaging) detected by slit-lamp examination;

[0028] (6) characteristic bone lesions (such as sphenoid dysplasia, anterolateral tibial bowing, or long bone pseudarthrosis); and

[0029] (7) Heterozygous pathogenic NF1 variant, with a variant allele fraction of 50% in apparently normal tissues (such as leukocytes).

[0030] In one embodiment of any of the methods described herein,

[0031] (a) For a body surface area not exceeding 0.69 m 2 patients who were initially administered 1 mg of mitrametinib orally twice daily (i.e., a total of 2 mg per day),

[0032] (b) For body surface areas between 0.7 and 1.04 m 2 patients who were initially administered 2 mg of mitrametinib orally twice daily (i.e., a total of 4 mg per day),

[0033] (c) For a body surface area of ​​1.05 to 1.49 m 2 patients who were initially administered 3 mg of midametinib orally twice daily (i.e., a total of 6 mg per day), and

[0034] (d) For a body with a surface area of ​​at least 1.5 m 2 The patients were initially administered 4 mg of mitrametinib orally twice daily (ie, a total of 8 mg per day).

[0035] The inventors found that less than 2 mg / m 2 The body surface area dose in pediatric patients (such as those with a body surface area of ​​0.69 m2 or less) 2 In one embodiment, for patients with a body surface area of ​​no more than 0.69 m 2 Pediatric patients were initially administered 1 mg of mitrametinib orally twice daily (ie, a total of 2 mg per day).

[0036] In another embodiment, for patients aged 2 to 10 years with a body surface area not exceeding 0.69 m 2 In yet another embodiment, for patients aged 2 to 8 years and with a body surface area of ​​no more than 0.69 m 2 In yet another embodiment, for patients aged 2 to 7 years and with a body surface area of ​​no more than 0.69 m 2 In yet another embodiment, for patients aged 2 to 6 years and with a body surface area of ​​no more than 0.69 m 2 In yet another embodiment, for patients aged 2 to 5 years and with a body surface area of ​​no more than 0.69 m 2 Patients were initially administered 1 mg of mitrametinib orally twice daily (ie, a total of 2 mg per day).

[0037] In another embodiment of any of the methods described herein, the method comprises orally administering 1 mg of mirdametinib twice daily (ie, a total of 2 mg per day).

[0038] In another embodiment of any of the methods described herein, the maximum oral daily dose administered to the patient is 4 mg mirametinib twice daily (ie, a total of 8 mg per day).

[0039] In one embodiment of any of the methods described herein, about 2 mg / m is orally administered to the patient twice daily. 2 Midametinib.

[0040] In one embodiment of any of the methods described herein, within each four-week period, midametinib is administered for the first three weeks and is discontinued in the last week.

[0041] In one embodiment of any of the methods described herein, the patient has at least a 20% reduction in plexiform neurofibroma volume following treatment with mirametinib as determined by volumetric magnetic resonance imaging analysis.

[0042] In one embodiment of any of the methods described herein, the treating results in a decrease in pain intensity.

[0043] In one embodiment of any of the methods described herein, the treating results in a decrease in pain interference.

[0044] In one embodiment of any of the methods described herein, the administered dose is reduced due to an adverse event, wherein the dose is reduced as follows:

[0045] (a) If the oral dose at the time of the event was 1 mg mirametinib twice daily, the reduced daily dose was 1 mg taken orally in the morning only;

[0046] (b) If the oral dose at the time of the event was 2 mg mirametinib twice daily, the reduced daily dose was 2 mg orally administered in the morning and 1 mg orally administered in the afternoon or evening;

[0047] (c) if the oral dose at the time of the event was 3 mg mirametinib twice daily, the reduced daily dose is 2 mg orally administered twice daily; and

[0048] (d) If the oral dose at the time of the event was 4 mg mirametinib twice daily, the reduced daily dose was 3 mg orally administered twice daily.

[0049] In one embodiment of any of the methods described herein, the adverse event leading to dose reduction is acneiform.

[0050] In one embodiment of any method described herein, the method further comprises, prior to treatment, (i) determining whether to select midametinib as a treatment method for the patient and (ii) selecting it as a treatment method for the patient based at least in part on the objective response rate of midametinib, wherein the objective response rate is defined as a tumor size reduction of at least 20% using a centralized read MRI volume analysis. In one embodiment, in step (i), midametinib is selected based on a response rate of at least 70%. In another embodiment, in step (i), midametinib is selected based on a response rate of at least 75%. In yet another embodiment, in step (i), midametinib is selected based on a response rate of at least 80%. In yet another embodiment, in step (i), midametinib is selected based on a response rate of at least 85%. In yet another embodiment, in step (i), midametinib is selected based on a response rate of at least 90%. In yet another embodiment, in step (i), midametinib is selected based on a response rate of at least 95%.

[0051] Another aspect is a method of treating pediatric patients 2 to 5 years old with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering 1 mg of mirdametinib twice daily to the patient.

[0052] Yet another aspect of the present invention is a method of treating a pediatric patient aged 2 to 6 years with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering 1 mg of mirdametinib twice daily to the patient.

[0053] Yet another aspect of the present invention is a method of treating a pediatric patient aged 2 to 7 years with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering 1 mg of mirdametinib twice daily to the patient.

[0054] Yet another aspect of the invention is a method of treating pediatric patients aged 2 to 8 years with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering 1 mg of mirdametinib twice daily to the patient.

[0055] Yet another aspect of the invention is a method of treating pediatric patients aged 2 to 10 years with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) by orally administering 1 mg of mirdametinib twice daily to the patient.

[0056] In one embodiment of any of the methods described herein, the pediatric patient has not been previously exposed to a MEK inhibitor.

[0057] In some aspects, mitrametinib is dispersible in drinking liquids or orodispersible in the patient's saliva. In some aspects, mitrametinib is orally administered in a solid dosage form. In some aspects, the solid dosage form is a tablet or capsule. In some aspects, the solid dosage form is a capsule. In some aspects, the solid dosage form is a dispersible tablet.

[0058] In some aspects, midametinib is administered as monotherapy. DETAILED DESCRIPTION

[0059] I. definition

[0060] To facilitate understanding of the disclosure described herein, a number of terms are defined below.

[0061] Generally, the nomenclature used herein and the laboratory procedures in 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.

[0062] In this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly indicates otherwise. The term "a" (or "an") and the terms "one or more" and "at least one" may be used interchangeably herein. In some aspects, the term "a" or "an" refers to "single". In other aspects, the term "a" or "an" includes "two or more" or "multiple".

[0063] Furthermore, “and / or” when used herein should be considered as a specific disclosure of each of the two specified features or components, either together or not together with the other. Thus, the term “and / or” as used herein in phrases such as “A and / or B” is meant to include: “both A and B”; “A or B”; “A” (alone); and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0064] The term "midametinib" refers to a single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzamide (free base form). The teachings of midametinib throughout the specification also apply to pharmaceutically acceptable salts of midametinib. For example, the disclosure of a method of treating inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) with midametinib also means that a pharmaceutically acceptable salt of midametinib can be administered to treat inoperable PN associated with NF1.

[0065] The term "mg / m 2 ” refers to the patient per m 2 Dose per body surface area in milligrams.

[0066] The term "patient" or "subject" refers to a human.

[0067] The term "pediatric" as used herein refers to human subjects aged 2 to 15 years at the time of treatment. The term "pediatric" can be further divided into different subgroups, including: neonates (from birth to the first 28 days of life); infants (29 days to less than two years); children (two years to less than 12 years); and adolescents (12 to 15 years. See, e.g., Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Edition Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Edition New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Edition Baltimore: Williams & Wilkins; 1994. In some additional embodiments, pediatric patients are 2 to 8 years old, 2 to 7 years old, 2 to 6 years old, or 2 to 5 years old.

[0068] The term "dispersible" as used herein refers to a composition (e.g., tablet, powder, granule, small tablet or pill) that disintegrates and / or dissolves when combined with water or another potable liquid (e.g., non-aqueous beverage) or (when placed in the subject's mouth) the subject's own saliva, whether or not agitation or temperature regulation is added. In some aspects, the 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 potable liquid. Such disintegration or dissolution does not have to be complete. For example, a dispersible tablet may be almost completely dissolved, but some undissolved particulate matter may remain. Dispersible formulations of midametinib suitable for use in the methods described herein include those described in U.S. Patent No. 11,571,402, which is hereby incorporated by reference.

[0069] The term "orodispersible" refers to a composition that, if administered orally, is capable of dissolving or disintegrating in the mouth of a subject (ie, dissolving or disintegrating in the saliva of a subject) without first having to be dissolved or disintegrated in a separate container.

[0070] As used herein, the terms "treat," "treated," and "treating" mean therapeutic treatment, and also refer to prophylactic or preventative measures, wherein the purpose is to prevent or slow down (mitigate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Thus, patients in need of treatment include those who have been diagnosed with or suspected of having the disorder. Beneficial or desired clinical results include, but are not limited to, relief of symptoms; a reduction in the extent of the condition, disorder, or disease; stabilization of the condition, disorder, or disease state (i.e., not worsening); a delay in the onset or slowing of the progression of the condition, disorder, or disease; an improvement or alleviation (whether partial or complete) of the condition, disorder, or disease state, whether detectable or undetectable; an improvement in at least one measurable physical parameter that is not necessarily discernible by the patient; or an enhancement or improvement of the condition, disorder, or disease. Treatment includes inducing clinically significant relief without excessive side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment. The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more 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 of a cell, tissue, system, animal, or human that the researcher, veterinarian, physician, or clinician is seeking.

[0071] In certain aspects, if the patient exhibits one or more of the following, then according to the methods described herein, the subject's tumor is successfully "treated": tumor size reduction; relief of one or more symptoms associated with a given tumor; tumor volume reduction; 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), progressive disease (PD) reduction, time to progression (TTP) extension or any combination thereof. In some aspects, nationally or internationally recognized standards for given tumor treatment outcomes can be used to determine whether a therapeutically effective amount of mitrametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0072] If the patient shows one or more of the following, then according to the methods described herein, the subject's cancer (e.g., ovarian cancer) is successfully "treated": the number of cancer cells is reduced or completely disappeared; relief of one or more symptoms associated with a specified tumor; reduced morbidity and mortality; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete remission (CR), minimal residual disease (MRD), partial remission (PR), disease stabilization (SD), disease progression (PD) reduction, progression time (TTP) extension or any combination thereof. In some aspects, nationally or internationally recognized standards for given cancer treatment outcomes can be used to determine whether a therapeutically effective amount of midametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0073] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to pharmaceutically acceptable materials, compositions or vehicles, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials. In one embodiment, each component is "pharmaceutically acceptable", i.e., compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with human and animal tissues or organs 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 ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th ed., Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd ed., 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).

[0074] The term "pharmaceutically acceptable salt" refers to relatively nontoxic inorganic and organic acid addition salts of mitrametinib. These salts can be prepared in situ during the administration of the vehicle or the dosage form manufacturing process, or by reacting the free base form of mitrametinib with a suitable organic or inorganic acid alone and separating the salt formed thereby in the subsequent purification process. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate and lauryl sulfonate. See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19.

[0075] Pharmaceutically acceptable salts of Midametinib also include conventional non-toxic salts or quaternary ammonium salts of the compound, such as salts from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid.

[0076] The term "about" or "approximately" means the acceptable error of a particular value determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to 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.

[0077] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are used with the clear understanding that they are to be construed as inclusive and not exclusive, and Applicant intends that each of these words be so construed in interpreting this patent, including the appended claims.

[0078] II. Treatment

[0079] Provided herein are methods for treating plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN), comprising administering mirdametinib or a pharmaceutically acceptable salt thereof to a pediatric patient (e.g., 2 to 15 years old) in need thereof.

[0080] In one embodiment of any of the methods described herein, the patient has progressive PN (demonstrated by a 20% increase in PN volume as determined by comparison of two MRI scans within a period of 12 months or less prior to the first dose of mirdametinib).

[0081] In one embodiment of any of the methods described herein, the patient suffers from PN that results in significant morbidity.

[0082] In one embodiment of any of the methods described herein, the patient has a lesion of the head and neck that compromises the airway or great blood vessels, a lesion of the brachial or lumbar plexus that causes nerve compression and loss of function, a lesion that causes severe deformity or significant disfigurement, a limb lesion that causes limb hypertrophy or loss of function, or a painful lesion. In one embodiment, the lesion that causes severe deformity or significant disfigurement is a tumor of the head and neck or a tumor elsewhere on the body that cannot be concealed by standard clothing.

[0083] In one embodiment of any of the methods described herein, the patient suffers from a paraspinal lesion.

[0084] In one embodiment of any of the methods described herein, the patient has a Lansky performance level of at least 60%.

[0085] In one embodiment of any of the methods described herein, the patient is clinically diagnosed with NF1 using the NIH Consensus Conference.

[0086] In one embodiment of any of the methods described herein, the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and meets one or more of the following:

[0087] (a) Individuals have six or more café-au-lait macules that are >5 mm in diameter before puberty and >15 mm after puberty;

[0088] (b) freckles in the armpits or groin area;

[0089] (c) optic nerve glioma;

[0090] (d) two or more Lisch nodules;

[0091] (e) characteristic bone lesions (sphenoid dysplasia or dysplastic thinning of the long bone cortex); and

[0092] (f) and first-degree relatives with NF1.

[0093] 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 certified laboratory.

[0094] In one embodiment of any of the methods described herein, the patient is diagnosed with NF1 using the NF1 criteria provided in Legius et al., Genetics in Medicine, 23, 1506-1513, 2021 (Table 1), which is hereby incorporated by reference.

[0095] In one embodiment of any of the methods described herein, the patient either (a) has a parent diagnosed with NF1 and meets one or more criteria of (1) to (7) or (b) has a parent not diagnosed with NF1 but meets two or more criteria of (1) to (7) (see, e.g., Legius et al., Genetics in Medicine, 23, 1506-1513, 2021 (Table 1)):

[0096] (1) The individual has six or more café-au-lait macules with a maximum diameter greater than 5 mm before puberty and a maximum diameter greater than 15 mm after puberty;

[0097] (2) freckles in the axillary or inguinal regions (in one embodiment, this criterion is met if only café-au-lait macules and freckles are present and at least one of the two pigmentation findings (café-au-lait macules or freckles) is bilateral);

[0098] (3) two or more neurofibromas of any type or one plexiform neurofibroma;

[0099] (4) glioma of the optic pathway;

[0100] (5) two or more iris Lisch nodules or two or more choroidal abnormalities (defined as bright, plaque-like nodules imaged by optical coherence tomography (OCT) / near-infrared reflectance (NIR) imaging) detected by slit-lamp examination;

[0101] (6) characteristic bone lesions (such as sphenoid dysplasia, anterolateral tibial bowing, or long bone pseudarthrosis); and

[0102] (7) Heterozygous pathogenic NF1 variant, with a variant allele fraction of 50% in apparently normal tissues (such as leukocytes).

[0103] In some embodiments of any of the methods described herein, a therapeutically effective amount of mirdametinib or a pharmaceutically acceptable salt thereof is administered.

[0104] In some embodiments of any of the methods described herein, the dosage is about 1 mg / m per day based on midametinib free base. 2 About 10 mg / m 2 Based on midametinib free base, approximately 1.5 mg / m per day 2 To about 9.5mg / m 2 Based on midametinib free base, approximately 2 mg / m per day 2 About 9 mg / m 2 Based on midametinib free base, approximately 2.5 mg / m per day 2 To about 8.5mg / m2 Based on midametinib free base, approximately 3 mg / m per day 2 About 8 mg / m 2 Based on midametinib free base, approximately 3.5 mg / m per day 2 To about 7.5mg / m 2 Based on midametinib free base, approximately 4 mg / m per day 2 About 7 mg / m 2 Based on midametinib free base, approximately 4.5 mg / m per day 2 To about 6.5mg / m 2 Or based on mitrametinib free base, approximately 5 mg / m per day 2 About 6 mg / m 2 In some embodiments of any of the methods described herein, about 1 mg / m per day based on the free base of midametinib is administered. 2 Based on midametinib free base, approximately 1.5 mg / m per day 2 Based on midametinib free base, approximately 2 mg / m per day 2 Based on midametinib free base, approximately 2.5 mg / m per day 2 Based on midametinib free base, approximately 3 mg / m per day 2 Based on midametinib free base, approximately 3.5 mg / m per day 2 Based on midametinib free base, approximately 4 mg / m per day 2 Based on midametinib free base, approximately 4.5 mg / m per day 2 Based on midametinib free base, approximately 5 mg / m per day 2 Based on midametinib free base, approximately 5.5 mg / m per day 2 Based on midametinib free base, approximately 6 mg / m per day 2 Based on midametinib free base, approximately 6.5 mg / m per day 2 Based on midametinib free base, approximately 7 mg / m per day 2 Based on midametinib free base, approximately 7.5 mg / m per day 2 Based on midametinib free base, approximately 8 mg / m per day 2 Based on midametinib free base, approximately 8.5 mg / m per day 2 Based on midametinib free base, approximately 9 mg / m per day 2 Based on midametinib free base, approximately 9.5 mg / m per day 2 Or based on mitrametinib free base, approximately 10 mg / m per day 2 Midametinib or a pharmaceutically acceptable salt thereof is administered in an amount of

[0105] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg to about 10 mg per day based on midametinib free base, about 1.5 mg to about 9.5 mg per day based on midametinib free base, about 2 mg to about 9 mg per day based on midametinib free base, about 2.5 mg to about 8.5 mg per day based on midametinib free base, about 3 mg to about 8 mg per day based on midametinib free base, about 3.5 mg to about 7.5 mg per day based on midametinib free base, about 4 mg to about 7 mg per day based on midametinib free base, about 4.5 mg to about 6.5 mg per day based on midametinib free base, or about 5 mg to about 6 mg per day based on midametinib free base. In some embodiments of any of the methods described herein, the dosage form is about 1 mg per day based on midametinib free base, about 1.5 mg per day based on midametinib free base, about 2 mg per day based on midametinib free base, about 2.5 mg per day based on midametinib free base, about 3 mg per day based on midametinib free base, about 3.5 mg per day based on midametinib free base, about 4 mg per day based on midametinib free base, about 4.5 mg per day based on midametinib free base, about ... Midametinib or a pharmaceutically acceptable salt thereof is administered in an amount of about 5.5 mg based on midametinib free base, about 6 mg based on midametinib free base, about 6.5 mg based on midametinib free base, about 7 mg based on midametinib free base, about 7.5 mg based on midametinib free base, about 8 mg based on midametinib free base, about 8.5 mg based on midametinib free base, about 9 mg based on midametinib free base, about 9.5 mg based on midametinib free base, or about 10 mg based on midametinib free base.

[0106] In some embodiments of any of the methods described herein, the composition comprises about 0.1 mg / m 2 About 10 mg / m 2 Based on midametinib free base, approximately 0.5 mg / m 2 To about 9.5mg / m 2 Based on midametinib free base, approximately 1 mg / m 2 About 9 mg / m 2 Based on midametinib free base, approximately 1.5 mg / m 2 To about 8.5mg / m 2 Based on midametinib free base, approximately 2 mg / m 2 About 8 mg / m 2Based on midametinib free base, approximately 2.5 mg / m 2 To about 7.5mg / m 2 Based on midametinib free base, approximately 3 mg / m 2 About 7 mg / m 2 Based on midametinib free base, approximately 3.5 mg / m 2 To about 6.5mg / m 2 Based on midametinib free base, approximately 4 mg / m 2 About 6 mg / m 2 or based on midametinib free base, approximately 4.5 mg / m 2 To about 5.5mg / m 2 In some embodiments of any of the methods described herein, the dosage form comprises about 0.1 mg / m 2 Based on midametinib free base, approximately 0.2 mg / m 2 Based on midametinib free base, approximately 0.3 mg / m 2 Based on midametinib free base, approximately 0.4 mg / m 2 Based on midametinib free base, approximately 0.5 mg / m 2 Based on midametinib free base, approximately 1 mg / m 2 Based on midametinib free base, approximately 1.5 mg / m 2 Based on midametinib free base, approximately 2 mg / m 2 Based on midametinib free base, approximately 2.5 mg / m 2 Based on midametinib free base, approximately 3 mg / m 2 Based on midametinib free base, approximately 3.5 mg / m 2 Based on midametinib free base, approximately 4 mg / m 2 Based on midametinib free base, approximately 4.5 mg / m 2 Based on midametinib free base, approximately 5 mg / m 2 Based on midametinib free base, approximately 5.5 mg / m 2 Based on midametinib free base, approximately 6 mg / m 2 Based on midametinib free base, approximately 6.5 mg / m 2 Based on midametinib free base, approximately 7 mg / m 2 Based on midametinib free base, approximately 7.5 mg / m 2 Based on midametinib free base, approximately 8 mg / m 2 Based on midametinib free base, approximately 8.5 mg / m 2Based on midametinib free base, approximately 9 mg / m 2 Based on midametinib free base, approximately 9.5 mg / m 2 Or based on midametinib free base, approximately 10 mg / m 2 Mildametinib or a pharmaceutically acceptable salt thereof is administered in a single dosage form.

[0107] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg to about 10 mg based on midametinib free base, about 0.5 mg to about 9.5 mg based on midametinib free base, about 1 mg to about 9 mg based on midametinib free base, about 1.5 mg to about 8.5 mg based on midametinib free base, about 2 mg to about 8 mg based on midametinib free base, about 2.5 mg to about 7.5 mg based on midametinib free base, about 3 mg to about 7 mg based on midametinib free base, about 3.5 mg to about 6.5 mg based on midametinib free base, about 4 mg to about 6 mg based on midametinib free base, or about 4.5 mg to about 5.5 mg based on midametinib free base. In some embodiments of any of the methods described herein, the composition comprises about 0.1 mg based on midametinib free base, about 0.2 mg based on midametinib free base, about 0.3 mg based on midametinib free base, about 0.4 mg based on midametinib free base, about 0.5 mg based on midametinib free base, about 1 mg based on midametinib free base, about 1.5 mg based on midametinib free base, about 2 mg based on midametinib free base, about 2.5 mg based on midametinib free base, about 3 mg based on midametinib free base, about 3.5 mg based on midametinib free base, about 4 mg based on midametinib free base. g, about 4.5 mg based on midametinib free base, about 5 mg based on midametinib free base, about 5.5 mg based on midametinib free base, about 6 mg based on midametinib free base, about 6.5 mg based on midametinib free base, about 7 mg based on midametinib free base, about 7.5 mg based on midametinib free base, about 8 mg based on midametinib free base, about 8.5 mg based on midametinib free base, about 9 mg based on midametinib free base, about 9.5 mg based on midametinib free base, or about 10 mg based on midametinib free base in a single dosage form.

[0108] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered once, twice, three times, or four times per day. In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered once per day. In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered twice per day.

[0109] In some embodiments of any of the methods described herein, the dosage is about 0.5 mg / m based on midametinib free base. 2 About 10 mg / m 2 Based on midametinib free base, approximately 1 mg / m 2 To about 9.5mg / m 2 Based on midametinib free base, approximately 1.5 mg / m 2 About 9 mg / m 2 Based on midametinib free base, approximately 2 mg / m 2 To about 8.5mg / m 2 Based on midametinib free base, approximately 2.5 mg / m 2 About 8 mg / m 2 Based on midametinib free base, approximately 3 mg / m 2 To about 7.5mg / m 2 Based on midametinib free base, approximately 3.5 mg / m 2 About 7 mg / m 2 Based on midametinib free base, approximately 4 mg / m 2 To about 6.5mg / m 2 Based on midametinib free base, approximately 4.5 mg / m 2 About 6 mg / m 2 or based on midametinib free base, approximately 5 mg / m 2 About 6 mg / m 2 In some embodiments of any of the methods described herein, about 0.5 mg / m 2 Based on midametinib free base, approximately 1 mg / m 2 Based on midametinib free base, approximately 1.5 mg / m 2 Based on midametinib free base, approximately 2 mg / m 2 Based on midametinib free base, approximately 2.5 mg / m 2 Based on midametinib free base, approximately 3 mg / m 2 Based on midametinib free base, approximately 3.5 mg / m 2 Based on midametinib free base, approximately 4 mg / m2 Based on midametinib free base, approximately 4.5 mg / m 2 Based on midametinib free base, approximately 5 mg / m 2 Based on midametinib free base, approximately 5.5 mg / m 2 Based on midametinib free base, approximately 6 mg / m 2 Based on midametinib free base, approximately 6.5 mg / m 2 Based on midametinib free base, approximately 7 mg / m 2 Based on midametinib free base, approximately 7.5 mg / m 2 Based on midametinib free base, approximately 8 mg / m 2 Based on midametinib free base, approximately 8.5 mg / m 2 Based on midametinib free base, approximately 9 mg / m 2 Based on midametinib free base, approximately 9.5 mg / m 2 Or based on midametinib free base, approximately 10 mg / m 2 Midametinib or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of

[0110] In some embodiments of any of the methods described herein, midametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily in an amount of about 0.5 mg to about 10 mg based on midametinib free base, about 1 mg to about 9.5 mg based on midametinib free base, about 1.5 mg to about 9 mg based on midametinib free base, about 2 mg to about 8.5 mg based on midametinib free base, about 2.5 mg to about 8 mg based on midametinib free base, about 3 mg to about 7.5 mg based on midametinib free base, about 3.5 mg to about 7 mg based on midametinib free base, about 4 mg to about 6.5 mg based on midametinib free base, about 4.5 mg to about 6 mg based on midametinib free base, or about 5 mg to about 6 mg based on midametinib free base. In some embodiments of any of the methods described herein, the amount of the drug is about 0.5 mg based on midametinib free base, about 1 mg based on midametinib free base, about 1.5 mg based on midametinib free base, about 2 mg based on midametinib free base, about 2.5 mg based on midametinib free base, about 3 mg based on midametinib free base, about 3.5 mg based on midametinib free base, about 4 mg based on midametinib free base, about 4.5 mg based on midametinib free base, about 5 mg based on midametinib free base, about 6 mg based on midametinib free base, about 7 mg based on midametinib free base, about 8 mg based on midametinib free base, about 9 mg based on midametinib free base, about 10 mg based on midametinib free base, about 11 mg based on midametinib free base, about 12 mg based on midametinib free base, about 13 mg based on midametinib free base, about 14 mg based on midametinib free base, about 15 mg based on midametinib free base, about 16 mg based on midametinib free base, about 17 mg based on midametinib free base, about 18 mg based on midametinib free base, about 19 mg based on midametinib free base, about 20 mg based on midametinib free base, about 21 mg based on midametinib free base, about 22 mg based on midametinib free base, about 24 mg based on midametinib free base, about 25 mg based on midametinib free base, about Midametinib or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 5.5 mg based on midametinib free base, about 6 mg based on midametinib free base, about 6.5 mg based on midametinib free base, about 7 mg based on midametinib free base, about 7.5 mg based on midametinib free base, about 8 mg based on midametinib free base, about 8.5 mg based on midametinib free base, about 9 mg based on midametinib free base, about 9.5 mg based on midametinib free base, or about 10 mg based on midametinib free base.

[0111] In some embodiments of any of the methods described herein, the dosage is no more than about 10 mg / m based on midametinib free base. 2 Based on midametinib free base, approximately 9.5 mg / m 2 Based on midametinib free base, approximately 9 mg / m 2 Based on midametinib free base, approximately 8.5 mg / m 2 Based on midametinib free base, approximately 8 mg / m 2 Based on midametinib free base, approximately 7.5 mg / m 2 Based on midametinib free base, approximately 7 mg / m 2 Based on midametinib free base, approximately 6.5 mg / m 2 Based on midametinib free base, approximately 6 mg / m 2Based on midametinib free base, approximately 5.5 mg / m 2 Based on midametinib free base, approximately 5 mg / m 2 Based on midametinib free base, approximately 4.5 mg / m 2 Based on midametinib free base, approximately 4 mg / m 2 Based on midametinib free base, approximately 3.5 mg / m 2 Based on midametinib free base, approximately 3 mg / m 2 Based on midametinib free base, approximately 2.5 mg / m 2 Based on midametinib free base, approximately 2 mg / m 2 or based on midametinib free base, approximately 1.5 mg / m 2 The total daily dose of mitrametinib or a pharmaceutically acceptable salt thereof is administered.

[0112] In some embodiments of any of the methods described herein, the dosage form is no more than about 10 mg based on midametinib free base, about 9.5 mg based on midametinib free base, about 9 mg based on midametinib free base, about 8.5 mg based on midametinib free base, about 8 mg based on midametinib free base, about 7.5 mg based on midametinib free base, about 7 mg based on midametinib free base, about 6.5 mg based on midametinib free base, about 6 mg based on midametinib free base, or about 10 mg based on midametinib free base. Midametinib or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 5.5 mg based on midametinib free base, about 5 mg based on midametinib free base, about 4.5 mg based on midametinib free base, about 4 mg based on midametinib free base, about 3.5 mg based on midametinib free base, about 3 mg based on midametinib free base, about 2.5 mg based on midametinib free base, about 2 mg based on midametinib free base, or about 1.5 mg based on midametinib free base.

[0113] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered as midametinib free base.

[0114] In some embodiments of any of the methods described herein, a therapeutically effective amount of midametinib free base is administered.

[0115] In some embodiments of any of the methods described herein, about 1 mg / m 2 About 10 mg / m 2 , about 1.5 mg / m per day 2 To about 9.5mg / m 2 , about 2 mg / m per day 2 About 9 mg / m2 , about 2.5 mg / m per day 2 To about 8.5mg / m 2 , about 3 mg / m per day 2 About 8 mg / m 2 , about 3.5 mg / m per day 2 To about 7.5mg / m 2 , about 4 mg / m per day 2 About 7 mg / m 2 , about 4.5 mg / m per day 2 To about 6.5mg / m 2 or about 5 mg / m2 per day 2 About 6 mg / m 2 In some embodiments of any of the methods described herein, about 1 mg / m 2 , about 1.5 mg / m per day 2 , about 2 mg / m per day 2 , about 2.5 mg / m per day 2 , about 3 mg / m per day 2 , about 3.5 mg / m per day 2 , about 4 mg / m per day 2 , about 4.5 mg / m per day 2 , about 5 mg / m per day 2 , about 5.5 mg / m per day 2 , about 6 mg / m per day 2 , about 6.5 mg / m per day 2 , about 7 mg / m per day 2 , about 7.5 mg / m per day 2 , about 8 mg / m per day 2 , about 8.5 mg / m per day 2 , about 9 mg / m per day 2 , about 9.5 mg / m per day 2 or about 10 mg / m2 per day 2 Midametinib free base was administered in an amount of

[0116] In some embodiments of any of the methods described herein, midametinib 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 of any of the methods described herein, midametinib 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.

[0117] In some embodiments of any of the methods described herein, the 2 About 10 mg / m 2 , about 0.5mg / m 2 To about 9.5mg / m 2 , about 1mg / m 2 About 9 mg / m 2 , about 1.5mg / m 2 To about 8.5mg / m 2 , about 2mg / m 2 About 8 mg / m 2 , about 2.5mg / m 2 To about 7.5mg / m 2 , about 3mg / m 2 About 7 mg / m 2 , about 3.5mg / m 2 To about 6.5mg / m 2 , about 4mg / m 2 About 6 mg / m 2 or about 4.5 mg / m 2 To about 5.5mg / m 2 In some embodiments of any of the methods described herein, the dosage form of midametinib free base is about 0.1 mg / m 2 , about 0.2mg / m 2 , about 0.3mg / m 2 , about 0.4mg / m 2 , about 0.5mg / m 2 , about 1mg / m 2 , about 1.5mg / m2 , 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 Midametinib free base is administered in a single dosage form.

[0118] In some embodiments of any of the methods described herein, midametinib free base is administered in a single dosage form comprising 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 of any of the methods described herein, midametinib 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.

[0119] In some embodiments of any of the methods described herein, midametinib free base is administered once, twice, three times, or four times per day. In some aspects, midametinib free base is administered once per day. In some embodiments of any of the methods described herein, midametinib free base is administered twice per day.

[0120] In some embodiments of any of the methods described herein, the dosage of about 0.5 mg / m 2 About 10 mg / m 2 , about 1mg / m 2To about 9.5mg / m 2 , about 1.5mg / m 2 About 9 mg / m 2 , about 2mg / m 2 To about 8.5mg / m 2 , about 2.5mg / m 2 About 8 mg / m 2 , about 3mg / m 2 To about 7.5mg / m 2 , about 3.5mg / m 2 About 7 mg / m 2 , about 4mg / m 2 To about 6.5mg / m 2 , about 4.5mg / m 2 About 6 mg / m 2 or about 5 mg / m 2 About 6 mg / m 2 In some embodiments of any of the methods described herein, about 0.5 mg / m 2 , about 1mg / m 2 , about 1.5mg / m 2 , about 2mg / m 2 , about 2.5mg / m 2 , about 3mg / m 2 , about 3.5mg / m 2 , about 4mg / m 2 , about 4.5mg / m 2 , about 5mg / m 2 , about 5.5mg / m 2 , about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2 , about 8.5mg / m 2 , about 9mg / m 2 , about 9.5mg / m 2 or about 10 mg / m 2 Midametinib free base was administered twice daily.

[0121] In some embodiments of any of the methods described herein, midametinib 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 of any of the methods described herein, midametinib 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.

[0122] In some embodiments of any of the methods described herein, the dosage is no more than 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 Midametinib free base was administered at a total daily dose of .

[0123] In some embodiments of any of the methods described herein, midametinib free base is administered at a total daily dose of no more than 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.

[0124] In some embodiments of any of the methods described herein, mirametinib or a pharmaceutically acceptable salt thereof exhibits high blood-brain barrier penetration.

[0125] In some embodiments of any of the methods described herein, the human has not been previously exposed to a MEK inhibitor. In some embodiments of any of the methods described herein, the human has not responded to previous treatment with one or more MEK inhibitors.

[0126] In some embodiments of any method described herein, midametinib or a pharmaceutically acceptable salt thereof is orally administered. In some aspects, midametinib or a pharmaceutically acceptable salt thereof is orally administered in a solid dosage form. In some embodiments of any method described herein, the solid dosage form is a tablet or a capsule. In some embodiments of any method described herein, the solid dosage form is a capsule. In some aspects, midametinib or a pharmaceutically acceptable salt thereof can be dispersed in a drinking liquid or can be orally dispersed in the patient's saliva. In one embodiment, midametinib or a pharmaceutically acceptable salt thereof is administered in the form of a dispersible formulation (such as a 0.5 mg or 1 mg midametinib dispersible tablet), as described in U.S. Patent No. 11,571,402, which is hereby incorporated by reference.

[0127] In some embodiments of any of the methods described herein, mirametinib or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat inoperable plexiform neurofibromas associated with neurofibromatosis type 1 (NF1).

[0128] In some embodiments of any of the methods described herein, mirdametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat inoperable plexiform neurofibromas associated with neurofibromatosis type 1 (NF1).

[0129] Example

[0130] Example 1: Single dose of mirdametinib (1:1) for the treatment of children, adolescents and young adults with brain cancer Phase I / II evaluation of a brain-penetrant MEK1 / 2 inhibitor

[0131] The multi-arm Phase I / II trial of midametinib will be conducted in patients with brain cancer aged ≥2 years and <25 years. Phase I requires participants to have no prior exposure to MEK inhibitors and to have recurrent / progressive disease with biopsy-proven evidence of MAPK pathway activation. Using a rolling 6 design, three escalating dose levels (2 mg / m 2 / dose BID, 2.5mg / m 2 / dose BID and 3mg / m 2 / dose BID).

[0132] The median age of participants in this study was 10 years (range, 3-21). No dose-limiting toxicities occurred at all three dose levels. No MEK-related retinopathy or cardiac disease was observed. No disease progression occurred. To date, mitramerinib has been well tolerated and clinically promising when administered continuously in patients with brain cancer.

[0133] Embodiment 2: Midametinib In patients with neurofibromatosis type 1 that is progressive or causing severe morbidity A phase 2b trial in adult and pediatric patients with inoperable plexiform neurofibromas (PN) associated with NF1.

[0134] This study was designed to evaluate the efficacy, safety, and tolerability of mirdametinib in participants ≥2 years of age with inoperable NF1-related plexiform neurofibromas (PNs) that were progressing and / or causing severe morbidity.

[0135] Approximately 120 participants will be screened (assessed for eligibility as described below) to allow for approximately 100 participants to be assigned to study treatment. Of these participants, approximately 50 will be aged ≥ 18 years and approximately 50 will be between the ages of 2 and 17 years.

[0136] Participants will be screened for up to 28 days prior to the first dose of mirdametinib study treatment. Study treatment will be administered orally at twice-daily (BID) doses as specified in the table below. Dosing cycles are 28 days (4-week course), with 3 weeks on / 1 week off. The treatment period will last up to 24 cycles, followed by a 30-day safety follow-up period.

[0137] <![CDATA[BSA of the subject (m 2 )]]> ≤0.69 0.7 to 1.04 1.05 to 1.49 ≥1.5 BID dose (mg) 1 2 3 4

[0138] Partial response was defined as a ≥20% reduction in PN compared with baseline using centrally read MRI volumetric analysis.

[0139] Inclusion criteria

[0140] Patients were eligible for study participation only if all of the following criteria applied:

[0141] 1. Participants must be ≥2 years old (inclusive) when signing the informed consent / assent form.

[0142] 2. Participants must have a clinical diagnosis of NF1 using the National Institutes of Health (NIH) Consensus Conference criteria with at least 1 additional diagnostic criterion (including 2.1–2.6, see below) in addition to the presence of PN, or have a constitutional NF1 mutation documented by a Clinical Laboratory Improvement Amendments / College of American Pathologists-certified laboratory; additional criteria are as follows:

[0143] 2.1. The individual has six or more café-au-lait macules that are >5 mm in diameter before puberty and >15 mm after puberty

[0144] 2.2. Freckles in the armpits or groin area;

[0145] 2.3. Optic nerve glioma;

[0146] 2.4. Two or more Lisch nodules;

[0147] 2.5. Characteristic bone lesions (sphenoid dysplasia or long bone cortical thinning and dysplasia);

[0148] 2.6. A first-degree relative has NF1.

[0149] 3. Participants must have PN that is progressive (including 3.1) or causes severe morbidity, such as (but not limited to) lesions in the head and neck that damage the airway or great blood vessels, brachial or lumbar plexus lesions that cause nerve compression and loss of function, lesions that cause severe deformity or significant disfigurement (including 3.2), limb lesions that cause limb hypertrophy or loss of function, and painful lesions. Participants with paraspinal PN will be eligible for this study. If there are consistent clinical and radiological findings, histological confirmation of the tumor is not necessary, but if there is clinical suspicion of malignant degeneration of the PN, histological confirmation should be considered;

[0150] 3.1. For participants enrolled due to tumor progression, progression was defined as:

[0151] 3.1.1. A measurable increase in PN size (≥20% increase in volume) is documented by comparing two MRI scans within a period of 12 months or less before the first dose of study treatment (midametinib).

[0152] 3.2. For participants enrolled with “severely deforming” or “significantly disfiguring” tumors, eligible tumors will be limited to tumors of the head and neck or tumors in other parts of the body that cannot be concealed by standard clothing.

[0153] 4. Participants whose PN is considered inoperable, defined as a PN that cannot be completely removed surgically without substantial risk of morbidity due to: PN encapsulated by or in close proximity to vital structures, invasiveness or high vascularity of the PN, or the participant refuses surgery. Participants who have previously undergone PN surgery will be eligible to participate in the study after surgery, provided that the PN is not completely removed and can be evaluated by volumetric analysis.

[0154] 5. Participants must have a target PN, defined as the most clinically relevant PN suitable for volumetric MRI analysis. For the purposes of this study, the target PN must be seen on at least 3 consecutive MRI slices, and the field of view must contain the entire tumor of interest. The target PN must be volumetrically analyzable, at least 5 mL in volume, and will be classified as a "typical PN," "nodular PN," or "solitary nodular PN" prior to the first dose of study treatment, as determined by central radiology review.

[0155] 6. Participants aged ≥18 years must have PN suitable for percutaneous biopsy and must be willing to undergo tumor biopsy to provide fresh tumor tissue before and during treatment; serial biopsies should not have contraindications; patients aged 2 to 17 years should not undergo biopsy unless there is a clinical indication to obtain fresh tumor tissue.

[0156] 7. Participants aged ≥16 years must have a Karnofsky performance level of ≥60%, and participants aged <16 years must have a Lansky performance level of ≥60%.

[0157] 8. The participant has adequate organ and bone marrow function as defined by the following screening laboratory values:

[0158] 8.1. Absolute neutrophil count ≥1500 cells / μL;

[0159] 8.2.Platelets ≥100x 10 3 / μL;

[0160] 8.3. Hemoglobin ≥9.5 g / dL;

[0161] 8.4. Serum albumin ≥2.8 g / dL;

[0162] 8.5. Calculated creatinine clearance ≥ 60 mL / min at screening (by Cockcroft-Gault formula) or normal serum creatinine based on age as described in the table below.

[0163]

[0164]

[0165] 9. Participants are able to swallow the capsule whole.

[0166] 10. The participant is willing and able to comply with all aspects of the program.

[0167] 11. Participants must weigh at least 10 kg (inclusive) when signing the informed consent / assent form.

[0168] 12. Participants must have a body surface area (BSA) of at least 0.4m 2 (inclusive), calculated using the Du Bois formula (BSA = 0.007184 × W 0.425 ×H 0.725 ).

[0169] 13. Male or Female

[0170] Contraceptives used by men or women should comply with local regulations on contraceptive methods for participants in clinical research.

[0171] a. Male participants:

[0172] Male participants were eligible to participate if they agreed to the following during treatment and for at least 90 days after the last dose of study treatment:

[0173] Avoid sperm donation

[0174] Plus:

[0175] Abstinence from heterosexual intercourse as their preferred and customary lifestyle (long-term and sustained abstinence) and commitment to remain abstinent

[0176] or

[0177] ·Must agree to use male condoms when having sex with a woman of child bearing potential (WOCBP).

[0178] b. Female participants:

[0179] Female participants were eligible to participate if they were not pregnant or breastfeeding and met at least one of the following criteria:

[0180] Not a woman of childbearing potential

[0181] ·or

[0182] Be WOCBP and use a highly effective (failure rate <1% per year) method of contraception, preferably with low user dependence, during treatment and for at least 30 days after the last dose of study treatment, and agree not to donate ova (eggs, oocytes) for reproductive purposes during the study and for a 90-day period.

[0183] ○ WOCBP must have a negative serum pregnancy test result at Screening and must have a negative urine pregnancy test result at the Baseline Visit prior to the first dose of study treatment.

[0184] Exclusion criteria

[0185] Participants will be excluded from the study if any of the following criteria apply:

[0186] 1. The participant's screening alanine aminotransferase (ALT) value is >2.0x upper limit of normal (ULN);

[0187] 2. Participants have a screening total bilirubin value >1.5x ULN (if the bilirubin is fractionated and direct bilirubin <35%, separated bilirubin >1.5x ULN is acceptable);

[0188] 3. Participants have a history of hypercalcemia related to malignant tumors;

[0189] 4. Participants have active parathyroid disorder, hyperphosphatemia (serum phosphorus >1x ULN) at screening, and / or serum calcium (mg / dL) x serum phosphorus (mg / dL) product >70 at screening.

[0190] 5. Any history of clinically significant active or known liver disease, or known liver or biliary abnormalities (except Gilbert's syndrome or asymptomatic gallstones);

[0191] 5.1 Hepatitis serology and viral load will be tested at screening. Patients who are positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody at screening shall not be enrolled until the hepatitis B virus (HBV) deoxyribonucleic acid (DNA) titer is further confirmed to be <500IU / mL or the HCV ribonucleic acid (RNA) polymerase chain reaction test is negative;

[0192] 6. Patients with lymphoma, leukemia or any malignant tumor (including malignant glioma or malignant peripheral nerve sheath tumor (MPNST)) in the past 5 years, except for basal cell or squamous cell carcinoma of the skin that has been resected and has no evidence of metastatic disease within 3 years;

[0193] 7. Suffered from breast cancer in the past 10 years;

[0194] 8. Participants with evidence of active optic pathway glioma or other low-grade glioma who require treatment with chemotherapy or radiation therapy. Participants who do not require treatment are eligible. For the purposes of this study, ophthalmologic findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) or long-standing orbitotemporal PN (such as visual loss, strabismus) will not be considered significant abnormalities;

[0195] 9. After correction of electrolytes at screening (three ECG readings taken 2 to 3 minutes apart and averaged), the participant's QT interval abnormality has been corrected by the Fridericia formula (>450msec for male participants, >470msec for female participants, or >480msec for participants with bundle branch block);

[0196] 10. Participants experience any of the following within 6 months (24 weeks) after signing the informed consent / assent form: clinically significant heart disease, myocardial infarction, severe / unstable angina, coronary artery / peripheral artery bypass surgery, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism;

[0197] 11. Participants have a documented left ventricular ejection fraction (LVEF) <55% or a history of congestive heart failure as assessed by echocardiography;

[0198] 12. Participants have a history or evidence of retinal pathology on ophthalmological 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:

[0199] 12.1 Intraocular pressure ≥21 mmHg;

[0200] 12.2 Serum cholesterol>300 mg / dL;

[0201] 12.3 Serum triglycerides>300 mg / dL;

[0202] 12.4 Hyperglycemia (fasting blood glucose >125 mg / dL or random blood glucose >200 mg / dL);

[0203] 12.5 Age-specific hypertension

[0204] i. Participants aged ≥ 13 years and blood pressure ≥ 140 / 90 mm Hg

[0205] ii. Participants aged ≤ 12 years and blood pressure ≥ 95th percentile for age + 12 mmHg (Section 10.11);

[0206] 13. Participants have a history of glaucoma;

[0207] 14. Participants have a history of positive human immunodeficiency virus (HIV) antibody test;

[0208] 15. Participants have a known malabsorption syndrome or pre-existing gastrointestinal condition that may impair absorption of mirdametinib (e.g., gastric bypass surgery, gastric band surgery, or other gastric surgery). Delivery of mirdametinib via nasogastric or gastrostomy tube is not permitted.

[0209] 16. Participants have received NF1 PN targeted therapy (e.g., MEK inhibitors, farnesyl transferase inhibitors, kinase inhibitors, etc.) within 28 days (or approximately 5.5 half-lives, whichever is longer) of the first dose of study treatment. If a participant has progression at enrollment but has no relevant morbidity, NF1 targeted therapy must not be administered after progression is observed (Inclusion Criteria 3.1.1). All toxicities from previous therapy must resolve to ≤ Grade 1 or baseline;

[0210] 17. Participants have previously received or are currently receiving midametinib therapy;

[0211] 18. Participants are receiving systemic or ocular glucocorticoid therapy within 14 days before the first dose of study treatment (except for participants with endocrine defects, who are allowed to receive physiological or stress doses of steroids if necessary);

[0212] 19. Participants had received radiotherapy within 6 months before signing the informed consent / assent form. Participants who had received orbital radiation at any time were excluded;

[0213] 20. Currently enrolled or participated in any other clinical study in the past within 28 days after signing the informed consent / assent form (observational studies are excluded);

[0214] 21. Participants cannot tolerate MRI or are in the group with contraindications to MRI;

[0215] 22. MRI volume analysis cannot reliably assess tumors;

[0216] 23. Allergies to the study treatment or its components, or drugs, or other allergies that the investigator or medical monitor considers contraindications to participation in this study;

[0217] 24. Participants have active bacterial, fungal, or viral infections, including but not limited to the use of antibiotics, antifungal agents, or antiviral agents at the time of screening;

[0218] 25. Potential medical conditions, laboratory abnormalities, or alcohol or drug abuse or dependence that the investigator believes are unfavorable to the implementation of study treatment or affect the interpretation of drug toxicity or adverse events; or insufficient compliance during the study period according to the investigator's judgment; or

[0219] 26. The participant has experienced other serious acute or chronic medical or psychiatric disorders, including recent (within 1 year of signing the informed consent / assentment form) or active suicidal ideation or behavior, or laboratory abnormalities that may increase the risks associated with participation in the study or the management of study treatment or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant unsuitable for participation in this study.

[0220] Supportive care

[0221] Skin Adverse Events:

[0222] Supportive care for rash with medications is permitted. Early initiation of rash treatment is strongly recommended to minimize the duration and severity of adverse events.

[0223] Acne-like rash Pustular rashes can be treated with topical clindamycin gel or lotion applied BID. In severe cases, semisynthetic oral tetracyclines (such as doxycycline or minocycline) may also be useful for older children, adolescents, and adults but should be avoided in children under 8 years of age because of the risk to developing teeth.

[0224] Eczematous rash / xerosis : Eczematous / dry rashes and other macular (non-acneform) rashes should be treated with moisturizers such as Cerave or Eucerin or other equivalent products. If symptomatic, low-potency topical steroids such as 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 equivalents may also be used.

[0225] Ketoconazole shampoo should be used for any rash involving the scalp.

[0226] Paronychia: If the paronychia is acute and nonsurgical (ie, no fluctuation to suggest an abscess), it may resolve with just 3 to 4 warm soaks daily. If there is extensive redness suggesting possible cellulitis, or if there is nonsurgical paronychia but the participant has diabetes or is immunocompromised, oral antibiotics with coverage for Staphylococcus aureus should be started. Antibiotic options include penicillin / clindamycin / first-generation cephalosporin / Augmentin (amoxicillin and clavulanate) with coverage for S. aureus.

[0227] If an abscess develops, surgical management with incision and drainage, with or without debridement, should be performed. Any infectious organisms found should be treated accordingly. If the participant is diabetic or immunocompromised, oral antibiotics that ensure coverage for S. aureus should be started before culture and sensitivity reports are obtained (see above). Antibiotic therapy should be adjusted appropriately once culture reports are obtained.

[0228] Prohibition or restriction of concomitant medications / treatments

[0229] Prior use of mitrametinib is prohibited.

[0230] Alternative therapies for the treatment of PN (e.g., MEK inhibitors, farnesyl transferase inhibitors, kinase inhibitors, etc.) are prohibited within 28 days (or 5.5 half-lives, whichever is longer) of the first dose of study treatment and throughout the treatment period. If a participant has progression at enrollment but has no associated morbidity, no NF1-targeted therapy may be administered after progression is observed (Inclusion Criteria 3.1.1).

[0231] • During the entire treatment period, medical treatment (eg, chemotherapy, biological therapy, radiation therapy) for any NF1-related tumors (such as optic pathway gliomas) was prohibited.

[0232] Chronic systemic or ocular glucocorticoid therapy was prohibited within 14 days before the first dose of study treatment and throughout the treatment period (except for participants with endocrine deficiencies who were allowed to receive physiologic or stress doses of steroids if necessary). In addition, corticosteroids were allowed as premedication for blood product transfusions or as treatment for acute allergic reactions or bronchospasm.

[0233] 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. When a term in this application is found to have a different definition in a document incorporated herein by reference, the definition provided herein serves as the definition of that term.

[0234] Although the invention has been described in conjunction with specific aspects thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any changes, uses or modifications that generally follow the following principles, and include such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains, and may be applied to the basic features set forth above, and follow the scope of the claims.

Claims

1. A method of treating a pediatric human patient aged 2 to 15 years with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1), comprising orally administering to the patient an effective amount of mirdametinib.

2. The method of claim 1, wherein the patient has symptomatic, inoperable plexiform neurofibromas.

3. A method of treating a pediatric human patient aged 2 to 15 years with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) that are progressing or causing significant morbidity, comprising orally administering to the patient an effective amount of mirdametinib.

4. The method of any of the preceding claims, wherein the patient suffers from progressive PN.

5. The method of any of the preceding claims, wherein the patient suffers from PN that causes significant morbidity.

6. The method of any of the preceding claims, wherein the patient has a lesion of the head and neck that compromises the airways or great vessels, a lesion of the brachial or lumbar plexus that causes nerve compression and loss of function, a lesion that causes severe deformity or significant disfigurement, a limb lesion that causes limb hypertrophy or loss of function, or a painful lesion.

7. The method of claim 6, wherein the lesion causing severe deformity or significant disfigurement is a tumor of the head and neck or other part of the body that cannot be concealed by standard clothing.

8. The method of any one of the preceding claims, wherein the patient suffers from a paraspinal lesion.

9. The method of any of the preceding claims, wherein the patient has a Lansky performance level of at least 60%.

10. The method of any of the preceding claims, wherein the patient has a clinical diagnosis of NF1 using the NIH Consensus Conference and meets one or more of the following: (a) Individuals have six or more café-au-lait macules that are >5 mm in diameter before puberty and >15 mm after puberty; (b) freckles in the armpits or groin area; (c) optic nerve glioma; (d) two or more Lisch nodules; (e) characteristic bone lesions (sphenoid dysplasia or dysplastic thinning of the long bone cortex); and (f) First-degree relative with NF1.

11. The method of any of the preceding claims, wherein the patient has a constitutional NF1 mutation documented by a Clinical Laboratory Improvement Amendments / College of American Pathologists certified laboratory.

12. The method of any of the preceding claims, wherein the patient either (a) has a parent diagnosed with NF1 and meets one or more of the criteria of (1) to (7), or (b) has a parent not diagnosed with NF1 but meets two or more of the criteria of (1) to (7): (1) The individual has six or more café-au-lait macules with a maximum diameter greater than 5 mm before puberty and a maximum diameter greater than 15 mm after puberty; (2) Freckles in the armpits or groin area; (3) two or more neurofibromas of any type or one plexiform neurofibroma; (4) glioma of the optic pathway; (5) two or more iris Lisch nodules or two or more choroidal abnormalities (defined as bright, plaque-like nodules imaged by optical coherence tomography (OCT) / near-infrared reflectance (NIR) imaging) detected by slit-lamp examination; (6) characteristic bone lesions (such as sphenoid dysplasia, anterolateral tibial bowing, or long bone pseudarthrosis); and (7) Heterozygous pathogenic NF1 variants, with a variant allele fraction of 50% in apparently normal tissues such as leukocytes.

13. The method of any one of the preceding claims, wherein about 2 mg / m is administered to the patient twice daily. 2 .

14. The method of any one of claims 1 to 12, wherein (a) For a body surface area not exceeding 0.69 m 2 patients who were initially administered 1 mg of mitrametinib twice daily, (b) For body surface areas between 0.7 and 1.04 m 2 patients who were initially administered 2 mg mitrametinib twice daily, (c) For a body surface area of ​​1.05 to 1.49 m 2 patients who were initially administered 3 mg midametinib twice daily, and (d) For a body with a surface area of ​​at least 1.5 m 2 The patients were initially administered 4 mg midametinib twice daily.

15. The method of any one of the preceding claims, wherein the maximum daily dose is 4 mg midametinib twice daily.

16. The method of any one of the preceding claims, wherein within each four-week period, the midametinib is administered for the first three weeks and is discontinued in the last week.

17. The method of any one of the preceding claims, wherein the patient has at least a 20% reduction in plexiform neurofibroma volume following treatment with mirdametinib as determined by volumetric magnetic resonance imaging analysis.

18. The method of any one of the preceding claims, wherein the treatment results in a reduction in pain intensity.

19. The method of any one of the preceding claims, wherein the treatment results in a reduction in pain interference.

20. The method of any one of the preceding claims, wherein the administered dose is reduced due to an adverse event, wherein the dose is reduced as follows: (a) if the dose at the time of the event was 1 mg mitrametinib twice daily, the reduced daily dose is 1 mg mitrametinib administered only in the morning; (b) if the dose at the time of the event was 2 mg mitrametinib twice daily, the reduced daily dose is 2 mg mitrametinib in the morning and 1 mg mitrametinib in the afternoon or evening; (c) if the dose at the time of the event was 3 mg of mitrametinib twice daily, the reduced daily dose is 2 mg of mitrametinib twice daily; and (d) If the dose at which the event occurred was 4 mg mitralinib twice daily, the reduced daily dose is 3 mg mitralinib twice daily.

21. The method of claim 20, wherein the adverse event leading to the dose reduction is acneiform.

22. The method of any of the preceding claims, wherein the method further comprises, prior to treatment, (i) determining whether to select mirametinib as a treatment for the patient and (ii) selecting mirametinib as a treatment for the patient based at least in part on an objective response rate to mirametinib, wherein the objective response rate is defined as at least a 20% reduction in tumor size using centrally read MRI volumetric analysis.

23. The method of claim 22, wherein in step (i), midametinib is selected based on a response rate of at least 70%.

24. A method of treating a human pediatric patient aged 2 to 5 years with inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) comprising orally administering to said patient 1 mg of mirdametinib twice daily.

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