Dosage forms of midametinib

Abstract

The present disclosure relates to an oral dosage form, such as a capsule, comprising (a) midametinib having a d90 of not more than 250 microns, a d50 of not more than 50 microns, or both, and (b) one or more pharmaceutically acceptable excipients. These dosage forms are useful for the treatment of tumors and cancers, such as plexus neurofibroma (PN), plexus neurofibroma associated with type 1 neurofibromatosis (NF1-PN), high-grade glioma (HGG), low-grade ovarian cancer, Langerhans cell tissue cell hyperplasia (LCH), brain cancer, and cancer that has metastatic to the brain of a patient. The present disclosure also relates to an improved dosage regimen for midametinib treatment.

Description

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

[0002] The present disclosure relates to an oral dosage form, such as a capsule, comprising (a) mirdametinib having a d90 of no more than 250 microns, a d50 of no more than 50 microns, or both, and (b) one or more pharmaceutically acceptable excipients. The present disclosure also relates to improved dosage regimens for mirdametinib therapy. BACKGROUND

[0003] Mirdametinib is an allosteric, small molecule targeted to mitogen-activated protein kinase kinase (MEK).

[0004] There is a need for effective therapeutic methods to treat neurofibromatosis type 1 (NF1)-associated inoperable plexiform neurofibromas (PNs). SUMMARY

[0005] One aspect of the present invention is an oral dosage form comprising (a) mirdametinib having a d90 of no more than 250 microns and (b) one or more pharmaceutically acceptable excipients. In one embodiment, the d90 of mirdametinib is in the range of 50 to 150 microns. In another embodiment, the d90 of mirdametinib is in the range of 150 to 250 microns. In yet another embodiment, the d50 of mirdametinib is no more than 50 microns. In yet another embodiment, the d50 of mirdametinib is 1 to 25 microns. In yet another embodiment, the d50 of mirdametinib is 25 to 50 microns. In yet another embodiment, the d50 of mirdametinib is no more than 30 microns. The oral dosage form can be a solid oral dosage form, such as a capsule or a tablet (e.g., a dispersible tablet). In one embodiment, the oral dosage form contains 1 mg of mirdametinib. In another embodiment, the oral dosage form contains 2 mg of mirdametinib.

[0006] Another aspect is an oral dosage form comprising (a) mirdametinib having a d50 of no more than 50 microns and (b) one or more pharmaceutically acceptable excipients. In one embodiment, the d50 of mirdametinib is 1 to 25 microns. In yet another embodiment, the d50 of mirdametinib is 25 to 50 microns. In yet another embodiment, the d50 of mirdametinib is no more than 30 microns. The oral dosage form can be a solid oral dosage form, such as a capsule or a tablet (e.g., a dispersible tablet). In one embodiment, the oral dosage form contains 1 mg of mirdametinib. In another embodiment, the oral dosage form contains 2 mg of mirdametinib.

[0007] In one embodiment, the dosage form is a capsule prepared by (i) roller compaction of a blend of midostaurin and one or more pharmaceutically acceptable excipients, and (ii) encapsulation of the compacted blend into a capsule.

[0008] Another aspect is an oral dosage form comprising (a) 1 mg of midostaurin having a d90 of no more than 250 microns and (b) one or more pharmaceutically acceptable excipients, wherein the AUC 0-12h less than 400 ng-h / mL, C max no more than 40 ng / mL, or both. In one embodiment, the AUC 0-12h less than 200 ng-h / mL. In another embodiment, the AUC 0-12h less than 100 ng-h / mL. In yet another embodiment, the C max no more than 32 ng / mL. In yet another embodiment, the C max no more than 30 ng / mL.

[0009] Yet another aspect is an oral dosage form comprising (a) 1 mg of midostaurin having a d50 of no more than 50 microns and (b) one or more pharmaceutically acceptable excipients, wherein the AUC 0-12h less than 400 ng-h / mL, C max no more than 40 ng / mL, or both. In one embodiment, the AUC 0-12h less than 200 ng-h / mL. In another embodiment, the AUC 0-12h less than 100 ng-h / mL. In yet another embodiment, the C max no more than 32 ng / mL. In yet another embodiment, the C max no more than 30 ng / mL.

[0010] In one embodiment, the oral dosage form of any of the embodiments described herein releases at least 80% of the midostaurin within 15 minutes, as measured according to the USP Basket Method in 0.1 N HC1 (0.1 N aqueous HC1) at 75 rpm.

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

[0012] Yet another aspect is a method of treating a human patient having type 1 neurofibromatosis (NF1)-associated inoperable plexiform neurofibroma (PN) that is progressing or leading to significant morbidity, comprising orally administering to the patient an effective amount of one or more oral dosage forms described herein.

[0013] In one embodiment of any of the methods described herein, the patient has progressive PN (i.e., a 20% increase in PN volume as evidenced by comparing two MRI scans 12 months or less prior to the first dose of midostaurin).

[0014] In one embodiment of any of the methods described herein, the patient has PN leading to significant morbidity.

[0015] In one embodiment of any of the methods described herein, the patient has a lesion in the head and neck that impairs the airway or large blood vessels, a lesion in the brachial or lumbar plexus that causes compression of nerves and loss of function, a lesion that causes severe deformity or significant disfigurement, a lesion in a limb that causes hypertrophy or loss of function, or a painful lesion. In one embodiment, the lesion that causes severe deformity or significant disfigurement is a tumor in the head and neck or a tumor in other parts of the body that cannot be hidden by standard clothing.

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

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

[0018] In one embodiment of any of the methods described herein, the patient is diagnosed with NF1 using the NIH Consensus Conference clinical criteria and meets one or more of the following:

[0019] (a) the individual has six or more cafe-au-lait spots, >5 mm in diameter before puberty and >15 mm in diameter after puberty;

[0020] (b) freckling in the axillary or inguinal region;

[0021] (c) optic glioma;

[0022] (d) two or more Lisch nodules;

[0023] (e) characteristic bony lesions (sphenoid dysplasia or thinning of the cortical bone of the long bones); and

[0024] (f) a first degree relative with NF1.

[0025] In one embodiment of any of the methods described herein, the patient has a constitutional NF1 mutation recorded by the Clinical Laboratory Improvement Amendments / American Society of Pathologists-accredited laboratory.

[0026] In one embodiment of any of the methods described herein, the patient either (a) has parents diagnosed with NF1 and meets one or more of criteria (1) to (7) or (b) has parents not diagnosed with NF1 but meets two or more of criteria (1) to (7):

[0027] (1) the individual has six or more cafe-au-lait spots, >5 mm in diameter before puberty and >15 mm in diameter after puberty;

[0028] (2) freckling in the axillary or inguinal region;

[0029] (3) two or more neurofibromas of any type or one plexiform neurofibroma

[0030] (4) optic pathway glioma;

[0031] (5) two or more iris Lisch nodules or two or more choroidal abnormalities (defined as bright, patchy nodules imaged by optical coherence tomography (OCT) / near-infrared reflectance (NIR) imaging) found by slit lamp examination;

[0032] (6) characteristic bony lesions (such as sphenoid dysplasia, tibial cortical thickening, or pseudarthrosis of the long bones); and

[0033] (7) a heterozygous disease-causing NF1 variant with a variant allele fraction of 50% in apparently normal tissue (such as white blood cells).

[0034] In one embodiment of any of the methods described herein, the patient is 2 years to 15 years of age. In another embodiment of any of the methods described herein, the patient is at least 16 years of age.

[0035] In one embodiment, the patient is administered about 2 mg / m 2 of midostaurin twice daily.

[0036] In another embodiment of any of the methods described herein,

[0037] (a) for a patient with a body surface area of no more than 0.69 m 2 , the patient is initially administered 1 mg of midostaurin orally twice daily (i.e., 2 mg total daily),

[0038] (b) for a patient with a body surface area of 0.7 to 1.04 m 2 , the patient is initially administered 2 mg of midostaurin orally twice daily (i.e., 4 mg total daily),

[0039] (c) for a patient with a body surface area of 1.05 to 1.49 m 2 , the patient is initially administered 3 mg of midostaurin orally twice daily (i.e., 6 mg total daily), and

[0040] (d) for a patient with a body surface area of at least 1.5 m 2 , the patient is initially administered 4 mg of midostaurin orally twice daily (i.e., 8 mg total daily).

[0041] In yet another embodiment of any of the methods described herein,

[0042] (a) for a patient with a body surface area of at most 0.59 m 2 or 0.4 to 0.59 m 2 , the patient is initially administered 1 mg of midostaurin orally twice daily,

[0043] (b) for a patient with a body surface area of 0.6 to 0.79 m 2 , the patient is initially administered 1.5 mg of midostaurin orally twice daily,

[0044] (c) for a patient with a body surface area of 0.8 to 0.99 m 2 , the patient is initially administered 2 mg of midostaurin orally twice daily,

[0045] (d) for a patient with a body surface area of 1.0 to 1.19 m 2 , the patient is initially administered 2.5 mg of midostaurin orally twice daily,

[0046] (e) for a patient having a body surface area of 1.2 to 1.39 m 2 the patient is initially administered 3 mg of midostaurin orally twice per day,

[0047] (f) for a patient having a body surface area of 1.4 to 1.59 m 2 the patient is initially administered 3.5 mg of midostaurin orally twice per day, and

[0048] (g) for a patient having a body surface area of at least 1.6 m 2 the patient is initially administered 4 mg of midostaurin orally twice per day. In one embodiment, the patient is less than 12 years old. In another embodiment, the midostaurin is administered in one or more tablets, such as one or more dispersible tablets. In another embodiment, the midostaurin is administered in one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of the foregoing. The tablets can be dispersible tablets. One embodiment is a method of treating a human patient (or any such patient as described herein) having neurofibromatosis type 1 (NF1)-associated inoperable plexiform neurofibroma (PN), comprising the above-described method of administering midostaurin.

[0049] In yet another embodiment of any of the methods described herein,

[0050] (a) for a patient having a body surface area of up to 0.69 m 2 or 0.4 to 0.69 m 2 the patient is initially administered 1 mg of midostaurin orally twice per day,

[0051] (b) for a patient having a body surface area of 0.7 to 1.04 m 2 the patient is initially administered 2 mg of midostaurin orally twice per day,

[0052] (c) for a patient having a body surface area of 1.05 to 1.49 m 2 the patient is initially administered 3 mg of midostaurin orally twice per day, and

[0053] (d) for a patient having a body surface area of at least 1.5 m 2mg midostaurin twice daily. In one embodiment, the patient is at least 12 years old. In one embodiment, the midostaurin is administered in the form of one or more capsules, such as in the form of one or more 1 mg capsules, one or more 2 mg capsules, or any combination of the foregoing. One embodiment is a method of treating a human patient (or any such patient as described herein) having neurofibromatosis type 1 (NF1)-associated inoperable plexiform neurofibroma (PN), comprising the above-described method of administering midostaurin.

[0054] In yet another embodiment of any of the methods described herein,

[0055] (a) for a patient having a body surface area of 0.4 to 0.59 m 2 (or up to 0.59 m 2 ), the patient is initially administered 1 mg of midostaurin orally twice daily,

[0056] (b) for a patient having a body surface area of 0.6 to 0.79 m 2 , the patient is initially administered 1.5 mg of midostaurin orally twice daily,

[0057] (c) for a patient having a body surface area of 0.8 to 0.99 m 2 , the patient is initially administered 2 mg of midostaurin orally twice daily,

[0058] (d) for a patient having a body surface area of 1.0 to 1.39 m 2 , the patient is initially administered 2.5 mg of midostaurin orally twice daily,

[0059] (e) for a patient having a body surface area of 1.4 to 1.59 m 2 , the patient is initially administered 3 mg of midostaurin orally twice daily,

[0060] (f) for a patient having a body surface area of 1.6 to 1.69 m 2 , the patient is initially administered 3.5 mg of midostaurin orally twice daily, and

[0061] (g) for a patient having a body surface area of at least 1.7 m 2mg midostaurin. In one embodiment, the patient is less than 12 years old. In one embodiment, the midostaurin is administered in the form of one or more tablets (such as one or more dispersible tablets). In another embodiment, the midostaurin 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 can be dispersible tablets. One embodiment is a method of treating a human patient (or any such patient as described herein) having neurofibromatosis type 1 (NF1)-associated inoperable plexiform neurofibroma (PN), comprising the above-described method of administering midostaurin.

[0062] One embodiment is a method of administering midostaurin to a patient (such as a human patient) in need thereof by orally administering midostaurin to the patient, wherein

[0063] (a) for a patient having a body surface area of 0.4 to 0.59 m 2 (or up to 0.59 m 2 ), the patient is initially administered 1 mg midostaurin orally twice per day,

[0064] (b) for a patient having a body surface area of 0.6 to 0.79 m 2 , the patient is initially administered 1.5 mg midostaurin orally twice per day,

[0065] (c) for a patient having a body surface area of 0.8 to 0.99 m 2 , the patient is initially administered 2 mg midostaurin orally twice per day,

[0066] (d) for a patient having a body surface area of 1.0 to 1.19 m 2 , the patient is initially administered 2.5 mg midostaurin orally twice per day,

[0067] (e) for a patient having a body surface area of 1.2 to 1.39 m 2 , the patient is initially administered 3 mg midostaurin orally twice per day,

[0068] (f) for a patient having a body surface area of 1.4 to 1.59 m 2 , the patient is initially administered 3.5 mg midostaurin orally twice per day, and

[0069] (g) for a patient having a body surface area of at least 1.6 m 2mg midostaurin. In one embodiment, the patient is less than 12 years old. In one embodiment, the midostaurin is administered in one or more tablets, such as one or more dispersible tablets. In another embodiment, the midostaurin is administered in one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of any of the foregoing. The tablets can be dispersible tablets. In one embodiment, the midostaurin can have a d50, d90, or both, as described herein. In another embodiment, the midostaurin is administered in a dosage form, such as a tablet (e.g., a dispersible tablet) or a capsule, as described herein. One embodiment is a method of treating a human patient (or any such patient as described herein) having neurofibromatosis type 1 (NF1)-associated inoperable plexiform neurofibroma (PN), comprising the above-described method of administering midostaurin.

[0070] Another embodiment is a method of administering midostaurin to a patient, such as a human patient, in need thereof, by orally administering midostaurin to the patient, wherein

[0071] (a) for a patient having a body surface area of 0.4 to 0.69 m 2 (or up to 0.69 m 2 ), the patient is initially administered 1 mg midostaurin orally twice per day,

[0072] (b) for a patient having a body surface area of 0.7 to 1.04 m 2 , the patient is initially administered 2 mg midostaurin orally twice per day,

[0073] (c) for a patient having a body surface area of 1.05 to 1.49 m 2 , the patient is initially administered 3 mg midostaurin orally twice per day, and

[0074] (d) for a patient having a body surface area of at least 1.5 m 2 , the patient is initially administered 4 mg midostaurin orally twice per day. In one embodiment, the patient is at least 12 years old. In one embodiment, the midostaurin is administered in one or more capsules, such as in one or more 1 mg capsules, one or more 2 mg capsules, or any combination of any of the foregoing. One embodiment is a method of treating a human patient (or any such patient as described herein) having neurofibromatosis type 1 (NF1)-associated inoperable plexiform neurofibroma (PN), comprising the above-described method of administering midostaurin.

[0075] Yet another embodiment is a method of administering midostaurin to a patient (such as a human patient) in need thereof by orally administering midostaurin to the patient, wherein

[0076] (a) for a patient having a body surface area of 0.4 to 0.59 m 2 (or up to 0.59 m 2 ), the patient is initially administered 1 mg of midostaurin orally twice per day,

[0077] (b) for a patient having a body surface area of 0.6 to 0.79 m 2 , the patient is initially administered 1.5 mg of midostaurin orally twice per day,

[0078] (c) for a patient having a body surface area of 0.8 to 0.99 m 2 , the patient is initially administered 2 mg of midostaurin orally twice per day,

[0079] (d) for a patient having a body surface area of 1.0 to 1.39 m 2 , the patient is initially administered 2.5 mg of midostaurin orally twice per day,

[0080] (e) for a patient having a body surface area of 1.4 to 1.59 m 2 , the patient is initially administered 3 mg of midostaurin orally twice per day,

[0081] (f) for a patient having a body surface area of 1.6 to 1.69 m 2 , the patient is initially administered 3.5 mg of midostaurin orally twice per day, and

[0082] (g) for a patient having a body surface area of at least 1.7 m 2 , the patient is initially administered 4 mg of midostaurin orally twice per day. In one embodiment, the patient is less than 12 years old. In another embodiment, the midostaurin is administered in one or more tablets (such as one or more dispersible tablets). In another embodiment, the midostaurin is administered in one or more 0.5 mg tablets, one or more 1 mg tablets, or any combination of the foregoing. The tablets can be dispersible tablets. One embodiment is a method of treating a human patient (or any such patient as described herein) having neurofibromatosis type 1 (NF1)-associated inoperable plexiform neurofibroma (PN) comprising the above-described method of administering midostaurin.

[0083] In one embodiment of any of the methods described herein, the maximum daily dose is 4 mg of midostaurin twice per day.

[0084] In one embodiment of any of the methods described herein, during each four-week period, midostaurin is administered during the first three weeks and withheld during the last week.

[0085] In any of the methods described herein, when the dosage form is a tablet (such as a dispersible tablet), the tablet to be administered can first be dispersed in water (such as drinking water) (e.g., about 5 to 10 mL of water) to form an oral suspension, optionally agitated to leave no lumps remaining, and administered (preferably within 30 minutes). In some embodiments, one or more oral tablets are dispersed in about 5 to about 10 mL of water in a container, wherein the tablets are agitated to leave no lumps remaining in the water. In some embodiments, the oral suspension is to be administered within 30 minutes. In some cases, the patient rinses the container with additional drinking water (e.g., about 5 to 10 mL of water) with the suspension and administers to the patient to ensure the entire dose is taken.

[0086] In one embodiment of any of the methods described herein, the dose administered is reduced due to an adverse event, wherein the dose reduction is as follows:

[0087] (a) if the dose at the time of the event was 1 mg of midostaurin twice daily, the reduced daily dose is 1 mg administered only in the morning;

[0088] (b) if the dose at the time of the event was 2 mg of midostaurin twice daily, the reduced daily dose is 2 mg administered in the morning and 1 mg administered in the afternoon or evening;

[0089] (c) if the dose at the time of the event was 3 mg of midostaurin twice daily, the reduced daily dose is 2 mg twice daily; and

[0090] (d) if the dose at the time of the event was 4 mg of midostaurin twice daily, the reduced daily dose is 3 mg twice daily. In one embodiment of any of the methods described herein, the adverse event that results in a dose reduction is acneiform.

[0091] In one embodiment of any of the methods described herein, the method further comprises, prior to the treatment, (i) determining whether midostaurin is selected as a treatment for the patient, and (ii) selecting midostaurin as a treatment for the patient based at least in part on an objective response rate of midostaurin, wherein the objective response rate is defined as a reduction in tumor size of at least 20% using a centralized read MRI volumetric analysis. In one embodiment, in step (i), midostaurin is selected based on a response rate of at least 70%. In another embodiment, in step (i), midostaurin is selected based on a response rate of at least 75%. In yet another embodiment, in step (i), midostaurin is selected based on a response rate of at least 80%. In yet another embodiment, in step (i), midostaurin is selected based on a response rate of at least 85%. In yet another embodiment, in step (i), midostaurin is selected based on a response rate of at least 90%. In yet another embodiment, in step (i), midostaurin is selected based on a response rate of at least 95%.

[0092] In one embodiment of any of the methods described herein, the patient has a reduction in plexiform neurofibroma volume of at least 20% after treatment with midostaurin, as determined by volumetric magnetic resonance imaging analysis.

[0093] In one embodiment of any of the methods described herein, the treatment results in a reduction in pain intensity.

[0094] In one embodiment of any of the methods described herein, the treatment results in a reduction in pain interference.

[0095] Another aspect is a method for treating a tumor or cancer in a human patient, comprising administering to the patient one or more oral dosage forms comprising midostaurin as described herein, the tumor or cancer 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 a cancer that has metastasized to the brain of the patient.

[0096] In some aspects, a therapeutically effective amount of midostaurin or a pharmaceutically acceptable salt thereof is administered orally. In some aspects, midostaurin or a pharmaceutically acceptable salt thereof is administered orally in an amount of about 1 mg / m 2 to about 10 mg / m 2 based on midostaurin free base per day. In some aspects, midostaurin or a pharmaceutically acceptable salt thereof is administered orally in an amount of about 1 mg to about 10 mg based on midostaurin free base per day.

[0097] In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered orally in a single dosage form comprising about 0.1 mg / m 2 to about 10 mg / m 2 In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered in a single dosage form comprising about 0.1 mg to about 10 mg, based on midostaurin free base.

[0098] In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered once daily. In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0099] In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, exhibits high blood brain barrier penetrance.

[0100] In some aspects, the patient is a human. In some aspects, the human is > 2 years of age and < 25 years of age.

[0101] In some aspects, the human has not been previously exposed to a MEK inhibitor.

[0102] In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy to treat a tumor or cancer. In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered in combination with another active ingredient and / or surgery to treat a tumor or cancer.

[0103] In any embodiment herein, a dose of midostaurin can be administered in the form of one or more 0.5 mg, 1 mg, or 2 mg midostaurin dosage forms, or any combination of the foregoing. For example, a 3.5 mg dose can be administered in the form of three 1 mg midostaurin dosage forms (e.g., tablets) and one 0.5 mg midostaurin dosage form (e.g., tablet).

[0104] In one embodiment, midostaurin is provided in the form of 0.5 or 1 mg midostaurin tablets (e.g., dispersible tablets). In another embodiment, midostaurin is provided in the form of 1 or 2 mg midostaurin capsules. In yet another embodiment, midostaurin is provided in the form of 0.5 or 1 mg midostaurin tablets (e.g., dispersible tablets) and 1 or 2 mg midostaurin capsules. BRIEF DESCRIPTION OF DRAWINGS

[0105] Figure 1 is a graph showing the release of midostaurin from 1 mg and 2 mg capsules prepared with midostaurin from Batch No. 1 and Batch No. 2 as described in Example 2 in 0.1 N HC1 at 75 rpm according to the USP Basket Method.

[0106] Figure 2is a graph showing the release of midametinib from 2 mg capsules prepared with midametinib from Batch 1, Batch 2, and Batch 3 as described in Example 2 according to the USP basket method in 0.1 N HCl at 75 rpm. DETAILED DESCRIPTION

[0107] I. Definitions

[0108] To facilitate understanding of the disclosure described herein, a number of terms are defined below.

[0109] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0110] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The term "a" (or "an") and the terms "one or more" and "at least one" are used interchangeably herein. In some aspects, the term "a" or "an" refers to "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."

[0111] The term "midametinib" refers to a single enantiomer, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzamide. The teachings throughout this specification regarding midametinib also apply to pharmaceutically acceptable salts of midametinib. For example, the disclosure of a method for treating inoperable plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1) with midametinib also implies that a pharmaceutically acceptable salt of midametinib can be administered to treat inoperable PN associated with NF1.

[0112] The term "mg / m 2 " refers to mg / m 2 Dosage based on the patient's body surface area.

[0113] The term "subject" refers to an animal, including but not limited to a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to, for example, a mammalian subject, such as a human subject.

[0114] The term "AUC0-12h AUC0-12 refers to the area under the plasma concentration-time curve from time 0 to the end of 12 hours.

[0115] The term "Cmax" refers to the maximum plasma concentration. max AUC0-12 refers to the area under the plasma concentration-time curve from time 0 to the end of 12 hours.

[0116] As used herein, the term "dispersible" refers to a composition (e.g., a tablet, powder, granule, minitablet, or pill) that disintegrates and / or dissolves upon combination with water or another drinkable liquid (e.g., a non-water beverage), or disintegrates and / or dissolves upon being placed in the mouth of a subject with or without the addition of agitation or temperature change. In some aspects, the dispersible composition disintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after combination with water or another drinkable liquid. Such disintegration or dissolution need not be complete. For example, a dispersible tablet can dissolve almost completely, but some undissolved particulate matter can remain.

[0117] As used herein, the terms "treat," "treated," and "treating" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to enhance or improve a desirable clinical outcome. Thus, those in need of treatment include patients who have been diagnosed with or suspected of having the disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay or slowing of condition, disorder or disease progression; amelioration or remission (whether partial or total), whether detectable or undetectable, of condition, disorder or disease; improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement of the proliferation or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without undue

[0118] In certain aspects, a subject’s tumor is successfully “treated” according to the methods described herein if the patient exhibits one or more of the following: a reduction in tumor size; relief from one or more symptoms associated with a particular tumor; a reduction in tumor volume; an improvement in quality of life; an increase in progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increase in time to progression (TTP), or any combination thereof. In some aspects, the determination of whether a therapeutically effective amount of midostaurin meets any of these particular endpoints (e.g., CR, PFS, PR) can be made using nationally or internationally recognized standards for the given tumor treatment outcome.

[0119] If a patient exhibits one or more of the following, a subject’s cancer (e.g., ovarian cancer) is successfully “treated” according to the methods described herein: a reduction or complete disappearance of cancerous cells; relief from one or more symptoms associated with a specified tumor; a reduction in morbidity and mortality; an improvement in quality of life; an increase in progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete remission (CR), minimal residual disease (MRD), partial remission (PR), stable disease (SD), a decrease in progressive disease (PD), an increase in time to progression (TTP), or any combination thereof. In some aspects, the determination of whether a therapeutically effective amount of midostaurin meets any of these particular endpoints (e.g., CR, PFS, PR) can be made using nationally or internationally recognized standards for the given cancer treatment outcome.

[0120] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" mean a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson, Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0121] The term "pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic acid addition salts of midostaurin. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or separately by reacting the purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactibionate, and laurylsulphonate salts. See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.

[0122] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0123] As used herein, “D50” or “d50” (also referred to as median diameter) corresponds to the value below which 50% of the particles have a lower volume diameter. “D90” or “d90” corresponds to the value below which 90% of the particles have a lower volume diameter. Particle size can be measured using wet method standard laser diffraction particle size measurement techniques known in the art. One example of an instrument that measures dry powder particle size is the Mastersizer 3000 manufactured by Malvern Panalytical Ltd. (Malvern, UK). As particles are often non-spherical, it is difficult and complex to provide a size description of these non-spherical particles. As used herein, “volume diameter” refers to the diameter of a sphere having the same volume as the non-spherical particle.

[0124] The terms “comprise,” “comprises” and “comprising” are used in the sense of the open-ended group that they belong to, namely in the sense of “including but not limited to,” and allows for “including,” “comprising,” and the occurrence of zero instances of the material which follows the comma, as well as positive instances of the material which follows the comma. Unless the context requires otherwise, the terms “comprise,” “comprises” and “comprising” are used on the basis and clear understanding that they are to be interpreted inclusively and not exclusivity, and that the applicant intends for each of these words to be interpreted in such manner when interpreting this patent, including the claims appended hereto.

[0125] II. Oral dosage form

[0126] The oral dosage form contains midostaurin having a d90 of no more than 250 microns, a d50 of no more than 50 microns, or both. In one embodiment, the oral dosage form contains 0.5 mg midostaurin, 1.0 mg midostaurin, 1.5 mg midostaurin, 2.0 mg midostaurin, 2.5 mg midostaurin, 3.0 mg midostaurin, 3.5 mg midostaurin, or 4.0 mg midostaurin.

[0127] In one embodiment, the oral dosage form contains 0.5 mg midostaurin.

[0128] In another embodiment, the oral dosage form contains 1.0 mg midostaurin.

[0129] In another embodiment, the oral dosage form contains 2.0 mg midostaurin.

[0130] Midostaurin can exist in a crystalline form in an oral dosage form, such as any one described in U.S. Patent Nos. 6,960,614, 7,060,856, 11,066,358, and 11,084,780, which are hereby incorporated by reference in their entireties. In some aspects, the crystalline form of midostaurin is selected from: (a) crystalline Form IV of midostaurin characterized by an X-ray powder diffraction (XRPD) pattern having peaks at 4.6 ± 0.2, 7.3 ± 0.2, and 14.6 ± 0.2 degrees 2-theta; (b) crystalline Form I of midostaurin 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 2-theta; and (c) crystalline Form II of midostaurin characterized by an XRPD pattern having peaks at 5.5 ± 0.2 and 19.6 ± 0.2 degrees 2-theta.

[0131] In some aspects, the crystalline Form IV of midostaurin is characterized by an XRPD pattern having peaks at 4.6 ± 0.2, 7.3 ± 0.2 (or 7.2 ± 0.2), and 14.6 ± 0.2 degrees 2-theta (Form IV). In some aspects, the crystalline form of midostaurin is characterized by an XRPD pattern having peaks at 4.6 ± 0.2, 7.3 ± 0.2 (or 7.2 ± 0.2), 14.6 ± 0.2, and 25.0 ± 0.2 degrees 2-theta.

[0132] In some aspects, the crystalline form of midostaurin is characterized by a differential scanning calorimetry (DSC) curve that does not include an endotherm beginning at about 117 °C.

[0133] In some aspects, the crystalline form of midostaurin does not contain any amount of Form I or Form II that can be detected by XRPD and / or DSC. Form I and Form II are described in U.S. Patent No. 6,960,614.

[0134] In some aspects, the crystalline form of midostaurin is anhydrous.

[0135] In some aspects, the crystalline form of midostaurin is Form IV. In some aspects, the crystalline form of midostaurin is substantially pure Form IV (such as described in U.S. Patent No. 11,066,358, which is incorporated herein by reference). Form IV is described in U.S. Patent Nos. 7,060,856 and 11,066,358. In some aspects, substantially pure Form IV midostaurin exhibits an XRPD pattern and / or a DSC curve that is substantially unchanged after storage for 3 months at standard warehouse conditions (15-25 °C and < 65% relative humidity). In some aspects, substantially pure Form IV midostaurin exhibits an XRPD pattern and / or a DSC curve that is substantially unchanged after storage for 6 months at standard warehouse conditions (15-25 °C and < 65% relative humidity). In some aspects, substantially pure Form IV midostaurin exhibits an XRPD pattern and / or a DSC curve that is substantially unchanged after storage for 1 year at standard warehouse conditions (15-25 °C and < 65% relative humidity).

[0136] In some aspects, the XRPD pattern is generated using a PANALYTICAL ® X'Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV / 40 mA) radiation, a step size of 0.03° 2Q, equipped with an X'CELERATOR ® real-time multi-strip detector configured as follows: (a) on the incident beam side as follows: variable divergence slit (10 mm illumination length), 0.04 rad soller slit, fixed anti-scatter slit (0.50°), and 10 mm beam mask, and (b) on the diffracted beam side as follows: variable anti-scatter slit (10 mm viewing length) and 0.04 rad soller slit or BRUKER ® D8 ® ADVANCE TM system using Cu Ka (40 kV / 40 mA) radiation, a step size of 0.03° 2Q, equipped with a LYNXEYE TM detector configured as follows: (a) on the incident beam side as follows: Göebel mirror, mirror exit slit (0.2 mm), 2.5° soller slit, beam knife; and (b) on the diffracted beam side as follows: anti-scatter slit (8 mm) and 2.5° soller slit; wherein the sample is flat on a zero background Si wafer. In some aspects, the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature ramp rate of about 15 °C / min.

[0137] The oral dosage form can contain one or more diluents, disintegrants, lubricants, or any combination of any of the foregoing. In one embodiment, the oral dosage form comprises (a) about 0.1 weight / weight % to about 5 weight / weight % of midostaurin, (b) about 50 weight / weight % to about 98 weight / weight % of one or more diluents; (c) about 1 weight / weight % to about 10 weight / weight % of one or more disintegrants; and (d) up to about 5 weight / weight % of one or more lubricants.

[0138] Suitable diluents include, but are not limited to, microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate, dicalcium phosphate, and any combination of any of the foregoing. In one embodiment, the oral dosage form includes the diluent microcrystalline cellulose.

[0139] 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 of any of the foregoing. In one embodiment, the oral dosage form includes the disintegrant croscarmellose sodium.

[0140] 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, glyceryl dibehenate, talc, and any combination of any of the foregoing. In one embodiment, the oral dosage form includes the lubricant magnesium stearate.

[0141] The oral dosage form can be a capsule, such as a hard gelatin capsule.

[0142] The oral dosage form can comprise one or more pharmaceutically acceptable carriers. In some aspects, the oral dosage form is dispersible. In some aspects, the oral dosage form is oromucosally dispersible. The oral dosage form can be a tablet, a powder, a granule, a minitablet, or a pellet (also referred to as a bead). In some aspects, the oral dosage form is a powder. In some aspects, the oral dosage form is a dispersible powder. In some aspects, a capsule or sachet comprises the dispersible powder. In some aspects, the oral dosage form is in the form of a granule. In some aspects, the granule is a dispersible granule. In some aspects, a capsule or sachet comprises the dispersible granule. In some aspects, the oral dosage form is in the form of a minitablet. In some aspects, the minitablet is a dispersible minitablet. In some aspects, a capsule or sachet comprises the dispersible minitablet. In some aspects, the oral dosage form is in the form of a pellet. In some aspects, the pellet is a dispersible pellet. In some aspects, a capsule or sachet comprises the dispersible pellet.

[0143] In some aspects, the oral dosage form is a tablet. In some aspects, the tablet is a dispersible tablet. In some aspects, the tablet is an oromucosally dispersible tablet.

[0144] In some aspects, the oral dosage form is a dispersible tablet, a dispersible powder, a dispersible granule, a dispersible minitablet, or a dispersible pill, and comprises about 0.1 mg to about 20 mg of midostaurin, wherein the components of the oral dosage form are as follows: (a) about 0.1 weight / weight % to about 7 weight / weight % of midostaurin; (b) about 50 weight / weight % to about 98 weight / weight % of one or more diluents; (c) about 1 weight / weight % to about 10 weight / weight % of one or more disintegrants; (d) optionally 0 weight / weight % to about 5 weight / weight % of one or more flavoring agents; (e) optionally 0 weight / weight % to about 5 weight / weight % of one or more sweetening agents; and (f) optionally 0 weight / weight % to about 5 weight / weight % of one or more lubricants.

[0145] In some aspects, the oral dosage form is a dispersible tablet, a dispersible powder, a dispersible granule, a dispersible minitablet, or a dispersible pill, and comprises about 0.1 mg to about 20 mg of midostaurin, wherein the components of the oral dosage form are as follows: (a) about 0.2 weight / weight % to about 1.5 weight / weight % of midostaurin; (b) about 75 weight / weight % to about 98 weight / weight % of one or more diluents; (c) about 3 weight / weight % to about 8 weight / weight % of one or more disintegrants; (d) optionally 0 weight / weight % to about 5 weight / weight % of one or more flavoring agents; (e) optionally 0 weight / weight % to about 5 weight / weight % of one or more sweetening agents; and (f) optionally 0 weight / weight % to about 5 weight / weight % of one or more lubricants.

[0146] In some aspects, the oral dosage form is a dispersible tablet, a dispersible powder, a dispersible granule, a dispersible minitablet, or a dispersible pill, and comprises about 0.1 mg to about 20 mg of midostaurin, wherein the components of the oral dosage form are as follows: (a) about 0.5 weight / weight % to about 1.2 weight / weight % of midostaurin; (b) about 85 weight / weight % to about 95 weight / weight % of one or more diluents; (c) about 3.5 weight / weight % to about 6 weight / weight % of one or more disintegrants; (d) optionally 0 weight / weight % to about 2.5 weight / weight % of one or more flavoring agents; (e) optionally 0 weight / weight % to about 2 weight / weight % of one or more sweetening agents; and (f) optionally about 0.5 weight / weight % to about 2 weight / weight % of one or more lubricants.

[0147] In some aspects, the oral dosage form is a dispersible tablet, a dispersible powder, a dispersible granule, a dispersible minitablet, or a dispersible pill, and comprises about 0.5 mg of midostaurin. In some aspects, the oral dosage form comprises about 1 mg of midostaurin. In some aspects, the oral dosage form is a dispersible tablet, a dispersible powder, a dispersible granule, a dispersible minitablet, or a dispersible pill, and comprises about 2 mg of midostaurin. In some aspects, the oral dosage form is a dispersible tablet, a dispersible powder, a dispersible granule, a dispersible minitablet, or a dispersible pill, and comprises about 3 mg of midostaurin. In some aspects, the oral dosage form is a dispersible tablet, a dispersible powder, a dispersible granule, a dispersible minitablet, or a dispersible pill, and comprises about 4 mg of midostaurin.

[0148] In some aspects, the at least one diluent is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch, pregelatinized starch, calcium sulfate, calcium carbonate, and dibasic calcium phosphate. In some aspects, the at least one diluent is microcrystalline cellulose.

[0149] In some aspects, the at least one disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and alginic acid. In some aspects, the at least one disintegrant is croscarmellose sodium.

[0150] In some aspects, the at least one flavoring agent is selected from the group consisting of natural or synthetic flavors, including but not limited to grape flavoring, bubble gum 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 aspects, the at least one flavoring agent is grape flavoring.

[0151] In some aspects, the at least one sweetener is selected from the group consisting of sucralose, acesulfame potassium, saccharin, sucrose, xylitol, mannitol, sorbitol, dextrose, fructose, and aspartame. In some aspects, the at least one sweetener is sucralose.

[0152] In some aspects, the at least one lubricant is selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate, glycerol diacetate, and talc. In some aspects, the at least one lubricant is magnesium stearate.

[0153] III. Method of treatment

[0154] Provided herein are methods for treating a tumor or cancer 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 a cancer that has metastasized to the brain of a patient, comprising administering to a patient in need thereof, midostaurin, or a pharmaceutically acceptable salt thereof.

[0155] In some aspects of any 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.

[0156] In some aspects of any 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.

[0157] In some aspects of any of the methods described herein, the tumor or cancer is a low-grade ovarian cancer. In some aspects, the tumor or cancer is Langerhans cell histiocytosis. In some aspects, the tumor or cancer is a brain cancer. In some aspects, the tumor or cancer is a cancer that has metastasized to the brain of a patient, including lung cancer, breast cancer, and melanoma.

[0158] In some aspects of any of the methods described herein, the therapeutically effective amount of midostaurin, or a pharmaceutically acceptable salt thereof, is administered orally.

[0159] In some aspects of any of the methods described herein, the midostaurin, or a pharmaceutically acceptable salt thereof, is administered at about 1 mg / m 2 to about 10 mg / m 2 , about 1.5 mg / m 2 to about 9.5 mg / m 2 , about 2 mg / m 2 to about 9 mg / m 2 , about 2.5 mg / m 2 to about 8.5 mg / m 2 , about 3 mg / m 2 to about 8 mg / m 2 , about 3.5 mg / m 2 to about 7.5 mg / m 2 , about 4 mg / m 2about 7 mg / m 2 about 4.5 mg / m 2 about 6.5 mg / m 2 about 5 mg / m 2 about 6 mg / m 2 about 1 mg / m 2 about 1.5 mg / m 2 about 2 mg / m 2 about 2.5 mg / m 2 about 3 mg / m 2 about 3.5 mg / m 2 about 4 mg / m 2 about 4.5 mg / m 2 about 5 mg / m 2 about 5.5 mg / m 2 about 6 mg / m 2 about 6.5 mg / m 2 about 7 mg / m 2 about 7.5 mg / m 2 about 8 mg / m 2 about 8.5 mg / m 2 about 9 mg / m 2 about 9.5 mg / m 2 about 10 mg / m 2 about 7 mg / m

[0160] In some aspects of any of the methods described herein, the midostaurin or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg to about 10 mg per day on a mg of midostaurin free base basis, about 1.5 mg to about 9.5 mg per day on a mg of midostaurin free base basis, about 2 mg to about 9 mg per day on a mg of midostaurin free base basis, about 2.5 mg to about 8.5 mg per day on a mg of midostaurin free base basis, about 3 mg to about 8 mg per day on a mg of midostaurin free base basis, about 3.5 mg to about 7.5 mg per day on a mg of midostaurin free base basis, about 4 mg to about 7 mg per day on a mg of midostaurin free base basis, about 4.5 mg to about 6.5 mg per day on a mg of midostaurin free base basis, or about 5 mg to about 6 mg per day on a mg of midostaurin free base basis. In some aspects, the midostaurin or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg per day on a mg of midostaurin free base basis, about 1.5 mg per day on a mg of midostaurin free base basis, about 2 mg per day on a mg of midostaurin free base basis, about 2.5 mg per day on a mg of midostaurin free base basis, about 3 mg per day on a mg of midostaurin free base basis, about 3.5 mg per day on a mg of midostaurin free base basis, about 4 mg per day on a mg of midostaurin free base basis, about 4.5 mg per day on a mg of midostaurin free base basis, about 5 mg per day on a mg of midostaurin free base basis, about 5.5 mg per day on a mg of midostaurin free base basis, about 6 mg per day on a mg of midostaurin free base basis, about 6.5 mg per day on a mg of midostaurin free base basis, about 7 mg per day on a mg of midostaurin free base basis, about 7.5 mg per day on a mg of midostaurin free base basis, about 8 mg per day on a mg of midostaurin free base basis, about 8.5 mg per day on a mg of midostaurin free base basis, about 9 mg per day on a mg of midostaurin free base basis, about 9.5 mg per day on a mg of midostaurin free base basis, or about 10 mg per day on a mg of midostaurin free base basis.

[0161] In some aspects of any of the methods described herein, the midostaurin or pharmaceutically acceptable salt thereof is administered in an amount of about 0.1 mg / m 2 to about 10 mg / m 2 , about 0.5 mg / m 2 to about 9.5 mg / m 2 , about 1 mg / m 2 to about 9 mg / m 2 , about 1.5 mg / m 2 to about 8.5 mg / m 2 , about 2 mg / m 2about 8 mg / m 2 about 2.5 mg / m 2 about 7.5 mg / m 2 about 3 mg / m 2 about 7 mg / m 2 about 3.5 mg / m 2 about 6.5 mg / m 2 about 4 mg / m 2 about 6 mg / m 2 about 4.5 mg / m 2 about 5.5 mg / m 2 about 0.1 mg / m 2 about 0.2 mg / m 2 about 0.3 mg / m 2 about 0.4 mg / m 2 about 0.5 mg / m 2 about 1 mg / m 2 about 1.5 mg / m 2 about 2 mg / m 2 about 2.5 mg / m 2 about 3 mg / m 2 about 3.5 mg / m 2 about 4 mg / m 2 about 4.5 mg / m 2 about 5 mg / m 2 about 5.5 mg / m 2 about 6 mg / m 2 about 6.5 mg / m 2 about 7 mg / m 2 about 7.5 mg / m 2 about 8 mg / m 2about 8.5 mg / m2based on midostaurin free base 2 about 9 mg / m2based on midostaurin free base 2 about 9.5 mg / m2based on midostaurin free base 2 or about 10 mg / m2based on midostaurin free base 2 as a single dose.

[0162] In some aspects of any of the methods described herein, midostaurin or a pharmaceutically acceptable salt thereof is administered as a single dose comprising about 0.1 mg to about 10 mg based on midostaurin free base, about 0.5 mg to about 9.5 mg based on midostaurin free base, about 1 mg to about 9 mg based on midostaurin free base, about 1.5 mg to about 8.5 mg based on midostaurin free base, about 2 mg to about 8 mg based on midostaurin free base, about 2.5 mg to about 7.5 mg based on midostaurin free base, about 3 mg to about 7 mg based on midostaurin free base, about 3.5 mg to about 6.5 mg based on midostaurin free base, about 4 mg to about 6 mg based on midostaurin free base, or about 4.5 mg to about 5.5 mg based on midostaurin free base. In some aspects, midostaurin or a pharmaceutically acceptable salt thereof is administered as a single dose comprising about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg based on midostaurin free base.

[0163] In some aspects of any of the methods described herein, midostaurin, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, or four times per day. In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered once daily. In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0164] In some aspects of any of the methods described herein, midostaurin, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg / m 2 to about 10 mg / m 2 , about 1 mg / m 2 to about 9.5 mg / m 2 , about 1.5 mg / m 2 to about 9 mg / m 2 , about 2 mg / m 2 to about 8.5 mg / m 2 , about 2.5 mg / m 2 to about 8 mg / m 2 , about 3 mg / m 2 to about 7.5 mg / m 2 , about 3.5 mg / m 2 to about 7 mg / m 2 , about 4 mg / m 2 to about 6.5 mg / m 2 , about 4.5 mg / m 2 to about 6 mg / m 2 , or about 5 mg / m 2 to about 6 mg / m 2 of midostaurin free base per day. In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg / m 2 , about 1 mg / m 2 , about 1.5 mg / m 2 , about 2 mg / m 2 , about 2.5 mg / m 2 , about 3 mg / m 2 , about 3.5 mg / m 2 , about 4 mg / m2 about 4.5 mg / m2based on midostaurin free base 2 about 5 mg / m2based on midostaurin free base 2 about 5.5 mg / m2based on midostaurin free base 2 about 6 mg / m2based on midostaurin free base 2 about 6.5 mg / m2based on midostaurin free base 2 about 7 mg / m2based on midostaurin free base 2 about 7.5 mg / m2based on midostaurin free base 2 about 8 mg / m2based on midostaurin free base 2 about 8.5 mg / m2based on midostaurin free base 2 about 9 mg / m2based on midostaurin free base 2 about 9.5 mg / m2based on midostaurin free base 2 or about 10 mg / m2based on midostaurin free base 2 twice daily.

[0165] In some aspects of any of the methods described herein, midostaurin, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg to about 10 mg, based on midostaurin free base, about 1 mg to about 9.5 mg, based on midostaurin free base, about 1.5 mg to about 9 mg, based on midostaurin free base, about 2 mg to about 8.5 mg, based on midostaurin free base, about 2.5 mg to about 8 mg, based on midostaurin free base, about 3 mg to about 7.5 mg, based on midostaurin free base, about 3.5 mg to about 7 mg, based on midostaurin free base, about 4 mg to about 6.5 mg, based on midostaurin free base, about 4.5 mg to about 6 mg, based on midostaurin free base, or about 5 mg to about 6 mg, based on midostaurin free base, twice daily. In some aspects, midostaurin, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 0.5 mg, based on midostaurin free base, about 1 mg, based on midostaurin free base, about 1.5 mg, based on midostaurin free base, about 2 mg, based on midostaurin free base, about 2.5 mg, based on midostaurin free base, about 3 mg, based on midostaurin free base, about 3.5 mg, based on midostaurin free base, about 4 mg, based on midostaurin free base, about 4.5 mg, based on midostaurin free base, about 5 mg, based on midostaurin free base, about 5.5 mg, based on midostaurin free base, about 6 mg, based on midostaurin free base, about 6.5 mg, based on midostaurin free base, about 7 mg, based on midostaurin free base, about 7.5 mg, based on midostaurin free base, about 8 mg, based on midostaurin free base, about 8.5 mg, based on midostaurin free base, about 9 mg, based on midostaurin free base, about 9.5 mg, based on midostaurin free base, or about 10 mg, based on midostaurin free base, twice daily.

[0166] In some aspects of any of the methods described herein, midostaurin, or a pharmaceutically acceptable salt thereof, is administered in an amount of not more than about 10 mg / m 2 , about 9.5 mg / m 2 , about 9 mg / m 2 , about 8.5 mg / m 2 , about 8 mg / m 2 , about 7.5 mg / m 2 , about 7 mg / m 2 , about 6.5 mg / m2 about 6 mg / m 2 about 5.5 mg / m 2 about 5 mg / m 2 about 4.5 mg / m 2 about 4 mg / m 2 about 3.5 mg / m 2 about 3 mg / m 2 about 2.5 mg / m 2 about 2 mg / m 2 about 1.5 mg / m 2 about 1.5 mg / m

[0167] In some aspects of any of the methods described herein, midostaurin or a pharmaceutically acceptable salt thereof is administered at a total daily dose of no more than about 10 mg as the free base of midostaurin, about 9.5 mg as the free base of midostaurin, about 9 mg as the free base of midostaurin, about 8.5 mg as the free base of midostaurin, about 8 mg as the free base of midostaurin, about 7.5 mg as the free base of midostaurin, about 7 mg as the free base of midostaurin, about 6.5 mg as the free base of midostaurin, about 6 mg as the free base of midostaurin, about 5.5 mg as the free base of midostaurin, about 5 mg as the free base of midostaurin, about 4.5 mg as the free base of midostaurin, about 4 mg as the free base of midostaurin, about 3.5 mg as the free base of midostaurin, about 3 mg as the free base of midostaurin, about 2.5 mg as the free base of midostaurin, about 2 mg as the free base of midostaurin, or about 1.5 mg as the free base of midostaurin.

[0168] In some aspects of any of the methods described herein, midostaurin or a pharmaceutically acceptable salt thereof is administered as the free base of midostaurin.

[0169] Provided herein are methods for treating a tumor or cancer 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 a cancer that has metastasized to the brain of a patient, comprising administering to a patient in need thereof midostaurin free base.

[0170] In some aspects of any of the methods described herein, the tumor or cancer is plexiform neurofibroma. In some aspects, the tumor or cancer is a plexiform neurofibroma associated with neurofibromatosis type 1.

[0171] In some aspects of any of the methods described herein, the tumor or cancer is 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.

[0172] In some aspects of any of the methods described herein, the tumor or cancer is low-grade ovarian cancer.

[0173] In some aspects of any of the methods described herein, the tumor or cancer is Langerhans cell histiocytosis.

[0174] In some aspects of any of the methods described herein, the tumor or cancer is brain cancer.

[0175] In some aspects of any of the methods described herein, the tumor or cancer is a cancer that has metastasized to the brain of the patient, including lung cancer, breast cancer, and melanoma.

[0176] In some aspects of any of the methods described herein, a therapeutically effective amount of midostaurin free base is administered.

[0177] In some aspects of any of the methods described herein, the midostaurin free base is administered at about 1 mg / m 2 to about 10 mg / m 2 , about 1.5 mg / m 2 to about 9.5 mg / m 2 , about 2 mg / m 2 to about 9 mg / m 2 , about 2.5 mg / m 2 to about 8.5 mg / m 2 , about 3 mg / m 2 to about 8 mg / m 2 , about 3.5 mg / m 2 to about 7.5 mg / m 2 , about 4 mg / m 2 to about 7 mg / m 2 , about 4.5 mg / m 2 to about 6.5 mg / m 2 , or about 5 mg / m 2 to about 6 mg / m 2In some aspects, mirametinib free base is administered at about 1 mg / m per day. 2 , about 1.5 mg / m2 per day 2 , about 2 mg / m2 per day 2 , about 2.5 mg / m2 per day 2 , about 3 mg / m2 per day 2 , about 3.5 mg / m2 per day 2 , about 4 mg / m2 per day 2 , about 4.5 mg / m2 per day 2 , about 5 mg / m2 per day 2 , about 5.5 mg / m2 per day 2 , about 6 mg / m2 per day 2 , about 6.5 mg / m2 per day 2 , about 7 mg / m2 per day 2 , about 7.5 mg / m2 per day 2 , about 8 mg / m2 per day 2 , about 8.5 mg / m2 per day 2 About 9 mg / m2 / day 2 , about 9.5 mg / m2 per day 2 or about 10 mg / m2 per day 2 The amount of application.

[0178] In some aspects of any of the methods described herein, mirametinib free base is administered in an amount of about 1 mg to about 10 mg per day, about 1.5 mg to about 9.5 mg per day, about 2 mg to about 9 mg per day, about 2.5 mg to about 8.5 mg per day, about 3 mg to about 8 mg per day, about 3.5 mg to about 7.5 mg per day, about 4 mg to about 7 mg per day, about 4.5 mg to about 6.5 mg per day, or about 5 mg to about 6 mg per day. In some aspects, mirametinib free base is administered in an amount of about 1 mg per day, about 1.5 mg per day, about 2 mg per day, about 2.5 mg per day, about 3 mg per day, about 3.5 mg per day, about 4 mg per day, about 4.5 mg per day, about 5 mg per day, about 5.5 mg per day, about 6 mg per day, about 6.5 mg per day, about 7 mg per day, about 7.5 mg per day, about 8 mg per day, about 8.5 mg per day, about 9 mg per day, about 9.5 mg per day, or about 10 mg per day.

[0179] In some aspects of any of the methods described herein, mirametinib free base is present in an amount comprising about 0.1 mg / m 2 Up to 10 mg / m 2 , about 0.5 mg / m 2 to about 9.5 mg / m2 about 1 mg / m 2 to about 9 mg / m 2 about 1.5 mg / m 2 to about 8.5 mg / m 2 about 2 mg / m 2 to about 8 mg / m 2 about 2.5 mg / m 2 to about 7.5 mg / m 2 about 3 mg / m 2 to about 7 mg / m 2 about 3.5 mg / m 2 to about 6.5 mg / m 2 about 4 mg / m 2 to about 6 mg / m 2 or 4.5 mg / m 2 to about 5.5 mg / m 2 In some aspects, midostaurin free base is administered in a single dosage form comprising about 0.1 mg / m 2 about 0.2 mg / m 2 about 0.3 mg / m 2 about 0.4 mg / m 2 about 0.5 mg / m 2 about 1 mg / m 2 about 1.5 mg / m 2 about 2 mg / m 2 about 2.5 mg / m 2 about 3 mg / m 2 about 3.5 mg / m 2 about 4 mg / m 2 about 4.5 mg / m 2 about 5 mg / m 2 about 5.5 mg / m 2 about 6 mg / m 2 about 6.5 mg / m 2 about 7 mg / m 2 about 7.5 mg / m 2 about 8 mg / m 2 about 8.5 mg / m 2 about 9 mg / m 2 about 9.5 mg / m 2 or about 10 mg / m 2

[0180] ​In some aspects of any of the methods described herein, midostaurin free base is administered in a single dosage form comprising about 0.1 mg to about 10 mg, about 0.5 mg to about 9.5 mg, about 1 mg to about 9 mg, about 1.5 mg to about 8.5 mg, about 2 mg to about 8 mg, about 2.5 mg to about 7.5 mg, about 3 mg to about 7 mg, about 3.5 mg to about 6.5 mg, about 4 mg to about 6 mg, or about 4.5 mg to about 5.5 mg. In some aspects, midostaurin free base is administered in a single dosage form comprising about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0181] In some aspects of any of the methods described herein, midostaurin free base is administered once, twice, three times, or four times per day. In some aspects, midostaurin free base is administered once daily. In some aspects, midostaurin free base is administered twice daily.

[0182] In some aspects of any of the methods described herein, midostaurin free base is administered at about 0.5 mg / m 2 to about 10 mg / m 2 , about 1 mg / m 2 to about 9.5 mg / m 2 , about 1.5 mg / m 2 to about 9 mg / m 2 , about 2 mg / m 2 to about 8.5 mg / m 2 , about 2.5 mg / m 2 to about 8 mg / m 2 , about 3 mg / m 2 to about 7.5 mg / m 2 , about 3.5 mg / m 2 to about 7 mg / m 2 , about 4 mg / m 2 to about 6.5 mg / m 2 , about 4.5 mg / m 2 to about 6 mg / m 2 , or about 5 mg / m 2 to about 6 mg / m 2In some aspects, mirametinib free base is administered at about 0.5 mg / m 2 , about 1 mg / m 2 , about 1.5 mg / m 2 , about 2 mg / m 2 , about 2.5 mg / m 2 , about 3 mg / m 2 , about 3.5 mg / m 2 , about 4 mg / m 2 , about 4.5 mg / m 2 , about 5 mg / m 2 , about 5.5 mg / m 2 , about 6 mg / m 2 , about 6.5 mg / m 2 , about 7 mg / m 2 , about 7.5 mg / m 2 , about 8 mg / m 2 , about 8.5 mg / m 2 , about 9 mg / m 2 , about 9.5 mg / m 2 or about 10 mg / m 2 The amount is applied twice daily.

[0183] In some aspects of any of the methods described herein, mirametinib free base is administered twice daily in an amount of about 0.5 mg to about 10 mg, about 1 mg to about 9.5 mg, about 1.5 mg to about 9 mg, about 2 mg to about 8.5 mg, about 2.5 mg to about 8 mg, about 3 mg to about 7.5 mg, about 3.5 mg to about 7 mg, about 4 mg to about 6.5 mg, about 4.5 mg to about 6 mg, or about 5 mg to about 6 mg. In some aspects, mirametinib free base is administered twice daily in an amount of about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0184] In some aspects of any of the methods described herein, mirametinib free base is administered at a dose of no more than about 10 mg / m 2 , about 9.5 mg / m 2 , about 9 mg / m 2 , about 8.5 mg / m 2 , about 8 mg / m 2, about 7.5 mg / m 2 , about 7 mg / m 2 , about 6.5 mg / m 2 , about 6 mg / m 2 , about 5.5 mg / m 2 , about 5 mg / m 2 , about 4.5 mg / m 2 , about 4 mg / m 2 , about 3.5 mg / m 2 , about 3 mg / m 2 , about 2.5 mg / m 2 , about 2 mg / m 2 or about 1.5 mg / m 2 The total daily dose is administered.

[0185] In some aspects of any of the methods described herein, mirametinib free base is administered at a total daily dose of no more than about 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, or about 1.5 mg.

[0186] In some aspects of any of the methods described herein, mirdametinib or a pharmaceutically acceptable salt thereof exhibits high blood-brain barrier penetrability.

[0187] In some aspects of any of the methods described herein, the patient is a human.

[0188] In some aspects of any of the methods described herein, the human is ≥ 2 years old and < 25 years old. In some aspects, the human is ≥ 2 years old and 18 years old.

[0189] In some aspects of any of the methods described herein, the human has not been previously exposed to a MEK inhibitor. In some aspects, the human has not responded to prior treatment with one or more MEK inhibitors.

[0190] In some aspects of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered orally. In some aspects, midametinib or a pharmaceutically acceptable salt thereof is administered orally as a solid dosage form. In some aspects, the solid dosage form is a tablet or capsule. In some aspects, the solid dosage form is a capsule. In some aspects, midametinib or a pharmaceutically acceptable salt thereof can be dispersed in a drinkable liquid or can be orally dispersed in the patient's saliva.

[0191] In some aspects of any of the methods described herein, midostaurin or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat a tumor or cancer.

[0192] In some aspects of any of the methods described herein, midostaurin or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat a tumor or cancer.

[0193] EMBODIMENT

[0194] EMBODIMENT 1

[0195] Midostaurin free base (Batch Nos. 1, 2, and 3) having the properties of the following table were prepared.

[0196]

[0197] Example 2

[0198] Using one of Batch Nos. 1 and 2 from Example 1, 1 and 2 mg capsules having the formulations described in the following table were prepared. The ingredients were mixed and roller compacted, then encapsulated in capsule shells (size 3, opaque hard gelatin capsules).

[0199]

[0200] The solubility of the 1 mg and 2 mg capsules prepared with midostaurin in Batch Nos. 1 and 2 were measured according to the USP Basket Method in 0.1 N HC1 (0.1 N aqueous HC1) at 75 rpm, as shown in Figure 1 The tested capsules released more than 80% of the midostaurin within 15 minutes, as shown in the figure.

[0201] 2 mg capsules having the formulations provided above were prepared from Batch No. 3. The solubility of the 2 mg capsules prepared from Batch Nos. 1, 2, and 3 were measured according to the USP Basket Method in 0.1 N HC1 at 75 rpm, as shown in Figure 2 Definitions Oral dosage form Method of treatment Example 2 Figure 1 Figure 2 The tested capsules released more than 80% of the midostaurin within 15 minutes, as shown in the figure.

[0202] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent there is a conflict between the definitions in this application and that of a document incorporated by reference, the definition in this application applies.

[0203] While the application has been described in connection with specific aspects thereof, it will be understood that it is capable of further modification, and this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains and fall within the scope of the appended claims as appropriately applied.

Claims

1. An oral dosage form comprising (a) midostaurin having a d90 of no more than 250 microns and (b) one or more pharmaceutically acceptable excipients.

2. The oral dosage form of claim 1, wherein the midostaurin has a d50 of no more than 50 microns.

3. The oral dosage form of any one of the preceding claims, wherein the midostaurin has a d50 of no more than 30 microns.

4. The oral dosage form of any one of claims 1 to 3, wherein the dosage form is a capsule prepared by (i) roller compaction of a blend of the midostaurin and one or more pharmaceutically acceptable excipients and (ii) encapsulation of the compacted blend into a capsule.

5. An oral dosage form comprising (a) 1 mg of midostaurin having a d90 of no more than 250 microns and (b) one or more pharmaceutically acceptable excipients, wherein the AUC 0-12h of the dosage form is less than 400 ng-h / mL, C max of no more than 40 ng / mL, or both when orally administered on the first day of treatment with midostaurin.

6. The oral dosage form of claim 5, wherein the AUC of the dosage form when administered orally on the first day of treatment with midostaurin is less than 200 ng-h / mL. 0-12h less than 200 ng-h / mL.

7. The oral dosage form of claim 5, wherein when orally administered on the first day of treatment with mirametinib, the AUC 0-12h Less than 100 ng·h / mL.

8. The oral dosage form of any one of claims 5 to 7, wherein the Cmax of the dosage form when administered orally on the first day of treatment with midostaurin is not more than 32 ng / mL. max not more than 32 ng / mL.

9. The oral dosage form of any one of claims 5 to 7, wherein the Cmax of the dosage form when administered orally on the first day of treatment with midostaurin is not more than 30 ng / mL. max not more than 30 ng / mL.

10. The oral dosage form of any one of the preceding claims, wherein the dosage form is a capsule.

11. The oral dosage form of any one of the preceding claims, wherein the dosage form is a tablet.

12. The oral dosage form of any one of the preceding claims, wherein the dosage form is a dispersible tablet.

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

14. The method of claim 13, wherein the patient is administered about 2 mg / m 2 Midostaurin.

15. The method of claim 13, wherein (a) for patients with a body surface area of not more than 0.69 m 2 of midostaurin, twice daily for the first 21 days of each 28-day cycle, and (b) for patients with a body surface area of 0.7 to 1.04 m 2 the patient is initially administered 2 mg of midostaurin twice daily, (c) for patients with a body surface area of 1.05 to 1.49 m 2 of 3 mg of midostaurin twice daily, and thereafter (d) for patients with a body surface area of at least 1.5 m 2 The patient is initially administered 4 mg of midostaurin twice daily.

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

17. The method of claim 16, wherein the patient is less than 12 years old.

18. The method of claim 16 or 17, wherein the midostaurin 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.

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

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

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

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

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

24. The method of claim 23, wherein the patient is less than 12 years old.

25. The method of claim 23 or 24, wherein the midostaurin 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.

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

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

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

29. The method of any one of claims 13 to 28, wherein the method further comprises, prior to treatment, (i) determining whether to select midostaurin as a treatment for the patient, and (ii) selecting midostaurin as a treatment for the patient based at least in part on an objective response rate of midostaurin, wherein the objective response rate is defined as a reduction in tumor size of at least 20% using a centralized read MRI volumetric analysis.

30. The method of claim 29, wherein in step (i) midostaurin is selected based on a response rate of at least 70%.

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

32. The method of claim 31, wherein the patient is less than 12 years old.

33. The method of claim 31 or 32, wherein the midostaurin 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.

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

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

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

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

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

39. The method of claim 38, wherein the patient is less than 12 years old.

40. The method of claim 38 or 39, wherein the midostaurin 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.

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

42. The method of any one of claims 13 to 21, 23 to 36, and 38 to 41, wherein the midostaurin is in the form of one or more sprinkle tablets, and prior to administration, the one or more sprinkle tablets are dispersed in water to form a suspension, and the suspension is optionally agitated until no lumps remain.

43. The method of claim 42, wherein the one or more sprinkle tablets are dispersed in 5 to 10 mL of water to form the suspension.

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

45. The method of any one of claims 13 to 44, wherein each of the one or more oral dosage forms comprises (a) midostaurin having a d90 of no more than 250 microns and (b) one or more pharmaceutically acceptable excipients.

46. The method of claim 45, wherein the midostaurin has a d50 of no more than 50 microns.

47. The method of claim 45, wherein the midostaurin has a d50 of no more than 30 microns.

48. The method of any one of claims 45 to 47, wherein each of the one or more oral dosage forms is a capsule prepared by (i) roller compaction of a blend of the midostaurin and one or more pharmaceutically acceptable excipients and (ii) encapsulation of the compacted blend into a capsule.

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