Mildametinib dosage forms

Abstract

This disclosure relates to an oral dosage form (such as a capsule) comprising (a) mildametinib having a d90 of 250 microns or less, a d50 of 50 microns or less, or both, and (b) one or more pharmaceutically acceptable pharmaceutical excipients. Such dosage forms are useful in the treatment of tumors and cancers (such as plexus neurofibroma (PN), plexus neurofibroma associated with neurofibromatosis type 1 (NF1-PN), high-grade glioma (HGG), low-grade ovarian cancer, Langerhans cell histiocytosis (LCH), brain cancer, and cancers that have metastasized to the patient's brain). This disclosure also relates to improved dosage regimens for mildametinib treatment.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 490,626, filed on 16 March 2023, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to an oral dosage form (such as a capsule) comprising (a) mildametinib having a d90 of 250 microns or less, a d50 of 50 microns or less, or both, and (b) one or more pharmaceutically acceptable pharmaceutical excipients. This disclosure also relates to an improved dosage regimen for mildametinib treatment. [Background technology]

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

[0004] There is a need for effective treatments for inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1). [Overview of the project]

[0005] One aspect of the present invention is an oral dosage form comprising (a) mildametinib having a d90 of 250 microns or less, and (b) one or more pharmaceutically acceptable pharmaceutical excipients. In one embodiment, mildametinib has a d90 in the range of 50 to 150 microns. In another embodiment, mildametinib has a d90 in the range of 150 to 250 microns. In yet another embodiment, mildametinib has a d50 of 50 microns or less. In yet another embodiment, mildametinib has a d50 in the range of 1 to 25 microns. In yet another embodiment, mildametinib has a d50 of 25 to 50 microns. In yet another embodiment, mildametinib has a d50 of 30 microns or less. The oral dosage form may be a solid oral dosage form such as a capsule or tablet (e.g., a dispersible tablet). In one embodiment, the oral dosage form contains 1 mg of mildametinib. In another embodiment, the oral dosage form contains 2 mg of mildametinib.

[0006] Another embodiment is an oral dosage form comprising (a) mildametinib having a d50 of 50 microns or less, and (b) one or more pharmaceutically acceptable pharmaceutical excipients. In one embodiment, mildametinib has a d50 of 1 to 25 microns. In yet another embodiment, mildametinib has a d50 of 25 to 50 microns. In yet another embodiment, mildametinib has a d50 of 30 microns or less. The oral dosage form may be a solid oral dosage form such as a capsule or tablet (e.g., a dispersible tablet). In one embodiment, the oral dosage form contains 1 mg of mildametinib. In another embodiment, the oral dosage form contains 2 mg of mildametinib.

[0007] In one embodiment, the dosage form is a capsule prepared by (i) roller-compressing a blend of mildametinib and one or more pharmaceutically acceptable pharmaceutical additives, and (ii) encapsulating the compressed blend in a capsule.

[0008] Another aspect is an oral dosage form comprising (a) 1 mg of midostaurin having a d90 of 250 microns or less and (b) one or more pharmaceutically acceptable pharmaceutical additives, wherein the dosage form provides an AUC of less than 400 ng·h / mL upon oral administration on the first day of treatment with midostaurin 0~12h , a C of 40 ng / mL or less max , or both. In one embodiment, the dosage form provides an AUC of less than 200 ng·h / mL upon oral administration on the first day of treatment with midostaurin 0~12h . In another embodiment, the dosage form provides an AUC of less than 100 ng·h / mL upon oral administration on the first day of treatment with midostaurin 0~12h . In yet another embodiment, the dosage form provides a C of 32 ng / mL or less upon oral administration on the first day of treatment with midostaurin max . In yet another embodiment, the dosage form provides a C of 30 ng / mL or less upon oral administration on the first day of treatment with midostaurin max .

[0009] Yet another aspect is an oral dosage form comprising (a) 1 mg of midostaurin having a d50 of 50 microns or less and (b) one or more pharmaceutically acceptable pharmaceutical additives, wherein the dosage form provides an AUC of less than 400 ng·h / mL upon oral administration on the first day of treatment with midostaurin 0~12h , a C of 40 ng / mL or less max , or both. In one embodiment, the dosage form provides an AUC of less than 200 ng·h / mL upon oral administration on the first day of treatment with midostaurin 0~12h . In another embodiment, the dosage form provides an AUC of less than 100 ng·h / mL upon oral administration on the first day of treatment with midostaurin 0~12h . In yet another embodiment, the dosage form provides a C of 32 ng / mL or less upon oral administration on the first day of treatment with midostaurin max . In yet another embodiment, the dosage form provides a C of 30 ng / mL or less upon oral administration on the first day of treatment with midostaurin max .

[0010] In one embodiment, any oral dosage form of any embodiment described herein releases at least 80% of its mildametinib within 15 minutes when measured in 0.1N HCl (0.1N aqueous HCl solution) at 75 rpm according to the USP basket method.

[0011] Another embodiment is a method for treating a human patient (e.g., aged 2 years or older) having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), the method comprising orally administering one or more of the oral dosage forms described herein to the patient in an effective dose. In one embodiment, the patient has a symptomatic, inoperable plexiform neurofibroma.

[0012] Another aspect is a method for treating a human patient having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1) that is progressing or causing a marked pathological condition, the method comprising orally administering one or more of the oral dosage forms described herein to the patient in an effective dose.

[0013] In any embodiment of the method described herein, the patient has progressive PN (i.e., a 20% increase in PN volume documented by a comparison of two MRI scans within 12 months prior to the first dose of mildametinib).

[0014] In any embodiment of the method described herein, the patient has PN that causes a marked pathological condition.

[0015] In any embodiment of the method described herein, 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 enlargement or loss of function, or a painful lesion. In one embodiment, a lesion causing significant deformity or disfigurement is a tumor of the head and neck or a tumor of another body part that cannot be concealed by standard clothing.

[0016] In one embodiment of any of the methods described herein, the patient has a paravertebral lesion.

[0017] In one embodiment of any method described herein, the patient has at least 60% Lansky performance.

[0018] In any embodiment of the method described herein, the patient has a clinical diagnosis of NF1 using an NIH Consensus Conference and one or more of the following: (a) Six or more café-au-lait spots with a diameter greater than 5 mm in pre-pubescent individuals, and greater than 15 mm in diameter in post-pubescent individuals. (b) Freckle-like pigmented lesions in the axilla or groin, (c) optic glioma, (d) Two or more iris nodules, (e) Unique bone lesions (sphenoid dysplasia or thinning of the long cortex), and (f) First-degree relatives who have NF1.

[0019] In any one embodiment of the method described herein, the patient has a constitutional NF1 mutation documented in a Clinical Laboratory Improvement Amendments / College of American Pathologists accredited laboratory.

[0020] In any embodiment of the method described herein, the patient has (a) a parent diagnosed with NF1 and one or more criteria from (1) to (7), or (b) no parent diagnosed with NF1 but two or more criteria from (1) to (7): (1) Six or more café-au-lait spots with a maximum diameter exceeding 5 mm in pre-pubescent individuals, and with a maximum diameter exceeding 15 mm in post-pubescent individuals. (2) Freckle-like pigmented spots in the axilla or groin, (3) Two or more neurofibromas of any type, or one plexiform neurofibroma, (4) Scleral tract glioma, (5) Two or more iris nodules identified by slit-lamp examination, or two or more choroidal abnormalities (defined as distinct patchy nodules imaged by optical coherence tomography (OCT) / near-infrared reflection (NIR) imaging), (6) Unique bone lesions (such as sphenoid dysplasia, anterolateral curvature of the tibia, or pseudoarthrosis of long bones), and (7) A heterozygous pathogenic NF1 variant in which the proportion of variant alleles in seemingly normal tissues (such as white blood cells) is 50%.

[0021] In any one embodiment of the method described herein, the patient is between 2 and 15 years of age. In any other embodiment of the method described herein, the patient is at least 16 years of age.

[0022] In one embodiment, approximately 2 mg / m² 2 Mildametinib is administered to the patient twice a day.

[0023] In another embodiment of any of the methods described herein, (a) 0.69m 2 For patients with the following body surface area, the patient will initially receive 1 mg of mildametinib orally twice daily (i.e., a total of 2 mg per day). (b) 0.7~1.04m 2 For patients with a body surface area of ​​[specified], the patient is initially administered 2 mg of mildametinib orally twice daily (i.e., a total of 4 mg per day). (c) 1.05~1.49m 2 For patients with a body surface area of ​​[specified], the patient is initially administered 3 mg of mildametinib orally twice daily (i.e., a total of 6 mg per day). (d) at least 1.5m 2 For patients with a body surface area of ​​[specified], the patient is initially administered 4 mg of mildametinib orally twice daily (i.e., a total of 8 mg per day).

[0024] In yet another embodiment of the method described herein, (a) Maximum 0.59m2 or 0.4~0.59m 2 For patients with a body surface area of ​​[specified], the patient is initially given 1 mg of mildametinib orally twice daily. (b) 0.6~0.79m 2 For patients with a body surface area of ​​[specified], the patient will initially be administered 1.5 mg of mildametinib orally twice daily. (c) 0.8~0.99m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 2 mg of mildametinib orally twice daily. (d) 1.0~1.19m 2 For patients with a body surface area of ​​[specified], the patient will initially be administered 2.5 mg of mildametinib orally twice daily. (e) 1.2~1.39m 2 For patients with a body surface area of ​​the above, the patient will initially be given 3 mg of mildametinib orally twice daily. (f) 1.4~1.59m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 3.5 mg of mildametinib orally twice daily. (g) at least 1.6m 2 For patients with a body surface area of ​​, the patient is initially administered 4 mg of mildametinib orally twice daily. In one embodiment, the patient is under 12 years of age. In one embodiment, mildametinib is administered in the form of one or more tablets (such as one or more dispersible tablets). In another embodiment, mildametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of the foregoing. The tablets may be dispersible tablets. One embodiment is a method for treating a human patient (or any such patient described herein) having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), the method comprising the above-described method of administering mildametinib.

[0025] In yet another embodiment of the method described herein, (a) Maximum 0.69m 2 or 0.4~0.69m 2For patients with a body surface area of ​​[specified], the patient is initially given 1 mg of mildametinib orally twice daily. (b) 0.7~1.04m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 2 mg of mildametinib orally twice daily. (c) 1.05~1.49m 2 For patients with a body surface area of ​​the above, the patient will initially be given 3 mg of mildametinib orally twice daily. (d) at least 1.5m 2 For patients having a body surface area of ​​, the patient is initially administered 4 mg of mildametinib orally twice daily. In one embodiment, the patient is at least 12 years of age. In one embodiment, mildametinib is administered in the form of one or more capsules (such as one or more 1 mg capsules, one or more 2 mg capsules, or any combination of the foregoing). One embodiment is a method for treating a human patient (or any such patient described herein) having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), the method comprising the above-described method of administering mildametinib.

[0026] In yet another embodiment of the method described herein, (a) 0.4~0.59m 2 (or up to 0.59m) 2 For patients with a body surface area of ​​) the patient will initially be given 1 mg of mildametinib orally twice daily. (b) 0.6~0.79m 2 For patients with a body surface area of ​​[specified], the patient will initially be administered 1.5 mg of mildametinib orally twice daily. (c) 0.8~0.99m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 2 mg of mildametinib orally twice daily. (d) 1.0~1.39m 2 For patients with a body surface area of ​​[specified], the patient will initially be administered 2.5 mg of mildametinib orally twice daily. (e) 1.4~1.59m 2For patients with a body surface area of ​​the above, the patient will initially be given 3 mg of mildametinib orally twice daily. (f) 1.6~1.69m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 3.5 mg of mildametinib orally twice daily. (g) at least 1.7m 2 For patients with a body surface area of ​​, the patient is initially administered 4 mg of mildametinib orally twice daily. In one embodiment, the patient is under 12 years of age. In one embodiment, mildametinib is administered in the form of one or more tablets (such as one or more dispersible tablets). In another embodiment, mildametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of the foregoing. The tablets may be dispersible tablets. One embodiment is a method for treating a human patient (or any such patient described herein) having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), the method comprising the above-described method of administering mildametinib.

[0027] One embodiment is a method of administering mildametinib to a patient (such as a human patient) who requires the administration of mildametinib by orally administering mildametinib. (a) 0.4~0.59m 2 (or up to 0.59m) 2 For patients with a body surface area of ​​) the patient will initially be given 1 mg of mildametinib orally twice daily. (b) 0.6~0.79m 2 For patients with a body surface area of ​​[specified], the patient will initially be administered 1.5 mg of mildametinib orally twice daily. (c) 0.8~0.99m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 2 mg of mildametinib orally twice daily. (d) 1.0~1.19m 2 For patients with a body surface area of ​​[specified], the patient will initially be administered 2.5 mg of mildametinib orally twice daily. (e) 1.2~1.39m2 For patients with a body surface area of ​​the above, the patient will initially be given 3 mg of mildametinib orally twice daily. (f) 1.4~1.59m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 3.5 mg of mildametinib orally twice daily. (g) at least 1.6m 2 For patients with a body surface area of ​​, the patient is initially administered 4 mg of mildametinib orally twice daily. In one embodiment, the patient is under 12 years of age. In one embodiment, mildametinib is administered in the form of one or more tablets (such as one or more dispersible tablets). In another embodiment, mildametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of the foregoing. The tablets may be dispersible tablets. In one embodiment, mildametinib may have d50, d90, or both, as described herein. In another embodiment, mildametinib is administered in dosage form such as tablets (e.g., dispersible tablets) or capsules, as described herein. One embodiment is a method for treating a human patient (or any such patient as described herein) having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), the method comprising the above-described method of administering mildametinib.

[0028] Another embodiment is a method of administering mildametinib to a patient (such as a human patient) who requires the administration of mildametinib by orally administering mildametinib. (a) 0.4~0.69m 2 (or up to 0.69m) 2 For patients with a body surface area of ​​) the patient will initially be given 1 mg of mildametinib orally twice daily. (b) 0.7~1.04m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 2 mg of mildametinib orally twice daily. (c) 1.05~1.49m 2For patients with a body surface area of ​​the above, the patient will initially be given 3 mg of mildametinib orally twice daily. (d) at least 1.5m 2 For patients having a body surface area of ​​, the patient is initially administered 4 mg of mildametinib orally twice daily. In one embodiment, the patient is at least 12 years of age. In one embodiment, mildametinib is administered in the form of one or more capsules (such as one or more 1 mg capsules, one or more 2 mg capsules, or any combination of the foregoing). One embodiment is a method for treating a human patient (or any such patient described herein) having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), the method comprising the above-described method of administering mildametinib.

[0029] Another embodiment is a method of administering mildametinib to a patient (such as a human patient) who requires the administration of mildametinib by orally administering mildametinib. (a) 0.4~0.59m 2 (or up to 0.59m) 2 For patients with a body surface area of ​​) the patient will initially be given 1 mg of mildametinib orally twice daily. (b) 0.6~0.79m 2 For patients with a body surface area of ​​[specified], the patient will initially be administered 1.5 mg of mildametinib orally twice daily. (c) 0.8~0.99m 2 For patients with a body surface area of ​​[specified], the patient will initially be given 2 mg of mildametinib orally twice daily. (d) 1.0~1.39m 2 For patients with a body surface area of ​​[specified], the patient will initially be administered 2.5 mg of mildametinib orally twice daily. (e) 1.4~1.59m 2 For patients with a body surface area of ​​the above, the patient will initially be given 3 mg of mildametinib orally twice daily. (f) 1.6~1.69m 2For patients with a body surface area of ​​[specified], the patient will initially be given 3.5 mg of mildametinib orally twice daily. (g) at least 1.7m 2 For patients with a body surface area of ​​, the patient is initially administered 4 mg of mildametinib orally twice daily. In one embodiment, the patient is under 12 years of age. In one embodiment, mildametinib is administered in the form of one or more tablets (such as one or more dispersible tablets). In another embodiment, mildametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of the foregoing. The tablets may be dispersible tablets. One embodiment is a method for treating a human patient (or any such patient described herein) having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), the method comprising the above-described method of administering mildametinib.

[0030] In any embodiment of the method described herein, the maximum daily dose is 4 mg of mildametinib twice daily.

[0031] In any embodiment of the method described herein, mildametinib is administered for the first three weeks and then discontinued for the last week, over a period of four weeks.

[0032] In any of the methods described herein, if the dosage form is a tablet (such as a dispersible tablet), the tablet(s) to be administered may first be dispersed in water (such as drinking water) (e.g., about 5-10 mL of water) to form an oral suspension, which may optionally be mixed by stirring to ensure no clumps remain, and administered (preferably within 30 minutes). In some embodiments, one or more oral tablets are dispersed in about 5-10 mL of water in a container, and the tablets are mixed by stirring to ensure no clumps remain in the water. In some embodiments, the oral suspension will be administered within 30 minutes. In some cases, the patient may rinse the container containing the suspension with additional drinking water (e.g., about 5-10 mL of water) to ensure that the patient receives the entire dose.

[0033] In any embodiment of the method 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 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. (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. In any embodiment of the method described herein, the adverse event resulting in the dose reduction is acneiform rash.

[0034] In any one embodiment of the method described herein, the method further comprises, before treatment, (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient, at least in part based on its objective response rate, where the objective response rate is defined as a reduction of at least 20% in tumor size using centrally read MRI volume 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 another embodiment, in step (i), mildametinib is selected based on an objective response rate of at least 95%.

[0035] In any one embodiment of the method described herein, the patient has at least a 20% reduction in the volume of the plexiform neurofibroma as determined by volume magnetic resonance imaging after treatment with mildametinib.

[0036] In any embodiment of the method described herein, the treatment results in a reduction in pain intensity.

[0037] In any embodiment of the method described herein, the treatment results in a reduction of pain interference.

[0038] Another embodiment is a method for treating a tumor or cancer in a human patient 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 cancer, and cancer that has metastasized to the patient's brain, the method comprising administering to the patient one or more oral dosage forms comprising mildametinib as described herein.

[0039] In some embodiments, a therapeutically effective dose of mildametinib or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the mildametinib or a pharmaceutically acceptable salt thereof is approximately 1 mg / m² per day, based on mildametinib free base. 2 ~about 10mg / m 2 It is administered orally in the amount indicated. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered orally in an amount of approximately 1 mg to approximately 10 mg / day based on mildametinib free base.

[0040] In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is approximately 0.1 mg / m² based on mildametinib free base. 2 ~about 10mg / m 2 It is administered orally in a single dosage form. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered in a single dosage form containing about 0.1 mg to about 10 mg based on mildametinib free base.

[0041] In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered twice daily.

[0042] In some embodiments, mildametinib or its pharmaceutically acceptable salts exhibit high blood-brain barrier permeability.

[0043] In some embodiments, the patient is human. In some embodiments, the human's age is between 2 and 25 years.

[0044] In some cases, humans have never been exposed to MEK inhibitors before.

[0045] In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered as monotherapy for the treatment of tumors or cancer. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery for the treatment of tumors or cancer.

[0046] In any embodiment of this specification, the dose of mildametinib may be administered with one or more 0.5 mg, 1 mg, or 2 mg mildametinib dosage forms, or any combination of the foregoing. For example, a 3.5 mg dose may be administered as three 1 mg mildametinib dosage forms (e.g., tablets) and one 0.5 mg mildametinib dosage form (e.g., tablet).

[0047] In one embodiment, mildametinib is provided as 0.5 or 1 mg mildametinib tablets (e.g., dispersible tablets). In another embodiment, mildametinib is provided as 1 or 2 mg mildametinib capsules. In yet another embodiment, mildametinib is provided as 0.5 or 1 mg mildametinib tablets (e.g., dispersible tablets) and 1 or 2 mg mildametinib capsules. [Brief explanation of the drawing]

[0048] [Figure 1] This graph shows the release of mildametinib from 1 mg and 2 mg capsules prepared using mildametinib derived from lots #1 and #2 as described in Example 2, using the USP basket method at 75 rpm in 0.1 N HCl. [Figure 2] This graph shows the release of mildametinib from 2 mg capsules prepared using mildametinib derived from lots #1, #2, and #3 as described in Example 2, using the USP basket method at 75 rpm in 0.1 N HCl. [Modes for carrying out the invention]

[0049] I. Definition The following terms are defined to facilitate understanding of the disclosures set forth herein.

[0050] In general, the nomenclature used herein, as well as the experimental procedures in organic chemistry, medical chemistry, and pharmacology described herein, are well known and commonly adopted in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.

[0051] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly indicates 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 terms “a” or “an” mean “single.” In other embodiments, the terms “a” or “an” include “two or more” or “plural.”

[0052] The term "mildametinib" refers to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide. The teachings provided herein regarding mildametinib also apply equally to pharmaceutically acceptable salts of mildametinib. For example, this disclosure relating to a method of treating inoperable plexiform neurofibromas (PNs) associated with neurofibromatosis type 1 (NF1) using mildametinib also means that pharmaceutically acceptable salts of mildametinib may be administered to treat inoperable PNs associated with NF1.

[0053] "mg / m 2 The term "patient body surface area 1 m²" refers to the patient's body surface area. 2 This refers to the dosage in milligrams per unit.

[0054] The term "subject" refers to animals including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, with respect to mammalian subjects (such as human subjects).

[0055] "AUC 0~12h The term "area under the plasma concentration-time curve" refers to the area under the plasma concentration-time curve from time 0 to the end of time 12.

[0056] "C max The term "highest plasma concentration" refers to the highest plasma concentration.

[0057] As used herein, the term “dispersible” refers to a composition (e.g., tablets, powders, granules, minitablets, or pellets) that disintegrates and / or dissolves when placed in the mouth of an object with water or another drinking liquid (e.g., a beverage other than water), or with the object's own saliva, regardless of whether or not it is stirred or the temperature is altered. In some embodiments, a dispersible composition disintegrates or dissolves within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute after being combined with water or another drinking liquid. Such disintegration or dissolution does not need to be complete. For example, a dispersible tablet may dissolve almost completely, but some undissolved particulate matter may remain.

[0058] As used herein, the terms “to treat,” “to be treated,” and “to treat” mean both therapeutic treatment and preventive or inhibitory action, the purpose of which is to prevent or delay (reduce) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. Therefore, those requiring treatment include those already diagnosed with a disorder or suspected to have a disorder. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, whether detectable or undetectable; reduction of the severity of a condition, disorder, or disease; stabilization (i.e., non-worsening) of a condition, disorder, or disease; delay or slowing of the onset of progression of a condition, disorder, or disease; improvement or remission (partial or complete) of a condition, disorder, or disease; improvement of at least one measurable physical parameter not necessarily identifiable by the patient; or enhancement or improvement of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes extending survival compared to the predicted survival without treatment. The term "therapeutic dose" means the amount of a compound that, when administered, is sufficient to prevent or, to some extent, alleviate the onset of one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutic dose" also refers to the amount of a compound that is sufficient to elicit a biological or medical response in a cell, tissue, system, animal, or human being being sought by a researcher, veterinarian, physician, or clinician.

[0059] In certain embodiments, a patient is considered to have successfully “treated” the tumor if he or she exhibits one or more of the following: reduction in tumor size; improvement in quality of life; increased 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), reduced progression (PD), increased time to progression (TTP), or any combination thereof. In some embodiments, it may be determined whether an effective dose of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR) using nationally or internationally accepted criteria for treatment outcomes in a given tumor.

[0060] In certain embodiments, a patient is considered to have been successfully “treated” for cancer (e.g., ovarian cancer) according to the methods described herein if the patient exhibits one or more of the following: reduction or complete absence of cancer cells; relief of one or more symptoms associated with a particular cancer; reduction of morbidity and mortality; improvement of 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 of progression (PD), increase of time to progression (TTP), or any combination thereof. In some embodiments, it may be determined whether an effective dose of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR) using nationally or internationally accepted criteria for treatment outcomes in a given cancer.

[0061] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable pharmaceutical additive,” “physiologically acceptable carrier,” or “physiologically acceptable pharmaceutical additive” refer to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, pharmaceutical additives, solvents, or encapsulating materials. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs in a reasonable benefit / risk ratio without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. 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; and Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0062] The term “pharmaceutically acceptable salts” refers to inorganic and organic acid addition salts of mildametinib that are relatively non-toxic. These salts can be prepared in situ in the administration medium or dosage form manufacturing process, or by reacting the purified compound of the present invention in free base form with a suitable organic or inorganic acid individually and isolating the resulting salt 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.

[0063] The terms “about” or “approximately” mean an acceptable error to a particular value as determined by those skilled in the art, which in part depends on how the value is measured or determined. In certain embodiments, the terms “about” or “approximately” mean that the standard deviation is within 1, 2, 3, or 4. In certain embodiments, the terms “about” or “approximately” mean that the standard deviation is 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] As used herein, "D50" or "d50" is also known as the median diameter and corresponds to a value in which 50% of the particles have a smaller volume diameter. "D90" or "d90" corresponds to a value in which 90% of the particles have a smaller volume diameter. Particle size can be measured using standard wet laser diffraction particle size measurement techniques known in the art. An example of an apparatus for measuring the particle size of dry powder is the Mastersizer 3000 manufactured by Malvern Panalytical Ltd. (Malvern, UK). Since particles are often non-spherical, providing a dimensional description for such non-spherical particles is difficult and complex. As used herein, "volume diameter" refers to the diameter of a sphere with the same volume as the non-spherical particle.

[0065] Unless the context requires otherwise, the terms “comprise,” “comprises,” and “comprising” are to be interpreted inclusively, not exclusively, and the Applicant uses these terms in the interpretation of this Patent, including the following claims, with the clear understanding that each of these terms is intended to be interpreted in that way.

[0066] II. Oral Dosage Forms The oral dosage form contains mildametinib having a d90 of 250 microns or less, a d50 of 50 microns or less, or both. In one embodiment, the oral dosage form contains 0.5 mg of mildametinib, 1.0 mg of mildametinib, 1.5 mg of mildametinib, 2.0 mg of mildametinib, 2.5 mg of mildametinib, 3.0 mg of mildametinib, 3.5 mg of mildametinib, or 4.0 mg of mildametinib.

[0067] In one embodiment, the oral dosage form contains 0.5 mg of mildametinib.

[0068] In another embodiment, the oral dosage form contains 1.0 mg of mildametinib.

[0069] In another embodiment, the oral dosage form contains 2.0 mg of mildametinib.

[0070] Mildametinib may exist in crystalline form in oral dosage forms (such as any of the U.S. Patents No. 6,960,614, No. 7,060,856, No. 11,066,358, and No. 11,084,780 (these documents are incorporated herein by reference in their entirety)). In some embodiments, the crystalline form of mildametinib is selected from (a) crystalline form of mildametinib (form IV) characterized by a powder X-ray diffraction (XRPD) pattern having peaks at 4.6±0.2, 7.3±0.2, and 14.6±0.2 degrees 2θ, (b) crystalline form of mildametinib (form I) characterized by an XRPD pattern having peaks at 10.6±0.2, 13.7±0.2, 19.0±0.2, and 23.7±0.2 degrees 2θ, and (c) crystalline form of mildametinib (form II) characterized by an XRPD pattern having peaks at 5.5±0.2 and 19.6±0.2 degrees 2θ.

[0071] In some embodiments, the crystalline morphology of mildametinib (morphology IV) is characterized by an XRPD pattern with peaks at 4.6±0.2, 7.3±0.2 (or 7.2±0.2), and 2θ at 14.6±0.2 degrees (morphology IV).

[0072] In some embodiments, the crystalline morphology of mildametinib is characterized by an endothermic differential scanning calorimetry (DSC) profile with an initiation point at approximately 117°C.

[0073] In some embodiments, the crystalline form of mildametinib does not contain any amount of form I or form II detectable by XRPD and / or DSC. Forms I and II are described in U.S. Patent No. 6,960,614.

[0074] In some embodiments, mildametinib in crystalline form is anhydrous.

[0075] In some embodiments, the crystalline form of mildametinib is form IV. In some embodiments, the crystalline form of mildametinib is essentially pure form IV (such as that described in U.S. Patent No. 11,066,358 (which is incorporated herein by reference)). Form IV is described in U.S. Patents No. 7,060,856 and No. 11,066,358. In some embodiments, essentially pure form IV of mildametinib exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after 3 months of storage under standard warehouse conditions (15°C to 25°C and relative humidity ≤ 65%). In some embodiments, essentially pure form IV of mildametinib exhibits an XRPD pattern and / or DSC profile that remains substantially unchanged after 6 months of storage under standard warehouse conditions (15°C to 25°C and relative humidity ≤ 65%). In some embodiments, the essentially pure form IV of mildametinib exhibits a substantially unchanged XRPD pattern and / or DSC profile after one year of storage under standard warehouse conditions (15°C to 25°C and relative humidity ≤ 65%).

[0076] In some embodiments, a PANALYTICAL® X'Pert Pro diffractometer using Ni-filtered Cu Kα (45kV / 40mA) radiation and a step size of 0.03° 2θ is equipped with an X'CELERATOR® Real Time Multi-Strip detector, where (a) the incident beam side consists of a variable divergence slit (irradiation length 10mm), a 0.04rad solar slit, a fixed anti-scattering slit (0.50°), and a 10mm beam mask, and (b) the diffracted beam side consists of a variable anti-scattering slit (observation length 10mm) and a 0.04rad solar slit, or (a) the incident beam side consists of a Goebel mirror, a mirror exit slit (0.2mm), a 2.5° solar slit, and a beam knife, and (b) the diffracted beam side consists of an anti-scattering slit (8mm) and a 2.5° solar slit, and a LYNXEYE® detector is equipped with Cu Kα (40kV / 40mA) radiation and a step size of 0.03° 2θ. XRPD patterns are generated using a BRUKER® D8® ADVANCE® system with a step size of 2θ, and the sample is mounted flat on a zero-background Si wafer. In some embodiments, DSC patterns are generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature rise rate of approximately 15°C / min.

[0077] The oral dosage form may contain one or more diluents, disintegrants, lubricants, or any combination thereof. In one embodiment, the oral dosage form comprises (a) about 0.1 w / w% to about 5 w / w% of mildametinib, (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.

[0078] Suitable diluents include, but are not limited to, microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate, calcium hydrogen phosphate, and any combination thereof. In one embodiment, the oral dosage form contains microcrystalline cellulose as a diluent.

[0079] 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 any combination thereof. In one embodiment, the oral dosage form contains the disintegrant croscarmellose sodium.

[0080] Suitable lubricants include, but are not limited to, magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glycerol dibehenate, talc, and any combination thereof. In one embodiment, the oral dosage form contains magnesium stearate as a lubricant.

[0081] The oral dosage form may be a capsule (such as a hard gelatin capsule).

[0082] An oral dosage form may contain one or more pharmaceutically acceptable carriers. In some embodiments, the oral dosage form is dispersible. In some embodiments, the oral dosage form is orally dispersible. An oral dosage form may be a tablet, powder, granules, minitablet, or pellet (also called beads). In some embodiments, the oral dosage form is a powder. In some embodiments, the oral dosage form is a dispersible powder. In some embodiments, a capsule or sachet contains a dispersible powder. In some embodiments, the oral dosage form is in the form of granules. In some embodiments, the granules are dispersible granules. In some embodiments, a capsule or sachet contains dispersible granules. In some embodiments, the oral dosage form is in the form of minitablets. In some embodiments, the minitablets are dispersible minitablets. In some embodiments, a capsule or sachet contains dispersible minitablets. In some embodiments, the oral dosage form is in the form of pellets. In some embodiments, the pellets are dispersible pellets. In some embodiments, a capsule or sachet contains dispersible pellets.

[0083] In some embodiments, the oral dosage form is a tablet. In some embodiments, the tablet is a dispersible tablet. In some embodiments, the tablet is an orally dispersible tablet.

[0084] In some embodiments, the oral dosage form, which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, contains approximately 0.1 mg to approximately 20 mg of mildametinib, and the components of the oral dosage form are as follows: (a) approximately 0.1 wt / wt% to approximately 7 wt / wt% of mildametinib, (b) approximately 50 wt / wt% to approximately 98 wt / wt% of one or more diluents, (c) approximately 1 wt / wt% to approximately 10 wt / wt% of one or more disintegrants, (d) optionally, 0 wt / wt% to approximately 5 wt / wt% of one or more flavoring agents, (e) optionally, 0 wt / wt% to approximately 5 wt / wt% of one or more sweeteners, and (f) optionally, 0 wt / wt% to approximately 5 wt / wt% of one or more lubricants.

[0085] In some embodiments, the oral dosage form, which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, contains approximately 0.1 mg to approximately 20 mg of mildametinib, and the components of the oral dosage form are as follows: (a) approximately 0.2 wt / wt% to approximately 1.5 wt / wt% of mildametinib, (b) approximately 75 wt / wt% to approximately 98 wt / wt% of one or more diluents, (c) approximately 3 wt / wt% to approximately 8 wt / wt% of one or more disintegrants, (d) optionally, 0 wt / wt% to approximately 5 wt / wt% of one or more flavoring agents, (e) optionally, 0 wt / wt% to approximately 5 wt / wt% of one or more sweeteners, and (f) optionally, 0 wt / wt% to approximately 5 wt / wt% of one or more lubricants.

[0086] In some embodiments, the oral dosage form, which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, contains approximately 0.1 mg to approximately 20 mg of mildametinib, and the components of the oral dosage form are as follows: (a) approximately 0.5 wt / wt% to approximately 1.2 wt / wt% of mildametinib, (b) approximately 85 wt / wt% to approximately 95 wt / wt% of one or more diluents, (c) approximately 3.5 wt / wt% to approximately 6 wt / wt% of one or more disintegrants, (d) optionally, 0 wt / wt% to approximately 2.5 wt / wt% of one or more flavoring agents, (e) optionally, 0 wt / wt% to approximately 2 wt / wt% of one or more sweeteners, and (f) optionally, approximately 0.5 wt / wt% to approximately 2 wt / wt% of one or more lubricants.

[0087] In some embodiments, the oral dosage form, which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, contains about 0.5 mg of mildametinib. In some embodiments, the oral dosage form contains about 1 mg of mildametinib. In some embodiments, the oral dosage form, which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, contains about 2 mg of mildametinib. In some embodiments, the oral dosage form, which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, contains about 3 mg of mildametinib. In some embodiments, the oral dosage form, which is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, contains about 4 mg of mildametinib.

[0088] In some embodiments, at least one of the diluents is selected from microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate, and calcium hydrogen phosphate. In some embodiments, at least one of the diluents is microcrystalline cellulose.

[0089] In some embodiments, at least one of the disintegrants is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and alginic acid. In some embodiments, at least one of the disintegrants is croscarmellose sodium.

[0090] In some embodiments, at least one of the flavoring agents is selected from natural or synthetic flavoring agents (including, but not limited to, grape flavoring, bubblegum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring). In some embodiments, at least one of the flavoring agents is grape flavoring.

[0091] In some embodiments, at least one of the sweeteners is selected from sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some embodiments, at least one of the sweeteners is sucralose.

[0092] In some embodiments, at least one of the lubricants is selected from magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glycerol dibehenate, and talc. In some embodiments, at least one of the lubricants is magnesium stearate.

[0093] III. Treatment method Methods for treating tumors or cancers 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 cancer, and cancers that have metastasized to the brain of a patient are provided herein, the methods comprising administering mildametinib or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0094] In some aspects of the methods described herein, the tumor or cancer is a plexiform neurofibroma. In some aspects, the tumor or cancer is a plexiform neurofibroma associated with neurofibromatosis type 1.

[0095] In some aspects of the methods described herein, the tumor or cancer is a high-grade glioma. In some aspects, the high-grade glioma is a primary cancer. In some aspects, the high-grade glioma is a metastatic cancer.

[0096] In some aspects of any of the methods described herein, the tumor or cancer is low-grade ovarian cancer. In some aspects, the tumor or cancer is Langerhans cell histiocytosis. In some aspects, the tumor or cancer is brain cancer. In some aspects, the tumor or cancer is cancer (including lung cancer, breast cancer, and melanoma) that has metastasized to the brain of a patient.

[0097] In some aspects of the methods described herein, a therapeutically effective dose of mildametinib or a pharmaceutically acceptable salt thereof is administered orally.

[0098] In any aspect of the method described herein, mildametinib or a pharmaceutically acceptable salt thereof is approximately 1 mg / m² per day based on mildametinib free base. 2 ~about 10mg / m 2 Based on mildametinib free base, approximately 1.5 mg / m² per day. 2 ~about 9.5mg / m 2 Based on mildametinib free base, approximately 2 mg / m² per day. 2 ~about 9mg / m 2 Based on mildametinib free base, approximately 2.5 mg / m² per day. 2 ~about 8.5mg / m 2 Based on mildametinib free base, approximately 3 mg / m² per day. 2 ~about 8mg / m 2 Based on mildametinib free base, approximately 3.5 mg / m² per day. 2 ~about 7.5mg / m 2 Based on mildametinib free base, approximately 4 mg / m² per day. 2 ~about 7mg / m 2 Based on mildametinib free base, approximately 4.5 mg / m² per day. 2 ~about 6.5mg / m 2 Based on mildametinib free base, approximately 5 mg / m² per day. 2 ~about 6mg / m 2 It is administered in the amount of mildametinib. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is approximately 1 mg / m² per day based on mildametinib free base. 2, administered in an amount of about 1.5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 2 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 2.5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 3 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 3.5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 4 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 4.5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 5.5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 6 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 6.5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 7 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 7.5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 8 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 8.5 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 9 mg / m per day based on the free base of midostaurin 2 , administered in an amount of about 9.5 mg / m per day based on the free base of midostaurin 2 , or administered in an amount of about 10 mg / m per day based on the free base of midostaurin 2 is administered

[0099] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 1 mg to approximately 10 mg per day based on mildametinib free base, approximately 1.5 mg to approximately 9.5 mg per day based on mildametinib free base, approximately 2 mg to approximately 9 mg per day based on mildametinib free base, approximately 2.5 mg to approximately 8.5 mg per day based on mildametinib free base, approximately 3 mg to approximately 8 mg per day based on mildametinib free base, approximately 3.5 mg to approximately 7.5 mg per day based on mildametinib free base, approximately 4 mg to approximately 7 mg per day based on mildametinib free base, approximately 4.5 mg to approximately 6.5 mg per day based on mildametinib free base, or approximately 5 mg to approximately 6 mg per day based on mildametinib free base. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered in doses of approximately 1 mg per day based on mildametinib free base, approximately 1.5 mg per day based on mildametinib free base, approximately 2 mg per day based on mildametinib free base, approximately 2.5 mg per day based on mildametinib free base, approximately 3 mg per day based on mildametinib free base, approximately 3.5 mg per day based on mildametinib free base, approximately 4 mg per day based on mildametinib free base, approximately 4.5 mg per day based on mildametinib free base, approximately 5 mg per day based on mildametinib free base, and mildametinib free base. The drug is administered in doses of approximately 5.5 mg per day based on free methinib, approximately 6 mg per day based on free mildametinib, approximately 6.5 mg per day based on free mildametinib, approximately 7 mg per day based on free mildametinib, approximately 7.5 mg per day based on free mildametinib, approximately 8 mg per day based on free mildametinib, approximately 8.5 mg per day based on free mildametinib, approximately 9 mg per day based on free mildametinib, approximately 9.5 mg per day based on free mildametinib, or approximately 10 mg per day based on free mildametinib.

[0100] In any aspect of the method described herein, mildametinib or a pharmaceutically acceptable salt thereof is approximately 0.1 mg / m² based on mildametinib free base. 2 ~about 10mg / m 2 Based on mildametinib free base, approximately 0.5 mg / m² 2 ~about 9.5mg / m 2 Based on mildametinib free base, approximately 1 mg / m² 2 ~about 9mg / m 2 Based on mildametinib free base, approximately 1.5 mg / m² 2 ~about 8.5mg / m 2 Based on mildametinib free base, approximately 2 mg / m² 2 t~about 8mg / m 2 Based on mildametinib free base, approximately 2.5 mg / m² 2 ~about 7.5mg / m 2 Based on mildametinib free base, approximately 3 mg / m² 2 ~about 7mg / m 2 Based on mildametinib free base, approximately 3.5 mg / m² 2 ~about 6.5mg / m 2 Based on mildametinib free base, approximately 4 mg / m² 2 ~about 6mg / m 2 or approximately 4.5 mg / m² based on mildametinib free base. 2 ~about 5.5mg / m 2 It is administered in a single dosage form containing mildametinib. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered at approximately 0.1 mg / m² based on mildametinib free base. 2 Based on mildametinib free base, approximately 0.2 mg / m² 2 Based on mildametinib free base, approximately 0.3 mg / m² 2 Based on mildametinib free base, approximately 0.4 mg / m² 2 Based on mildametinib free base, approximately 0.5 mg / m² 2 Based on mildametinib free base, approximately 1 mg / m² 2 Based on mildametinib free base, approximately 1.5 mg / m² 2 Based on mildametinib free base, approximately 2 mg / m² 2Based on mildametinib free base, approximately 2.5 mg / m² 2 Based on mildametinib free base, approximately 3 mg / m² 2 Based on mildametinib free base, approximately 3.5 mg / m² 2 Based on mildametinib free base, approximately 4 mg / m² 2 Based on mildametinib free base, approximately 4.5 mg / m² 2 Based on mildametinib free base, approximately 5 mg / m² 2 Based on mildametinib free base, approximately 5.5 mg / m² 2 Based on mildametinib free base, approximately 6 mg / m² 2 Based on mildametinib free base, approximately 6.5 mg / m² 2 Based on mildametinib free base, approximately 7 mg / m² 2 Based on mildametinib free base, approximately 7.5 mg / m² 2 Based on mildametinib free base, approximately 8 mg / m² 2 Based on mildametinib free base, approximately 8.5 mg / m² 2 Based on mildametinib free base, approximately 9 mg / m² 2 Based on mildametinib free base, approximately 9.5 mg / m² 2 or approximately 10 mg / m² based on mildametinib free base. 2 It is administered in a single dosage form containing [the active ingredient].

[0101] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg to about 10 mg based on mildametinib free base, about 0.5 mg to about 9.5 mg based on mildametinib free base, about 1 mg to about 9 mg based on mildametinib free base, about 1.5 mg to about 8.5 mg based on mildametinib free base, about 2 mg to about 8 mg based on mildametinib free base, about 2.5 mg to about 7.5 mg based on mildametinib free base, about 3 mg to about 7 mg based on mildametinib free base, about 3.5 mg to about 6.5 mg based on mildametinib free base, about 4 mg to about 6 mg based on mildametinib free base, or about 4.5 mg to about 5.5 mg based on mildametinib free base. In some embodiments, mildametinib or its pharmaceutically acceptable salts are approximately 0.1 mg based on mildametinib free base, approximately 0.2 mg based on mildametinib free base, approximately 0.3 mg based on mildametinib free base, approximately 0.4 mg based on mildametinib free base, approximately 0.5 mg based on mildametinib free base, approximately 1 mg based on mildametinib free base, approximately 1.5 mg based on mildametinib free base, approximately 2 mg based on mildametinib free base, approximately 2.5 mg based on mildametinib free base, approximately 3 mg based on mildametinib free base, approximately 3.5 mg based on mildametinib free base, and mildametinib free salt It is administered in a single dosage form containing approximately 4 mg based on the base, approximately 4.5 mg based on mildametinib free base, approximately 5 mg based on mildametinib free base, approximately 5.5 mg based on mildametinib free base, approximately 6 mg based on mildametinib free base, approximately 6.5 mg based on mildametinib free base, approximately 7 mg based on mildametinib free base, approximately 7.5 mg based on mildametinib free base, approximately 8 mg based on mildametinib free base, approximately 8.5 mg based on mildametinib free base, approximately 9 mg based on mildametinib free base, approximately 9.5 mg based on mildametinib free base, or approximately 10 mg based on mildametinib free base.

[0102] In some embodiments of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is administered once, twice, three times, or four times per day. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered once per day. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is administered twice per day.

[0103] In any aspect of the method described herein, mildametinib or a pharmaceutically acceptable salt thereof is approximately 0.5 mg / m² based on mildametinib free base. 2 ~about 10mg / m 2 Based on mildametinib free base, approximately 1 mg / m² 2 ~about 9.5mg / m 2 Based on mildametinib free base, approximately 1.5 mg / m² 2 ~about 9mg / m 2 Based on mildametinib free base, approximately 2 mg / m² 2 ~about 8.5mg / m 2 Based on mildametinib free base, approximately 2.5 mg / m² 2 ~about 8mg / m 2 Based on mildametinib free base, approximately 3 mg / m² 2 ~about 7.5mg / m 2 Based on mildametinib free base, approximately 3.5 mg / m² 2 ~about 7mg / m 2 Based on mildametinib free base, approximately 4 mg / m² 2 ~about 6.5mg / m 2 Based on mildametinib free base, approximately 4.5 mg / m² 2 ~about 6mg / m 2 or based on mildametinib free base, approximately 5 mg / m² 2 ~about 6mg / m 2 It is administered twice daily in this amount. In some embodiments, mildametinib or a pharmaceutically acceptable salt thereof is approximately 0.5 mg / m² based on mildametinib free base. 2 Based on mildametinib free base, approximately 1 mg / m² 2 Based on mildametinib free base, approximately 1.5 mg / m² 2Based on mildametinib free base, approximately 2 mg / m² 2 Based on mildametinib free base, approximately 2.5 mg / m² 2 Based on mildametinib free base, approximately 3 mg / m² 2 Based on mildametinib free base, approximately 3.5 mg / m² 2 Based on mildametinib free base, approximately 4 mg / m² 2 Based on mildametinib free base, approximately 4.5 mg / m² 2 Based on mildametinib free base, approximately 5 mg / m² 2 Based on mildametinib free base, approximately 5.5 mg / m² 2 Based on mildametinib free base, approximately 6 mg / m² 2 Based on mildametinib free base, approximately 6.5 mg / m² 2 Based on mildametinib free base, approximately 7 mg / m² 2 Based on mildametinib free base, approximately 7.5 mg / m² 2 Based on mildametinib free base, approximately 8 mg / m² 2 Based on mildametinib free base, approximately 8.5 mg / m² 2 Based on mildametinib free base, approximately 9 mg / m² 2 Based on mildametinib free base, approximately 9.5 mg / m² 2 or approximately 10 mg / m² based on mildametinib free base. 2 It is administered twice a day in that amount.

[0104] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is administered twice daily in amounts of about 0.5 mg to about 10 mg based on mildametinib free base, about 1 mg to about 9.5 mg based on mildametinib free base, about 1.5 mg to about 9 mg based on mildametinib free base, about 2 mg to about 8.5 mg based on mildametinib free base, about 2.5 mg to about 8 mg based on mildametinib free base, about 3 mg to about 7.5 mg based on mildametinib free base, about 3.5 mg to about 7 mg based on mildametinib free base, about 4 mg to about 6.5 mg based on mildametinib free base, about 4.5 mg to about 6 mg based on mildametinib free base, or about 5 mg to about 6 mg based on mildametinib free base. In some embodiments, mildametinib or its pharmaceutically acceptable salts are approximately 0.5 mg based on mildametinib free base, approximately 1 mg based on mildametinib free base, approximately 1.5 mg based on mildametinib free base, approximately 2 mg based on mildametinib free base, approximately 2.5 mg based on mildametinib free base, approximately 3 mg based on mildametinib free base, approximately 3.5 mg based on mildametinib free base, approximately 4 mg based on mildametinib free base, approximately 4.5 mg based on mildametinib free base, mildametinib free base The drug is administered twice daily in amounts of approximately 5 mg based on the given dosage, approximately 5.5 mg based on free mildametinib, approximately 6 mg based on free mildametinib, approximately 6.5 mg based on free mildametinib, approximately 7 mg based on free mildametinib, approximately 7.5 mg based on free mildametinib, approximately 8 mg based on free mildametinib, approximately 8.5 mg based on free mildametinib, approximately 9 mg based on free mildametinib, approximately 9.5 mg based on free mildametinib, or approximately 10 mg based on free mildametinib.

[0105] In any aspect of the method described herein, mildametinib or a pharmaceutically acceptable salt thereof is approximately 10 mg / m² based on mildametinib free base. 2 Based on mildametinib free base, approximately 9.5 mg / m² 2Based on mildametinib free base, approximately 9 mg / m² 2 Based on mildametinib free base, approximately 8.5 mg / m² 2 Based on mildametinib free base, approximately 8 mg / m² 2 Based on mildametinib free base, approximately 7.5 mg / m² 2 Based on mildametinib free base, approximately 7 mg / m² 2 Based on mildametinib free base, approximately 6.5 mg / m² 2 Based on mildametinib free base, approximately 6 mg / m² 2 Based on mildametinib free base, approximately 5.5 mg / m² 2 Based on mildametinib free base, approximately 5 mg / m² 2 Based on mildametinib free base, approximately 4.5 mg / m² 2 Based on mildametinib free base, approximately 4 mg / m² 2 Based on mildametinib free base, approximately 3.5 mg / m² 2 Based on mildametinib free base, approximately 3 mg / m² 2 Based on mildametinib free base, approximately 2.5 mg / m² 2 Based on mildametinib free base, approximately 2 mg / m² 2 , or approximately 1.5 mg / m² based on mildametinib free base. 2 It is administered in a total daily dose not exceeding [amount].

[0106] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is approximately 10 mg based on mildametinib free base, approximately 9.5 mg based on mildametinib free base, approximately 9 mg based on mildametinib free base, approximately 8.5 mg based on mildametinib free base, approximately 8 mg based on mildametinib free base, approximately 7.5 mg based on mildametinib free base, approximately 7 mg based on mildametinib free base, approximately 6.5 mg based on mildametinib free base, and mildametinib The total daily dose is administered in amounts not exceeding approximately 6 mg based on free base of mildametinib, approximately 5.5 mg based on free base of mildametinib, approximately 5 mg based on free base of mildametinib, approximately 4.5 mg based on free base of mildametinib, approximately 4 mg based on free base of mildametinib, approximately 3.5 mg based on free base of mildametinib, approximately 3 mg based on free base of mildametinib, approximately 2.5 mg based on free base of mildametinib, approximately 2 mg based on free base of mildametinib, or approximately 1.5 mg based on free base of mildametinib.

[0107] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is administered as mildametinib free base.

[0108] Methods for treating tumors or cancers 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 cancer, and cancers that have metastasized to the brain of a patient are provided herein, the methods comprising administering mildametinib free base to a patient in need thereof.

[0109] In some aspects of the methods described herein, the tumor or cancer is a plexiform neurofibroma. In some aspects, the tumor or cancer is a plexiform neurofibroma associated with neurofibromatosis type 1.

[0110] In some aspects of the methods described herein, the tumor or cancer is a high-grade glioma. In some aspects, the high-grade glioma is a primary cancer. In some aspects, the high-grade glioma is a metastatic cancer.

[0111] In some aspects of any of the methods described herein, the tumor or cancer is low-grade ovarian cancer.

[0112] In some aspects of the methods described herein, the tumor or cancer is Langerhans cell histiocytosis.

[0113] In some aspects of any of the methods described herein, the tumor or cancer is brain cancer.

[0114] In some aspects of any of the methods described herein, the tumor or cancer is cancer (including lung cancer, breast cancer, and melanoma) that has metastasized to the patient's brain.

[0115] In some aspect of the method described herein, a therapeutically effective dose of mildametinib free base is administered.

[0116] In any aspect of the method described herein, mildametinib free base is approximately 1 mg / m² per day. 2 ~about 10mg / m 2 Approximately 1.5 mg / m² per day 2 ~about 9.5mg / m 2 Approximately 2 mg / m² per day 2 ~about 9mg / m 2 Approximately 2.5 mg / m² per day 2 ~about 8.5mg / m 2 Approximately 3 mg / m² per day 2 ~about 8mg / m 2 Approximately 3.5 mg / m² per day 2 ~about 7.5mg / m 2 Approximately 4 mg / m² per day 2 ~about 7mg / m 2 Approximately 4.5 mg / m² per day 2 ~about 6.5mg / m2 , or approximately 5 mg / m² per day 2 ~about 6mg / m 2 It is administered in the amount of [amount]. In some embodiments, mildametinib free base is approximately 1 mg / m² per day. 2 Approximately 1.5 mg / m² per day 2 Approximately 2 mg / m² per day 2 Approximately 2.5 mg / m² per day 2 Approximately 3 mg / m² per day 2 Approximately 3.5 mg / m² per day 2 Approximately 4 mg / m² per day 2 Approximately 4.5 mg / m² per day 2 Approximately 5 mg / m² per day 2 Approximately 5.5 mg / m² per day 2 Approximately 6 mg / m² per day 2 Approximately 6.5 mg / m² per day 2 Approximately 7 mg / m² per day 2 Approximately 7.5 mg / m² per day 2 Approximately 8 mg / m² per day 2 Approximately 8.5 mg / m² per day 2 Approximately 9 mg / m² per day 2 Approximately 9.5 mg / m² per day 2 , or approximately 10 mg / m² per day 2 It is administered in that amount.

[0117] In some aspects of the methods described herein, mildametinib free base is administered in amounts of approximately 1 mg to approximately 10 mg per day, approximately 1.5 mg to approximately 9.5 mg per day, approximately 2 mg to approximately 9 mg per day, approximately 2.5 mg to approximately 8.5 mg per day, approximately 3 mg to approximately 8 mg per day, approximately 3.5 mg to approximately 7.5 mg per day, approximately 4 mg to approximately 7 mg per day, approximately 4.5 mg to approximately 6.5 mg per day, or approximately 5 mg to approximately 6 mg per day. In some embodiments, mildametinib free base is administered in amounts of approximately 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg per day.

[0118] In any aspect of the method described herein, the amount of mildametinib free base is approximately 0.1 mg / m². 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 approximately 4.5 mg / m² 2 ~about 5.5mg / m 2 It is administered in a single dosage form containing [the active ingredient]. In some embodiments, the free base of mildametinib is approximately 0.1 mg / m². 2, about 0.2mg / m 2 , about 0.3mg / m 2 , about 0.4mg / m 2 , about 0.5mg / m 2 , about 1mg / m 2 , about 1.5mg / m 2 , about 2mg / m 2 , about 2.5mg / m 2 , about 3mg / m 2 , about 3.5mg / m 2 , about 4mg / m 2 , about 4.5mg / m 2 , about 5mg / m 2 , about 5.5mg / m 2 , about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2 , about 8.5mg / m 2 , about 9mg / m 2 , about 9.5mg / m 2 , or approximately 10 mg / m² 2 It is administered in a single dosage form containing [the active ingredient].

[0119] In some aspects of the methods described herein, mildametinib 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 aspects, mildametinib free base is administered in a single dosage form containing approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0120] In some embodiments of the methods described herein, mildametinib free base is administered once, twice, three times, or four times per day. In some embodiments, mildametinib free base is administered once per day. In some embodiments, mildametinib free base is administered twice per day.

[0121] In any aspect of the method described herein, the amount of mildametinib free base is approximately 0.5 mg / m². 2 ~about 10mg / m 2 , about 1mg / m 2 ~about 9.5mg / m 2 , about 1.5mg / m 2 ~about 9mg / m 2 , about 2mg / m 2 ~about 8.5mg / m 2 , about 2.5mg / m 2 ~about 8mg / m 2 , about 3mg / m 2 ~about 7.5mg / m 2 , about 3.5mg / m 2 ~about 7mg / m 2 , about 4mg / m 2 ~about 6.5mg / m 2 , about 4.5mg / m 2 ~about 6mg / m 2 , or approximately 5 mg / m² 2 ~about 6mg / m 2 It is administered twice daily in this amount. In some embodiments, the mildametinib free base is approximately 0.5 mg / m². 2 , about 1mg / m 2 , about 1.5mg / m 2 , about 2mg / m 2 , about 2.5mg / m 2 , about 3mg / m 2 , about 3.5mg / m 2 , about 4mg / m 2 , about 4.5mg / m 2 , about 5mg / m 2 , about 5.5mg / m 2 , about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2, about 8.5mg / m 2 , about 9mg / m 2 , about 9.5mg / m 2 , or approximately 10 mg / m² 2 It is administered twice a day in that amount.

[0122] In some aspects of the methods described herein, mildametinib free base is administered twice daily in amounts 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, mildametinib free base is administered twice daily in amounts of approximately 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0123] In any aspect of the method described herein, the amount of mildametinib free base is approximately 10 mg / m². 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 approximately 1.5 mg / m² 2 It is administered in a total daily dose not exceeding [amount].

[0124] In some aspects of the methods described herein, mildametinib free base is administered in a total daily dose not exceeding approximately 10 mg, approximately 9.5 mg, approximately 9 mg, approximately 8.5 mg, approximately 8 mg, approximately 7.5 mg, approximately 7 mg, approximately 6.5 mg, approximately 6 mg, approximately 5.5 mg, approximately 5 mg, approximately 4.5 mg, approximately 4 mg, approximately 3.5 mg, approximately 3 mg, approximately 2.5 mg, approximately 2 mg, or approximately 1.5 mg.

[0125] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof exhibits high blood-brain barrier permeability.

[0126] In some aspects of the methods described herein, the patient is a human being.

[0127] In some embodiments of the methods described herein, the age of the human is between 2 and 25 years. In some embodiments, the age of the human is between 2 and 18 years.

[0128] In some aspects of the methods described herein, the human being has never been exposed to a MEK inhibitor before. In some aspects, the human being has not responded to previous treatment with one or more MEK inhibitors.

[0129] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is administered orally. In some aspects, mildametinib or a pharmaceutically acceptable salt thereof is administered orally in solid dosage form. In some aspects, the solid dosage form is a tablet or a capsule. In some aspects, the solid dosage form is a capsule. In some aspects, mildametinib or a pharmaceutically acceptable salt thereof is dispersible in drinking liquids or orally dispersible in the patient's saliva.

[0130] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is administered as monotherapy for the treatment of tumors or cancer.

[0131] In some aspects of the methods described herein, mildametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery for the treatment of a tumor or cancer. [Examples]

[0132] Example 1 Mildametinib free bases (lots #1, 2, and 3) with the characteristics shown in the table below were prepared. [Table 1]

[0133] Example 2 Using either lot #1 or #2 obtained from Example 1, 1 mg and 2 mg capsules having the formulations listed in the table below were prepared. The ingredients were mixed, subjected to roller compression, and then encapsulated in capsule shells (size 3, opaque hard gelatin capsules). [Table 2]

[0134] The solubility of 1 mg and 2 mg capsules prepared using mildametinib from lots #1 and #2 was measured in 0.1 N HCl (0.1 N aqueous HCl solution) at 75 rpm using the USP basket method. The solubility is shown in Figure 1. As shown, the tested capsules released more than 80% of the mildametinib within 15 minutes.

[0135] 2 mg capsules containing the above formulation were prepared from lot #3. The solubility of 2 mg capsules prepared from lots #1, #2, and #3 was measured in 0.1 N HCl at 75 rpm using the USP basket method. The solubility is shown in Figure 2. As shown, the tested capsules released more than 80% of mildametinib within 15 minutes.

[0136] All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated to be incorporated herein by reference in whole. If a term in this application is found to have a different definition in a document incorporated herein by reference, the definition provided herein shall be the definition of that term.

[0137] Having described the present invention in detail with its specific embodiments, it will be understood that further modifications are possible. It will also be understood that this application is intended to cover any variations, uses, or adaptations of the disclosure, including deviations from the disclosure in accordance with the claims, applicable to the essential features set forth above, generally in principle and within the scope of known or common practices in the art to which the invention relates.

Claims

1. An oral dosage form comprising (a) mildametinib having a d90 of 250 microns or less, and (b) one or more pharmaceutically acceptable pharmaceutical excipients.

2. The oral dosage form according to claim 1, wherein the mildametinib has a d50 of 50 microns or less.

3. The oral dosage form according to claim 1 or 2, wherein the mildametinib has a d50 of 30 microns or less.

4. The oral dosage form according to any one of claims 1 to 3, wherein the dosage form is a capsule prepared by (i) roller-compressing a blend of mildametinib and one or more pharmaceutically acceptable pharmaceutical additives, and (ii) encapsulating the compressed blend in a capsule.

5. (a) 1 mg of mildametinib having a d90 of 250 microns or less, and (b) one or more pharmaceutically acceptable pharmaceutical excipients, wherein the dosage form, when administered orally on the first day of treatment with mildametinib, has an AUC of less than 400 ng / h / mL ０～１２ｈ , C 40 ng / mL or less ｍａｘ Oral dosage forms that provide either or both.

6. The aforementioned dosage form, when administered orally on the first day of treatment with mildametinib, has an AUC of less than 200 ng / h / mL. ０～１２ｈ The oral dosage form according to claim 5, which provides

7. The aforementioned dosage form, when administered orally on the first day of treatment with mildametinib, has an AUC of less than 100 ng / h / mL. ０～１２ｈ The oral dosage form according to claim 5, which provides

8. The aforementioned dosage form, when administered orally on the first day of treatment with mildametinib, has a C content of 32 ng g / mL or less. ｍａｘ An oral dosage form according to any one of claims 5 to 7, which provides

9. The aforementioned dosage form, when administered orally on the first day of treatment with mildametinib, contains less than 30 ng g / mL of C. ｍａｘ An oral dosage form according to any one of claims 5 to 7, which provides

10. The oral dosage form according to any one of claims 1 to 9, wherein the dosage form is a capsule.

11. The oral dosage form according to any one of claims 1 to 10, wherein the dosage form is a tablet.

12. The oral dosage form according to any one of claims 1 to 11, wherein the dosage form is a dispersible tablet.

13. A method for treating a human patient having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising orally administering to the patient an effective amount of one or more oral dosage forms described in any one of claims 1 to 12.

14. Approximately 2mg / m ２ The method according to claim 13, wherein mildametinib is administered to the patient twice daily.

15. (a) 0.69 m ２ For patients with the following body surface area, the patient will initially be administered 1 mg of mildametinib twice daily. For patients having a body surface area of (b) 0.7 to 1.04 m ２ the patient is initially administered 2 mg of midostaurin twice daily, (c) 1.05-1.49m ２ For patients with a body surface area, the patient is initially administered 3 mg of mildametinib twice daily. (d) at least 1.5 m ２ The method according to claim 13, wherein, for a patient having a body surface area, the patient is initially administered 4 mg of mildametinib twice daily.

16. (a) 0.4-0.59m ２ For patients with a body surface area, the patient is initially administered 1 mg of mildametinib twice daily. (b) 0.6-0.79m ２ For patients with a body surface area of ​​the above, the patient is initially administered 1.5 mg of mildametinib twice daily. (c) 0.8-0.99m ２ For patients with a body surface area, the patient is initially administered 2 mg of mildametinib twice daily. (d) 1.0-1.19m ２ For patients with a body surface area of ​​the above, the patient is initially administered 2.5 mg of mildametinib twice daily. (e) 1.2-1.39m ２ For patients with a body surface area, the patient is initially administered 3 mg of mildametinib twice daily. (f) 1.4-1.59m ２ For patients with a body surface area of ​​the above, the patient is initially administered 3.5 mg of mildametinib twice daily. (g) at least 1.6 m ２ The method according to claim 13, wherein, for a patient having a body surface area, the patient is initially administered 4 mg of mildametinib twice daily.

17. The method according to claim 16, wherein the patient is under 12 years of age.

18. The method according to claim 16 or 17, wherein the mildametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination thereof.

19. The method according to any one of claims 16 to 18, wherein the mildametinib is administered in the form of one or more dispersible tablets.

20. (a) 0.4-0.69m ２ For patients with a body surface area, the patient is initially administered 1 mg of mildametinib twice daily. (b) 0.7-1.04m ２ For patients with a body surface area, the patient is initially administered 2 mg of mildametinib twice daily. (c) 1.05-1.49m ２ For patients with a body surface area, the patient is initially administered 3 mg of mildametinib twice daily. (d) at least 1.5 m ２ The method according to claim 13, wherein, for a patient having a body surface area, the patient is initially administered 4 mg of mildametinib twice daily.

21. The method according to claim 20, wherein the patient is at least 12 years old.

22. The method according to claim 20 or 21, wherein the mildametinib is administered in the form of one or more capsules.

23. (a) 0.4-0.59m ２ For patients with a body surface area, the patient is initially administered 1 mg of mildametinib twice daily. (b) 0.6-0.79m ２ For patients with a body surface area of ​​the above, the patient is initially administered 1.5 mg of mildametinib twice daily. (c) 0.8-0.99m ２ For patients with a body surface area, the patient is initially administered 2 mg of mildametinib twice daily. (d) 1.0-1.39m ２ For patients with a body surface area of ​​the above, the patient is initially administered 2.5 mg of mildametinib twice daily. (e) 1.4-1.59m ２ For patients with a body surface area, the patient is initially administered 3 mg of mildametinib twice daily. (f) 1.6-1.69m ２ For patients with a body surface area of ​​the above, the patient is initially administered 3.5 mg of mildametinib twice daily. (g) at least 1.7 m ２ The method according to claim 13, wherein, for a patient having a body surface area, the patient is initially administered 4 mg of mildametinib twice daily.

24. The method according to claim 23, wherein the patient is under 12 years of age.

25. The method according to claim 23 or 24, wherein the mildametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination thereof.

26. The method according to any one of claims 23 to 25, wherein the mildametinib is administered in the form of one or more dispersible tablets.

27. The method according to any one of claims 13-16, 18-20, 22, 23, 25, and 26, wherein the patient is 2 to 15 years of age.

28. The method according to any one of claims 13 to 16, 18 to 20, 22, 23, 25, and 26, wherein the patient is at least 16 years of age.

29. The method according to any one of claims 13 to 28, further comprising, before treatment, (i) deciding whether to select mildametinib as a treatment for the patient, and (ii) selecting mildametinib as a treatment for the patient, at least in part on its objective response rate, wherein the objective response rate is defined as a reduction of at least 20% of tumor size using a monolithic MRI volumetric analysis.

30. The method according to claim 29, wherein in step (i), mildametinib is selected based on an objective response rate of at least 70%.

31. A method for treating a human patient having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising orally administering mildametinib to the patient, (a) 0.4-0.59m ２ For patients with a body surface area, the patient is initially administered 1 mg of mildametinib twice daily. (b) 0.6-0.79m ２ For patients with a body surface area of ​​the above, the patient is initially administered 1.5 mg of mildametinib twice daily. (c) 0.8-0.99m ２ For patients with a body surface area, the patient is initially administered 2 mg of mildametinib twice daily. (d) 1.0-1.19m ２ For patients with a body surface area of ​​the above, the patient is initially administered 2.5 mg of mildametinib twice daily. (e) 1.2-1.39m ２ For patients with a body surface area, the patient is initially administered 3 mg of mildametinib twice daily. (f) 1.4-1.59m ２ For patients with a body surface area of ​​the above, the patient is initially administered 3.5 mg of mildametinib twice daily. (g) at least 1.6 m ２ For patients having a body surface area, the patient is initially administered 4 mg of mildametinib twice daily.

32. The method according to claim 31, wherein the patient is under 12 years of age.

33. The method according to claim 31 or 32, wherein the mildametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination thereof.

34. The method according to any one of claims 31 to 33, wherein the mildametinib is administered in the form of one or more dispersible tablets.

35. A method for treating a human patient having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising orally administering mildametinib to the patient, (a) 0.4-0.69m ２ For patients with a body surface area, the patient is initially administered 1 mg of mildametinib twice daily. (b) 0.7-1.04m ２ For patients with a body surface area, the patient is initially administered 2 mg of mildametinib twice daily. (c) 1.05-1.49m ２ For patients with a body surface area, the patient is initially administered 3 mg of mildametinib twice daily. (d) at least 1.5 m ２ For patients having a body surface area, the patient is initially administered 4 mg of mildametinib twice daily.

36. The method according to claim 35, wherein the patient is at least 12 years old.

37. The method according to claim 35 or 36, wherein the mildametinib is administered in the form of one or more capsules.

38. A method for treating a human patient having an inoperable plexiform neurofibroma (PN) associated with neurofibromatosis type 1 (NF1), comprising orally administering mildametinib to the patient, (a) 0.4-0.59m ２ For patients with a body surface area, the patient is initially administered 1 mg of mildametinib twice daily. (b) 0.6-0.79m ２ For patients with a body surface area of ​​the above, the patient is initially administered 1.5 mg of mildametinib twice daily. (c) 0.8-0.99m ２ For patients with a body surface area, the patient is initially administered 2 mg of mildametinib twice daily. (d) 1.0-1.39m ２ For patients with a body surface area of ​​the above, the patient is initially administered 2.5 mg of mildametinib twice daily. (e) 1.4-1.59m ２ For patients with a body surface area, the patient is initially administered 3 mg of mildametinib twice daily. (f) 1.6-1.69m ２ For patients with a body surface area of ​​the above, the patient is initially administered 3.5 mg of mildametinib twice daily. (g) at least 1.7 m ２ For patients having a body surface area, the patient is initially administered 4 mg of mildametinib twice daily.

39. The method according to claim 38, wherein the patient is under 12 years of age.

40. The method according to claim 38 or 39, wherein the mildametinib is administered in the form of one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination thereof.

41. The method according to any one of claims 38 to 40, wherein the mildametinib is administered in the form of one or more dispersible tablets.

42. The method according to any one of claims 13-21, 23-36, and 38-41, wherein the mildametinib is in the form of one or more dispersible tablets, and before administration, the one or more dispersible tablets are dispersed in water to form a suspension, and optionally, the suspension is mixed by stirring until no clumps remain.

43. The method according to claim 42, wherein the suspension is formed by dispersing one or more dispersible tablets in 5 to 10 mL of water.

44. The method according to claim 42 or 43, wherein the suspension is administered to the patient within 30 minutes of being prepared.

45. The method according to any one of claims 13 to 44, wherein each of the one or more oral dosage forms comprises (a) mildametinib having a d90 of 250 microns or less, and (b) one or more pharmaceutically acceptable pharmaceutical additives.

46. The method according to claim 45, wherein the mildametinib has a d50 of 50 microns or less.

47. The method according to claim 45, wherein the mildametinib has a d50 of 30 microns or less.

48. The method according to any one of claims 45 to 47, wherein each of the one or more oral dosage forms is a capsule prepared by (i) roller-compressing a blend of mildametinib and one or more pharmaceutically acceptable pharmaceutical additives, and (ii) encapsulating the compressed blend in a capsule.

Images