WO2026006011A1 - Schéma posologique pour traitement par mirdamétinib - Google Patents

Schéma posologique pour traitement par mirdamétinib

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Publication number
WO2026006011A1
WO2026006011A1 PCT/US2025/033463 US2025033463W WO2026006011A1 WO 2026006011 A1 WO2026006011 A1 WO 2026006011A1 US 2025033463 W US2025033463 W US 2025033463W WO 2026006011 A1 WO2026006011 A1 WO 2026006011A1
Authority
WO
WIPO (PCT)
Prior art keywords
patient
mirdametinib
pharmaceutically acceptable
acceptable salt
lesions
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/033463
Other languages
English (en)
Inventor
Uchenna H. Iloeje
Abrahama J. LANGSETH
Todd Webster SHEARER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SpringWorks Therapeutics Inc
Original Assignee
SpringWorks Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US18/912,218 external-priority patent/US12390430B1/en
Application filed by SpringWorks Therapeutics Inc filed Critical SpringWorks Therapeutics Inc
Publication of WO2026006011A1 publication Critical patent/WO2026006011A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Mirdametinib is an allosteric, small molecule targeting mitogen-activated protein kinase kinase (MEK).
  • the patient is initially administered 4 mg mirdametinib twice daily, and wherein the method further comprises one or more of the following:
  • LVEF left ventricle ejection fraction
  • the method includes all of (a) through (g). [0008] In one embodiment of any method of any embodiment described herein, step (g) comprises considering permanent discontinuation of administration of mirdametinib.
  • the method further comprises, at the first signs of dermatologic adverse reactions, initiating supportive care.
  • Pustular rash may be treated with topical clindamycin gel or lotion (for example, applied twice daily).
  • semisynthetic oral tetracyclines such as doxycycline or minocycline may also be useful for children over 8 years old, adolescents, and adults.
  • Eczematous or dry skin rash and other macular (non-acneiform) rash can be treated with a moisturizer.
  • a topical steroid such as betamethasone valerate lotion (e.g., 0.05%), desonide cream (e.g., 0.05%), fluocinolone acetonide solution (e.g., 0.01%), dexamethasone sodium phosphate cream (e.g., 0.1%), hydrocortisone acetate cream (e.g., 1%), or methylprednisolone acetate cream (e.g., 0.25%) may be applied.
  • betamethasone valerate lotion e.g., 0.05%)
  • desonide cream e.g., 0.05%)
  • fluocinolone acetonide solution e.g., 0.01%
  • dexamethasone sodium phosphate cream e.g., 0.1%)
  • hydrocortisone acetate cream e.g., 1%
  • methylprednisolone acetate cream e.g., 0.25%
  • the patient suffers from a tumor or cancer.
  • the tumor or cancer is selected from plexiform neurofibromas (PN), plexiform neurofibromas 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 a patient's brain.
  • the patient has plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN).
  • NF1-PN patient has progressive PN.
  • the NF1-PN patient has PNs that cause significant morbidity.
  • the patient has symptomatic plexiform neurofibromas. In another embodiment of any of the methods described herein, the patient has symptomatic, inoperable plexiform neurofibromas.
  • the patient has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) that is progressing or causing significant morbidity.
  • the human patient has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) that is progressing or causing significant morbidity.
  • the patient is a pediatric patient. In another embodiment, the patient is an adult.
  • the administration of mirdametinib results in decreased pain intensity.
  • the administration of mirdametinib results in decreased pain interference.
  • Another embodiment is a method of treating an adult or pediatric human patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection) by orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein
  • NF1 neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • the patient is initially administered 4 mg mirdametinib twice daily, and wherein the method further comprises one or more of the following:
  • LVEF left ventricle ejection fraction
  • grade 3 e.g., grade 4
  • mirdametinib or pharmaceutically acceptable salt thereof upon the patient exhibiting at least grade 3 (e.g., grade 4) ocular toxicity, withholding the mirdametinib or pharmaceutically acceptable salt thereof until recovery to Grade 1 or lower or baseline and (1) if recovery occurs in no more than 14 days, resuming mirdametinib at a reduced dose or (2) if recovery occurs in more than 14 days, considering discontinuing administration of mirdametinib;
  • LVEF left ventricle ejection fraction
  • the adverse reaction in (h) or (i) is selected from diarrhea, abdominal pain, and fatigue.
  • the patient is an adult.
  • the patient is a pediatric patient.
  • the patient has neurofibromatosis type 1 (NF1) with progressive or symptomatic plexiform neurofibromas (PN) that is not amenable to complete resection.
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • Another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL or from about 100 to about 500 ng/mL (such as from about 130 to about 245, from about 150 to about 230, or from about 160 to about 215 ng/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof, and (ii) after the patient has an
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL or from about 100 to about 500 ng/mL (such as from about 130 to about 245, from about 150 to about 230, or from about 160 to about 215 ng/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof, and (ii) after the patient has
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng‘h/
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng’h/
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection).
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the method comprises orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein after the patient has an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient 1 mg of mirdametinib or a pharmaceutically acceptable salt thereof daily (e.g., 1 mg once daily), wherein the patient has a body surface area from 0.4 to 0.69 m 2
  • LVEF left ventricle ejection fraction
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein after the patient has a grade 3 or higher dermatitis acneiform or rash, withholding the mirdametinib or pharmaceutically acceptable salt thereof until improvement to no higher than a grade 1 and then administering to the patient 1 mg of mirdametinib or a pharmaceutically acceptable salt thereof once daily, wherein the patient has a body surface area from 0.4 to 0.69 m 2 .
  • NF1 neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein after the patient has an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient 3 mg of mirdametinib or a pharmaceutically acceptable salt thereof daily, wherein the patient has a body surface area from 0.7 to 1.04 m 2 (such as 2 mg in the morning, and 1 mg in the evening).
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein after the patient has a grade 3 or higher dermatitis acneiform or rash, withholding the mirdametinib or pharmaceutically acceptable salt thereof until improvement to no higher than a grade 1 and then administering to the patient 3 mg of mirdametinib or a pharmaceutically acceptable salt thereof daily (such as 2 mg in the morning, and 1 mg in the evening), wherein the patient has a body surface area from 0.7 to 1.04 m 2 .
  • NF1 neurofibromatosis type 1
  • PN neurofibromato
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein after the patient has an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient 4 mg of mirdametinib or a pharmaceutically acceptable salt thereof daily (such as 2 mg in the morning, and 2 mg in the evening), wherein the patient has a body surface area from 1.05 to 1.49 m 2
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein after the patient has a grade 3 or higher dermatitis acneiform or rash, withholding the mirdametinib or pharmaceutically acceptable salt thereof until improvement to no higher than a grade 1 and then administering to the patient 4 mg of mirdametinib or a pharmaceutically acceptable salt thereof daily (such as 2 mg in the morning, and 2 mg in the evening), wherein the patient has a body surface area from 1 .05 to 1 .49 m 2 .
  • NF1 neurofibromatosis type 1
  • PN
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein after the patient has an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient 6 mg of mirdametinib or a pharmaceutically acceptable salt thereof daily (such as 3 mg in the morning, and 3 mg in the evening), wherein the patient has a body surface area greater than or equal to 1.5 m 2
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein after the patient has a grade 3 or higher dermatitis acneiform or rash, withholding the mirdametinib or pharmaceutically acceptable salt thereof until improvement to no higher than a grade 1 and then administering to the patient 6 mg of mirdametinib or a pharmaceutically acceptable salt thereof daily (such as 3 mg in the morning, and 3 mg in the evening), wherein the patient has a body surface area greater than or equal to 1.5 m 2 .
  • NF1 neurofibromatosis type 1
  • PN neurofibromato
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection).
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the method comprises orally administering to the patient an effective amount of mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL or from about 100 to about 500 ng/mL, and (ii) upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering
  • LVEF left ventricle ejection fraction
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection).
  • the method comprises orally administering to the patient an effective amount of mirdametinib or a pharmaceutically acceptable salt thereof, wherein
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL or 100 to about 500 ng/mL, and
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection).
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the method comprises orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, an AUCiast of mirdametinib of from about 200 to about 720 ng'h/mL, and (ii) upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering
  • LVEF left ventricle ejection fraction
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection).
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the method comprises orally administering to the patient a daily dose of 2 mg of mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient a reduced daily dose of 1 mg of mirdametinib or the pharmaceutically acceptable salt thereof.
  • the 2 mg daily dose can be administered to the patient as, for example, two 1 mg dosages of mirdametinib or a pharmaceutically acceptable salt thereof (e.g., 1 mg in the morning and 1 mg in the evening).
  • the 1 mg reduced daily dose can administered to the patient, for example, once daily.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient a daily dose of 4 mg of mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient a reduced daily dose of 3 mg of mirdametinib or the pharmaceutically acceptable salt thereof.
  • LVEF left ventricle ejection fraction
  • the 4 mg daily dose can be administered to the patient as, for example, two 2 mg dosages of mirdametinib or a pharmaceutically acceptable salt thereof (e.g., 2 mg in the morning and 2 mg in the evening).
  • the 3 mg reduced daily dose can administered to the patient, for example, as a 2 mg dosage in the morning and a 1 mg dosage in the evening.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NTT who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient a daily dose of 6 mg of mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient a reduced daily dose of 4 mg of mirdametinib or the pharmaceutically acceptable salt thereof.
  • NF1 neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • the 6 mg daily dose can be administered to the patient as, for example, two 3 mg dosages of mirdametinib or a pharmaceutically acceptable salt thereof (e.g., 13 mg in the morning and 3 mg in the evening).
  • the 4 mg reduced daily dose can administered to the patient, for example, as a 2 mg dosage in the morning and a 2 mg dosage in the evening.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient a daily dose of 8 mg of mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient a reduced daily dose of 6 mg of mirdametinib or the pharmaceutically acceptable salt thereof.
  • LVEF left ventricle ejection fraction
  • the 8 mg daily dose can be administered to the patient as, for example, two 4 mg dosages of mirdametinib or a pharmaceutically acceptable salt thereof (e.g., 4 mg in the morning and 4 mg in the evening).
  • the 6 mg reduced daily dose can administered to the patient, for example, as a 3 mg dosage in the morning and a 3 mg dosage in the evening.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having a tumor or cancer and in need thereof, the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting a symptomatic retinal pigment epithelium detachment (RPED), withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution to Grade 1 or less or baseline and then administering the mirdametinib or pharmaceutically acceptable salt thereof at the same dose.
  • RPED retinal pigment epithelium detachment
  • the method comprises permanently discontinuing administration of mirdametinib upon the patient exhibiting retinal vein occlusion.
  • the method may further comprise withholding the mirdametinib or pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then restarting administration of the mirdametinib or pharmaceutically acceptable salt thereof at a reduced dose (such as the reduced dose described herein).
  • LVEF left ventricle ejection fraction
  • the patient exhibits an asymptomatic, absolute decrease in LVEF of 10% or greater and no more than 20% from baseline and is below the LLN.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL, prior to the patient exhibiting a symptomatic RPED. In some instances, the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL, prior to the patient exhibiting a symptomatic RPED.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) (e.g., a patient with NF1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) for a patient having a body surface area of 0.4 to 0.69 m 2 , the patient is initially administered 1 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily,
  • the patient is initially administered 4 mg mirdametinib or a pharmaceutically acceptable salt thereof twice daily, and wherein upon the patient exhibiting a symptomatic retinal pigment epithelium detachment (RPED), withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution to Grade 1 or less or baseline and then administering the mirdametinib or pharmaceutically acceptable salt thereof at the same dose.
  • RPED retinal pigment epithelium detachment
  • the method comprises permanently discontinuing administration of mirdametinib upon the patient exhibiting retinal vein occlusion.
  • the method may further comprise withholding the mirdametinib or pharmaceutically acceptable salt thereof until it is Grade
  • the patient exhibits an asymptomatic, absolute decrease in LVEF of 10% or greater and no more than 20% from baseline and is below the LLN.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL, prior to the patient exhibiting a symptomatic RPED.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL, prior to the patient exhibiting a symptomatic RPED.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a C
  • ia .v of mirdametinib of from about 95 to about 280 ng/mL or from about 100 to about 500 ng/mL (such as from about 130 to about 245, from about 150 to about 230, or from about 160 to about 215 ng/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof,.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng'h/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof,.
  • a AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng'h/mL), prior to withholding
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered in free base form (i.e., as mirdametinib).
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food.
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days or each 28-day cycle.
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity.
  • the treatment results in decreased pain intensity.
  • the patient is an adult patient having neurofibromatosis type 1 (NFl) who has symptomatic plexiform neurofibromas (PN).
  • NFl neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the patient is an adult patient having neurofibromatosis type 1 (NFl) with progressive or symptomatic plexiform neurofibromas (PN) that is not amenable to complete resection.
  • NFl neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the patient is a pediatric patient having neurofibromatosis type 1 (NFl) who has symptomatic plexiform neurofibromas (PN).
  • NFl neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the patient is a pediatric patient having neurofibromatosis type 1 (NFl) with progressive or symptomatic plexiform neurofibromas (PN) that is not amenable to complete resection.
  • NFl neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle.
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity.
  • the left ventricle ejection fraction is assessed by echocardiogram prior to initiating treatment with mirdametinib and every 3 months during the first year of treatment with mirdametinib.
  • a comprehensive ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes, such as blurred vision.
  • the patient has symptomatic plexiform neurofibromas (e.g., symptomatic, inoperable plexiform neurofibromas).
  • symptomatic plexiform neurofibromas e.g., symptomatic, inoperable plexiform neurofibromas.
  • the patient has progressive plexiform neurofibromas.
  • the patient has plexiform neurofibromas that cause significant morbidity.
  • the NF1-PN patient has head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function or painful lesions.
  • the lesions causing major deformity or are significantly disfiguring are tumors of the head and neck or those on other areas of the body that are unable to be concealed by standard garments.
  • the patient has paraspinal lesions.
  • the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference and one or more of the following:
  • the patient has a constitutional NF1 mutation documented in a Clinical Laboratory Improvement Amendments / College of American Pathologists certified lab.
  • the patient either (a) has a parent diagnosed with NF 1 and one or more criteria of (1) through (7) or (b) does not have a parent diagnosed with NF1 but has two or more criteria of (1) through (7):
  • two or more iris Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities defined as bright, patchy nodules imaged by optical coherence tomography (OCT)/near-infrared reflectance (NIR) imaging;
  • a distinctive osseus lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone
  • the mirdametinib is administered for the first three weeks and discontinued for the last one week.
  • the adverse event resulting in the dose reduction is acneiform. In another embodiment, the adverse event resulting in the dose reduction is dermatitis acneiform. In yet another embodiment, the adverse event resulting in the dose reduction is dermatitis acneiform, diarrhea, or nausea. In yet another embodiment, the adverse event resulting in the dose reduction in a pediatric patient is decreased neutrophil count.
  • the patient has at least a 20% reduction in plexiform neurofibroma volume as determined by volumetric magnetic resonance imaging analysis following treatment with mirdametinib.
  • the patient permanently discontinues treatment with mirdametinib due to a grade 4 adverse reaction, such as where the adverse reaction is abdominal pain, constipation, dermatitis acneiform, or diarrhea.
  • the pediatric patient permanently discontinues treatment with mirdametinib due to a grade 4 adverse reaction, such as where the adverse reaction is abdominal pain, constipation, dermatitis acneiform, or diarrhea.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib from about 95 or 100 ng/mL to about 500 ng/mL.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL (such as from about 130 to about 245, from about 150 to about 230, or from about 160 to about 215 ng/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof,.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng h/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof,.
  • a AUCiast of mirdametinib of from about 200 to about 720 ng h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng h/mL), prior to withholding
  • the patient is 2 to 15 years of age.
  • the method further comprises prior to treatment (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient at least partially based on its objective response rate, where the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis (for example, per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria).
  • the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis (for example, per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria).
  • the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis (for example, per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria).
  • the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis (for
  • Methods for treating a tumor or cancer selected from the group consisting of plexiform neurofibromas (PN), plexiform neurofibromas 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 a patient’ s brain, comprising administering to a patient in need thereof mirdametinib or a pharmaceutically acceptable salt thereof are also provided herein.
  • the mirdametinib or a pharmaceutically acceptable salt thereof may be administered according to the dosing scheme described herein.
  • a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof is administered.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg/m 2 to about 10 mg/m 2 per day, such as about 2 mg/m 2 per day, based on mirdametinib free base.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered once daily. In some aspects, the mirdametinib, or a pharmaceutically acceptable salt thereof, is administered twice daily.
  • the mirdametinib exhibits high blood-brain-barrier penetration.
  • the patient is a human.
  • the human has an age of > 2 and ⁇ 25.
  • the human patient has had no prior exposure to MEK inhibitors.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered orally.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is dispersible (e.g., a dispersible tablet such as described in U.S. Patent No. 11,571,402, which is hereby incorporated by reference) in a potable liquid (e.g., about 5 to about 10 mb of water) or orodispersible in a patient’s saliva.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered orally as a solid dosage form.
  • the solid dosage form is a tablet or capsule.
  • the solid dosage form is a capsule.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat the tumor or cancer.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and/or surgery to treat the tumor or cancer.
  • the mirdametinib is mirdametinib free base.
  • mirdametinib refers to the single enantiomer N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the teachings throughout the specification regarding mirdametinib equally apply to pharmaceutically acceptable salts of mirdametinib.
  • the disclosure of a method of treating neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) with mirdametinib also means that a pharmaceutically acceptable salt of mirdametinib can be administered to treat NF 1 associated inoperable PN.
  • mg/m 2 refers to the dose in milligrams per m 2 body surface area of the patient.
  • 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.
  • primate e.g., human
  • cow, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the patient may be a pediatric patient.
  • the term "pediatric” refers to a human subject under the age of 21 years at the time of treatment.
  • the term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first 28 days of life); infants (29 days of age to less than two years of age); children (two years of age to less than 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • neonates from birth through the first 28 days of life
  • infants 29 days of age to less than two years of age
  • children two years of age to less than 12 years of age
  • adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • Berhman R E Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996
  • Rudolph A M et al. Rudolph's Pediatrics, 21 st Ed.
  • the term “dispersible” as used herein refers to a composition (e.g., a tablet, powder, granules, minitablets, or pellets) which disintegrates and/or dissolves when combined with water or another potable liquid (e.g., a non-water beverage), or a subject’s own saliva when placed in the subject’s mouth, with or without the addition of agitation or temperature modification.
  • the dispersible composition disintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after being combined with water or another potable liquid. Such disintegration or dissolution need not be complete.
  • a dispersible tablet may dissolve almost entirely, but some undissolved particulate matter may remain.
  • orodispersible refers to a composition which is capable of dissolving or disintegrating in a subject’s mouth (i.e., dissolving or disintegrating in a subject’s saliva) if administered orally, without a requirement of first dissolving or disintegrating in a separate container.
  • the terms “treat,” “treated,” and “treating” mean 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 obtain beneficial or desired clinical results.
  • those in need of treatment include those already 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 a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • therapeutically effective amount is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a subject is successfully "treated” for a tumor, according to the methods described herein if the patient shows one or more of the following: a reduction in the size of the tumor; relief of one or more symptoms associated with the specific tumor; a reduction in the volume of the tumor; 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), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof.
  • nationally or internationally accepted standards of treatment outcomes in a given tumor can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g., CR, PFS, PR).
  • a subject is successfully "treated” for cancer, e.g., ovarian cancer, according to the methods described herein if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof.
  • nationally or internationally accepted standards of treatment outcomes in a given cancer can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g., CR, PFS, PR).
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • each component is "pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable 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.
  • pharmaceutically-acceptable salts refers to the relatively nontoxic, inorganic and organic acid addition salts of mirdametinib. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention 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, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts. See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19.
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acid; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isothionic.
  • baseline refers to an initial measurement of a condition that is taken at an early time point and used for comparison over time to look for changes.
  • Baseline may be a measurement just before treatment and used afterwards to see if the treatment had an effect.
  • the size of a tumor can be measured before treatment (baseline) and then afterwards to see if the treatment had an effect.
  • the terms “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • One aspect of the present invention is a method of administering mirdametinib to a human patient in need thereof by orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein
  • the patient is initially administered 4 mg mirdametinib twice daily, and wherein the method further comprises one or more of the following:
  • LVEF left ventricle ejection fraction
  • the initial dosage regimen is continued to be used, unless for instance, certain adverse events occur which require a reduction in the dosage regimen or discontinuation of treatment with mirdametinib as described herein.
  • Another aspect is a method of administering mirdametinib or a pharmaceutically acceptable salt thereof to a human patient in need thereof, where the patient suffered from an adverse reaction while being treating with mirdametinib which resolved after withholding the mirdametinib.
  • the method comprising administering to the patient a reduced dose of mirdametinib where the reduced dose is:
  • the adverse reaction was (A) an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) of 10% or greater from baseline and is below the lower limit of normal (LLN), (B) a grade 3 or higher dermatitis acneiform or rash, (C) any other intolerable grade 2 adverse reaction or any grade 3 adverse reaction, or (D) any grade 4 adverse reaction.
  • LVEF left ventricle ejection fraction
  • the patient suffers from a tumor or cancer.
  • the tumor or cancer is selected from plexiform neurofibromas (PN), plexiform neurofibromas 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 a patient's brain.
  • the tumor or cancer is high grade glioma.
  • the high grade glioma is a primary cancer.
  • the high grade glioma is a metastatic cancer.
  • 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 a cancer that has metastasized to the patient’s brain including lung cancer, breast cancer and melanoma.
  • the patient has plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN).
  • NF1-PN patient has progressive PN.
  • the NF1-PN patient has PNs that cause significant morbidity.
  • the patient has symptomatic plexiform neurofibromas. In another embodiment of any of the methods described herein, the patient has symptomatic, inoperable plexiform neurofibromas.
  • the patient has neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) that is progressing or causing significant morbidity.
  • the human patient has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) that is progressing or causing significant morbidity.
  • the patient is a pediatric patient. In another embodiment, the patient is an adult.
  • the patient has neurofibromatosis type 1 (NF1) with progressive or symptomatic plexiform neurofibromas (PN) that is not amenable to complete resection.
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the administration of mirdametinib results in decreased pain intensity.
  • the administration of mirdametinib results in decreased pain interference.
  • Yet another embodiment is a method of treating an adult or pediatric human patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection) by orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein
  • NF1 neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • the patient is initially administered 4 mg mirdametinib twice daily, and wherein the method further comprises one or more of the following:
  • LVEF left ventricle ejection fraction
  • LVEF left ventricle ejection fraction
  • the adverse reaction in (h) or (i) is selected from diarrhea, abdominal pain, and fatigue.
  • Yet another embodiment is a method of treating an adult or pediatric human patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), where the patient suffered from an adverse reaction while being treating with mirdametinib which resolved after withholding the mirdametinib.
  • the method comprising administering to the patient a reduced dose of mirdametinib where the reduced dose is:
  • the adverse reaction was (A) an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) of 10% or greater from baseline and is below the lower limit of normal (LLN), (B) a grade 3 or higher dermatitis acneiform or rash, (C) any other intolerable grade 2 adverse reaction or any grade 3 adverse reaction, or (D) any grade 4 adverse reaction.
  • LVEF left ventricle ejection fraction
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient an effective amount of mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL and (ii) upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient an effective amount of mirdametinib or a pharmaceutically acceptable salt thereof, wherein
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL and
  • Yet another embodiment is a method of treating an adult or pediatric patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein (i) the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, an AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL, and (ii) upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient a daily dose of 2 mg of mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient a reduced daily dose of 1 mg of mirdametinib or the pharmaceutically acceptable salt thereof.
  • the 2 mg daily dose can be administered to the patient as, for example, two 1 mg dosages of mird
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient a daily dose of 4 mg of mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient a reduced daily dose of 3 mg of mirdametinib or the pharmaceutically acceptable salt thereof.
  • LVEF left ventricle ejection fraction
  • the 4 mg daily dose can be administered to the patient as, for example, two 2 mg dosages of mirdametinib or a pharmaceutically acceptable salt thereof.
  • the 3 mg reduced daily dose can administered to the patient, for example, as a 2 mg dosage in the morning and a 1 mg dosage in the evening.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient a daily dose of 6 mg of mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient a reduced daily dose of 4 mg of mirdametinib or the pharmaceutically acceptable salt thereof.
  • LVEF left ventricle ejection fraction
  • the 6 mg daily dose can be administered to the patient as, for example, two 3 mg dosages of mirdametinib or a pharmaceutically acceptable salt thereof.
  • the 4 mg reduced daily dose can administered to the patient, for example, as a 2 mg dosage in the morning and a 2 mg dosage in the evening.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) and is in need thereof (e.g., a patient with NF1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient a daily dose of 8 mg of mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting an asymptomatic, absolute decrease in left ventricle ejection fraction (LVEF) 10% or greater from baseline and is below the lower limit of normal (LLN), withholding mirdametinib or a pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then administering to the patient a reduced daily dose of 6 mg of mirdametinib or the pharmaceutically acceptable salt thereof.
  • LVEF left ventricle ejection fraction
  • the 8 mg daily dose can be administered to the patient as, for example, two 4 mg dosages of mirdametinib or a pharmaceutically acceptable salt thereof.
  • the 6 mg reduced daily dose can administered to the patient, for example, as a 3 mg dosage in the morning and a 3 mg dosage in the evening.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having a tumor or cancer and in need thereof, the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein upon the patient exhibiting a symptomatic retinal pigment epithelium detachment (RPED), withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution to Grade 1 or less or baseline and then administering the mirdametinib or pharmaceutically acceptable salt thereof at the same dose.
  • RPED retinal pigment epithelium detachment
  • the method comprises permanently discontinuing administration of mirdametinib upon the patient exhibiting retinal vein occlusion.
  • the method may further comprise withholding the mirdametinib or pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then restarting administration of the mirdametinib or pharmaceutically acceptable salt thereof at a reduced dose (e.g., at a reduced dose as described herein).
  • a reduced dose e.g., at a reduced dose as described herein.
  • the patient exhibits an asymptomatic, absolute decrease in LVEF of 10% or greater and no more than 20% from baseline and is below the LLN.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL, prior to the patient exhibiting a symptomatic RPED.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmav of mirdametinib of from about 95 to about 280 ng/mL, prior to the patient exhibiting a symptomatic RPED.
  • Yet another embodiment is a method of treating a patient at least 2 years of age having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) (e.g., a patient with NF1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection), the method comprising orally administering to the patient mirdametinib or a pharmaceutically acceptable salt thereof, wherein
  • the patient is initially administered 4 mg mirdametinib twice daily, and wherein upon the patient exhibiting a symptomatic retinal pigment epithelium detachment (RPED), withholding the mirdametinib or pharmaceutically acceptable salt thereof until resolution to Grade 1 or less or baseline and then administering the mirdametinib or pharmaceutically acceptable salt thereof at the same dose.
  • RPED retinal pigment epithelium detachment
  • the method comprises permanently discontinuing administration of mirdametinib upon the patient exhibiting retinal vein occlusion.
  • the method may further comprise withholding the mirdametinib or pharmaceutically acceptable salt thereof until it is Grade 1 or lower and then restarting administration of the mirdametinib or pharmaceutically acceptable salt thereof at a reduced dose (e.g., at the reduced dose described herein).
  • a reduced dose e.g., at the reduced dose described herein.
  • the patient exhibits an asymptomatic, absolute decrease in LVEF of 10% or greater and no more than 20% from baseline and is below the LLN.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng’h/mL, prior to the patient exhibiting a symptomatic RPED.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmav of mirdametinib of from about 95 to about 280 ng/mL, prior to the patient exhibiting a symptomatic RPED.
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered with or without food.
  • NF1 neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • PN neurofibromatosis type 1
  • an adult patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection e.g., an adult patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection.
  • the patient is a pediatric patient having neurofibromatosis type 1 (NF1) who has progressive or symptomatic plexiform neurofibromas (PN) (e.g., a pediatric patient with NF 1 who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection).
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the treatment results in decreased pain intensity.
  • the treatment results in decreased pain interference.
  • the patient is an adult patient having neurofibromatosis type 1 (NFl) who has progressive or symptomatic plexiform neurofibromas (PN) (e.g., a patient with NFl who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection).
  • NFl neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the patient is a pediatric patient having neurofibromatosis type 1 (NFl) who has progressive or symptomatic plexiform neurofibromas (PN) (e.g., a patient with NFl who has progressive or symptomatic plexiform neurofibromas (PN) not amenable to complete resection).
  • NFl neurofibromatosis type 1
  • PN plexiform neurofibromas
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered for the first 21 days of each 28-day cycle.
  • the mirdametinib or pharmaceutically acceptable salt thereof is administered until plexiform neurofibromas progression or unacceptable toxicity.
  • the left ventricle ejection fraction is assessed by echocardiogram prior to initiating treatment with mirdametinib and every 3 months during the first year of treatment with mirdametinib.
  • a comprehensive ophthalmic assessment is conducted prior to initiating treatment with mirdametinib and at regular intervals during treatment with mirdametinib, and for new or worsening visual changes.
  • the patient has symptomatic, inoperable plexiform neurofibromas. In one embodiment of any method of any embodiment described herein, the patient has progressive or symptomatic, inoperable plexiform neurofibromas.
  • the patient has progressive plexiform neurofibromas.
  • the patient has plexiform neurofibromas that cause significant morbidity.
  • the NF1-PN patient has head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function or painful lesions.
  • the lesions causing major deformity or are significantly disfiguring are tumors of the head and neck or those on other areas of the body that are unable to be concealed by standard garments.
  • the patient has paraspinal lesions.
  • the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference and one or more of the following:
  • the patient has a constitutional NF1 mutation documented in a Clinical Laboratory Improvement Amendments / College of American Pathologists certified lab.
  • the patient either (a) has a parent diagnosed with NF 1 and one or more criteria of (1) through (7) or (b) does not have a parent diagnosed with NF 1 but has two or more criteria of (1) through (7): (1) six or more cafe-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals;
  • two or more iris Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities defined as bright, patchy nodules imaged by optical coherence tomography (OCT)/near-infrared reflectance (NIR) imaging;
  • a distinctive osseus lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone
  • the mirdametinib is administered for the first three weeks and discontinued for the last one week.
  • the adverse event resulting in the dose reduction is acneiform. In another embodiment, the adverse event resulting in the dose reduction is dermatitis acneiform. In yet another embodiment, the adverse event resulting in the dose reduction is dermatitis acneiform, diarrhea, or nausea. In yet another embodiment, the adverse event resulting in the dose reduction in a pediatric patient is decreased neutrophil count.
  • the patient has at least a 20% reduction in plexiform neurofibroma volume as determined by volumetric magnetic resonance imaging analysis following treatment with mirdametinib.
  • the patient permanently discontinues treatment with mirdametinib due to a grade 4 adverse reaction where the adverse reaction is abdominal pain, constipation, dermatitis acneiform, or diarrhea.
  • the pediatric patient permanently discontinues treatment with mirdametinib due to a grade 4 adverse reaction where the adverse reaction is abdominal pain, constipation, dermatitis acneiform, or diarrhea.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib from about 100 ng/mL to about 500 ng/mL.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL (such as from about 130 to about 245, from about 150 to about 230, or from about 160 to about 215 ng/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof,.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng h/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof,.
  • a AUCiast of mirdametinib of from about 200 to about 720 ng h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng h/mL), prior to withholding
  • the patient is 2 to 15 years of age.
  • the method further comprises prior to treatment (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient at least partially based on its objective response rate, where the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis (for example, per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria).
  • the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis (for example, per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria).
  • the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis (for example, per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria).
  • the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis (for
  • Methods for treating a tumor or cancer selected from the group consisting of plexiform neurofibromas (PN), plexiform neurofibromas 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 a patient’s brain, comprising administering to a patient in need thereof mirdametinib or a pharmaceutically acceptable salt thereof are also provided herein.
  • the mirdametinib or a pharmaceutically acceptable salt thereof may be administered according to the dosing scheme described herein.
  • the mirdametinib is administered for the first three weeks and discontinued for the last one week.
  • the patient has at least a 20% reduction in plexiform neurofibroma volume as determined by volumetric magnetic resonance imaging analysis following treatment with mirdametinib.
  • the treatment or administration of mirdametinib results in decreased pain intensity.
  • the treatment or administration of mirdametinib results in decreased pain interference.
  • the dose administered is reduced due to an adverse event, wherein the dose is reduced as follows:
  • the dose at the time of the event is 4 mg mirdametinib twice daily, then the reduced daily dose is 3 mg administered twice daily.
  • the adverse event resulting in the dose reduction is acneiform.
  • the patient is 2 to 15 years of age.
  • the method further comprises prior to treatment (i) determining whether to select mirdametinib as a treatment for the patient, and (ii) selecting mirdametinib as a treatment for the patient at least partially based on its objective response rate, where the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis.
  • mirdametinib is selected based on a response rate of at least 40% in adult patients, such as an objective response rate of 41%.
  • mirdametinib is selected based on a response rate of at least 50% in pediatric patients, such as an objective response rate of 52%.
  • a therapeutically effective amount of mirdametinib, or a pharmaceutically acceptable salt thereof, is administered.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered as mirdametinib free base.
  • the mirdametinib exhibits high blood-brain-barrier penetration.
  • the patient is a human.
  • the human patient has an age of > 2 and ⁇ 25 years. In some aspects, the human has an age of > 2 and 18 years.
  • the human patient has had no prior exposure to MEK inhibitors. In some aspects, the human patient has not responded to prior treatment to one or more MEK inhibitors.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered orally. In some aspects, the mirdametinib, 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, the mirdametinib, or a pharmaceutically acceptable salt thereof, is dispersible in a potable liquid (e.g., about 5 to about 10 mb of water) or orodispersible in a patient’s saliva.
  • a potable liquid e.g., about 5 to about 10 mb of water
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered as a dispersible formulation (such as a 0.5 mg or 1 mg mirdametinib dispersible tablet) as described in U.S. Patent No. 11,571,402, which is hereby incorporated by reference.
  • a tablet of mirdametinib prior to oral administration, is added to about 5 to about 10 mL of water and then gently swirled to disperse the tablet until no lumps remain. The oral solution is subsequently administered to a patient.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat the tumor or cancer.
  • the mirdametinib, or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and/or surgery to treat the tumor or cancer.
  • the adverse event resulting in a dose reduction is a laboratory abnormality.
  • the laboratory abnormality is increased blood creatine phosphokinase.
  • the laboratory abnormality is increased aspartate aminotransferase (AST).
  • the laboratory abnormality is increased alanine aminotransferase (ALT).
  • the laboratory abnormality is increased blood alkaline phosphatase.
  • the laboratory abnormality is decreased neutrophil count.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib from about 100 ng/mL to about 500 ng/mL, prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a Cmax of mirdametinib of from about 95 to about 280 ng/mL (such as from about 130 to about 245, from about 150 to about 230, or from about 160 to about 215 ng/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof.
  • a Cmax of mirdametinib of from about 95 to about 280 ng/mL (such as from about 130 to about 245, from about 150 to about 230, or from about 160 to about 215 ng/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof.
  • the patient exhibits, at steady state exposure from administration of mirdametinib or a pharmaceutically acceptable salt thereof, a AUCiast of mirdametinib of from about 200 to about 720 ng-h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng-h/mL), prior to withholding the mirdametinib or pharmaceutically acceptable salt thereof.
  • a AUCiast of mirdametinib of from about 200 to about 720 ng-h/mL (such as from about 250 to about 610, from about 250 to about 670, from about 350 to about 510, from about 350 to about 660, from about 380 to about 700, from about 380 to about 480, or from about 410 to about 510 ng-h/mL), prior to withholding the
  • the mirdametinib in the methods described herein may be orally administered in the form of an oral dosage form (such as a tablet or capsule).
  • the oral dosage form comprises (a) mirdametinib having a d90 no more than 250 microns and (b) one or more pharmaceutically acceptable excipients.
  • the mirdametinib has a d90 ranging from 50 to 150 microns.
  • the mirdametinib has a d90 ranging from 150 to 250 microns.
  • the mirdametinib has a d50 of no more than 50 microns.
  • the mirdametinib has a d50 of 1 to 25 microns. In yet another embodiment, the mirdametinib has a d50 of 25 to 50 microns. In yet another embodiment, the mirdametinib has a d50 of no more than 30 microns.
  • the oral dosage form may be a solid oral dosage form, such as a capsule or tablet (e.g., dispersible tablet). In one embodiment, the oral dosage form contains 1 mg mirdametinib. In another embodiment, the oral dosage form contains 2 mg mirdametinib.
  • the oral dosage form comprises (a) mirdametinib having a d50 no more than 50 microns and (b) one or more pharmaceutically acceptable excipients.
  • the mirdametinib has a d50 of 1 to 25 microns.
  • the mirdametinib has a d50 of 25 to 50 microns.
  • the mirdametinib has a d50 of no more than 30 microns.
  • the oral dosage form may be a solid oral dosage form, such as a capsule or tablet (e.g., dispersible tablet).
  • the oral dosage form contains 1 mg mirdametinib.
  • the oral dosage form contains 2 mg mirdametinib.
  • the oral dosage form is a capsule prepared by (i) roller compaction of a blend of the mirdametinib and one or more pharmaceutically acceptable excipients and (ii) encapsulating the compacted blend into a capsule.
  • the oral dosage form comprises (a) 1 mg mirdametinib having a d90 no more than 250 microns and (b) one or more pharmaceutically acceptable excipients, wherein the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, an AUCo-i2h less than 400 ng h/mL, a Cmax no more than 40 ng/mL, or both.
  • the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, an AUCo-i2h less than 200 ng h/mL.
  • the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, AUCo-i2h less than 100 ng h/mL. In yet another embodiment, the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, a Cmax no more than 32 ng/mL. In yet another embodiment, the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, a Cmax no more than 30 ng/mL.
  • an oral dosage form comprising (a) 1 mg mirdametinib having a d50 no more than 50 microns and (b) one or more pharmaceutically acceptable excipients, wherein the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, an AUC0-1211 less than 400 ng h/mL, a Cmax no more than 40 ng/mL, or both.
  • the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, an AUCo-i2h less than 200 ng h/mL.
  • the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, AUC0-1211 less than 100 ng h/mL. In yet another embodiment, the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, a Cmax no more than 32 ng/mL. In yet another embodiment, the dosage form provides upon oral administration, on the first day of treatment with mirdametinib, a Cmax no more than 30 ng/mL.
  • the oral dosage form of any embodiment described herein releases at least 80% of its mirdametinib within 15 minutes as measured according to the USP basket method in 0.1 N HC1 (0.1 N HCL aqueous solution) and at 75 rpm.
  • Example 1 Phase 2b Trial of Mirdametinib in Adult and Pediatric Patients with Neurofibromatosis Type 1 (NF 1)- Associated Inoperable Plexiform Neurofibromas (PNs) that are Progressing or Causing Significant Morbidity.
  • NF 1 Neurofibromatosis Type 1
  • PNs Plexiform Neurofibromas
  • This study is to evaluate the efficacy, safety, and tolerability of mirdametinib in participants > 2 years of age with symptomatic NF 1 -associated plexiform neurofibromas (PNs) that causes significant morbidity.
  • PNs neurofibromas
  • a partial response was defined as PN decrease > 20% compared to baseline using centrally read MRI volumetric analysis.
  • Participant must be > 2 years of age inclusive, at the time of signing the informed consent/assent.
  • progression is defined as:
  • PN that is deemed inoperable, defined as a PN that cannot be completely surgically removed without risk for substantial morbidity due to: encasement of or close proximity to vital structures, invasiveness, or high vascularity of the PN, or the participant refuses surgery. Participants who previously underwent surgery for a PN will be eligible to enter the study after the surgery, provided the PN was incompletely resected and is evaluable by volumetric analysis.
  • PN defined as the clinically most relevant PN, amenable to volumetric MRI analysis.
  • the target PN must be seen on at least 3 consecutive MRI slices and the field of view must contain the entire tumor of interest.
  • a target PN must be analyzable by volumetries, at least 5 mL in volume, and will be classified as “typical PN”, “nodular PN”, or "solitary nodular PN" prior to first dose of study treatment.
  • Participants > 18 years of age must have a PN amenable to a percutaneous biopsy and must be willing to undergo pre-, and on treatment tumor biopsies providing fresh tumor tissue; there should be no contraindication for serial biopsy; Patients 2 to 17 years of age should not undergo biopsy unless there is a clinical indication to obtain fresh tumor tissue.
  • Participants > 16 years of age must have a Karnofsky performance level of > 60%, and participants ⁇ 16 years must have a Lansky performance of > 60%. Participant has adequate organ and bone marrow function as defined by the following screening laboratory values:
  • Female participants are eligible to participate if they are not pregnant or breastfeeding, and at least one of the following conditions applies:
  • a WOCBP must have a negative serum pregnancy test result at Screening and a negative urine pregnancy test result at the Baseline visit prior to the first dose of study treatment.
  • Participant has a Screening alanine transaminase (ALT) value of > 2.0 x upper limit of normal (ULN);
  • Participant has a Screening total bilirubin value of > 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin ⁇ 35%);
  • Participant has a history of malignancy associated hypercalcemia; 4. Participant has an active parathyroid disorder, hyperphosphatemia at Screening (serum phosphorus > 1 x ULN), and/or serum calcium (mg/dL) x serum phosphorus (mg/dL) product > 70 at Screening.
  • liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones);
  • Hepatitis serology and viral load will be tested at Screening. Patients who are hepatitis B surface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody positive at Screening must not be enrolled until further definite testing with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) titers is ⁇ 500 lU/mL or HCV ribonucleic acid (RNA) polymerase chain reaction test is negative;
  • HBV hepatitis B virus
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • Lymphoma leukemia, or any malignancy (including malignant glioma or malignant peripheral nerve sheath tumor (MPNST)) within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years;
  • Participant has abnormal QT interval corrected by Fridericia’s formula (> 450 msec for male participants, > 470 msec for female participants, or > 480 msec for participants with bundle branch block) after electrolytes have been corrected (triplicate ECG readings taken 2 to 3 minutes apart and averaged) at Screening;
  • Participant has experienced any of the following within 6 months (24 weeks) of signing informed consent/assent: clinically significant cardiac disease, myocardial infarction, severe/unstable angina, coronary /peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism; 11. Participant has ever had a recorded left ventricular ejection fraction (LVEF) ⁇ 55% as assessed by echocardiogram, OR has a history of congestive heart failure;
  • LVEF left ventricular ejection fraction
  • Participant has a history of, or evidence of, retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration. Participants will be excluded from study participation if they currently are known to have any of the following risk factors for RVO:
  • Participant has a history of glaucoma
  • Participant has a history of a positive human immunodeficiency virus (HIV) antibody test
  • Participant has a known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of mirdametinib (e.g., gastric bypass, lap band, or other gastric procedures). Delivery of mirdametinib via nasogastric tube or gastrostomy tube is not allowed.
  • mirdametinib e.g., gastric bypass, lap band, or other gastric procedures. Delivery of mirdametinib via nasogastric tube or gastrostomy tube is not allowed.
  • NF 1 PN-targeted therapy e.g., MEK inhibitors, farnesyltransferase inhibitors, kinase inhibitors, etc.
  • NF 1 PN-targeted therapy e.g., MEK inhibitors, farnesyltransferase inhibitors, kinase inhibitors, etc.
  • participant enrolls with progression and no associated morbidities NF 1 -targeted therapy must not be administered after the observed progression (Inclusion Criterion 3.1.1). All toxicities from prior therapy must resolve to ⁇ Grade 1 or Baseline;
  • Participant previously received or is currently receiving therapy with mirdametinib; 18. Participant is receiving systemic or ocular glucocorticoid therapy (with the exception of participants with endocrine deficiencies who are allowed to receive physiologic or stress doses of steroids, if necessary) within 14 days prior to first dose of study treatment;
  • Participant has received radiation therapy within the 6 months prior to signing of informed consent/assent. Participants who have received radiation to the orbit at any time are excluded;
  • Participant is unable to tolerate MRI or for whom MRI is contraindicated;
  • Tumor is not able to be reliably evaluated by MRI volumetric analysis
  • Participant with active bacterial, fungal, or viral infection including but not limited to the use of antibiotics, antifungals, or antiviral agents at the time of screening;
  • Participant has experienced other severe acute or chronic medical or psychiatric conditions, including recent (within 1 year of signing informed consent/assent) or active suicidal ideation or behavior, or a laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the participant inappropriate for entry into this study.
  • Pustular rash may be treated with topical clindamycin gel or lotion applied BID.
  • semisynthetic oral tetracyclines such as doxycycline or minocycline may also be useful for older children, adolescents, and adults, but should be avoided in children younger than 8 years old because of risk to tooth development.
  • Eczematous rash/xerosis Eczematous/dry skin rash and other macular (non- acneiform) rash should be treated with a moisturizer such as Cerave or Eucerin or another equivalent product.
  • a low potency topical steroid such as betamethasone valerate lotion (0.05%), desonide cream (0.05%), fluocinolone acetonide solution (0.01%), dexamethasone sodium phosphate cream (0.1%), hydrocortisone acetate cream (1%), methylprednisolone acetate cream (0.25%) or equivalent may also be used if symptomatic.
  • Ketoconazole shampoo should be used for any rash involving the scalp.
  • Paronychia Paronychia if acute and non-surgical (i.e., no fluctuance suggesting an abscess) can resolve with warm soaks only applied 3 to 4 times daily. If there is extensive redness suggesting cellulitis, OR if there is non-surgical paronychia but the participant is a diabetic or is immuno- compromised, then an oral antibiotic that covers Staphylococcus aureus should be started.
  • the choice of antibiotics includes a Staphylococcus aureus covering penicillin/clindamycin/first generation cephalosporin/ Augmentin (amoxicillin and clavulanate).
  • PNs e.g. MEK inhibitors, farnesyltransferase inhibitors, kinase inhibitors, etc.
  • Alternative therapy for the treatment of PNs within 28 days (or 5.5 half-lives, whichever is longer) of first dose of study treatment and throughout the treatment period is prohibited. If participant enrolls with progression and no associated morbidities, NF 1 -targeted therapy must not be administered after the observed progression (Inclusion Criterion 3.1.1) • Medical treatment (e.g. chemotherapy, biologic therapy, radiation therapy) directed towards any NF 1 -related tumor such as optic pathway glioma is prohibited throughout the treatment period.
  • corticosteroids are permissible as premedication for blood product transfusions, or as treatment for an acute allergic reaction or bronchospasm.
  • AUC area under the plasma concentration-time curve
  • AUCinf AUC from dosing extrapolated to infinity
  • AUClast AUC from time zero to last measurable concentration
  • BID twice daily
  • C cycle
  • CES carboxyl esterase enzyme
  • Cmax maximum plasma concentration
  • CV coefficient of variability
  • D day
  • GMR geometric lease squares mean ratio
  • the major efficacy outcome measure was confirmed objective response rate (ORR), defined as the percentage of patients with complete response (disappearance of the target PN) or confirmed partial response (>20% reduction in PN volume confirmed at a subsequent tumor assessment within 2-6 months during the 24-cycle treatment phase).
  • ORR objective response rate
  • Responses were assessed by blinded independent central review (BICR) using volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria.
  • BICR volumetric magnetic resonance imaging
  • REiNS Neurofibromatosis and Schwannomatosis
  • Example 2 Mirdametinib Treatment for NF1 Patients
  • NF1 neurofibromatosis type 1
  • PN plexiform neurofibromas
  • Mirdametinib is available as two dosage forms: capsules (e.g., 1 or 2 mg capsules) or tablets for oral suspension (e.g., 1 mg tablets for oral suspension).
  • Mirdametinib capsules can be swallowed whole.
  • Mirdametinib tablets for oral suspension can be swallowed whole or can be dispersed in drinking water and administered orally as a liquid.
  • the dose of mirdametinib is based on body surface area (BSA) as shown in Table 1 below.
  • the dose of mirdametinib should be modified from that in Table 1 upon adverse reactions as indicated Table 3 below.
  • the reduced dose in Table 3 refers to the reduced dose in Table 2.
  • Mirdametinib can be taken with or without food.
  • Mirdametinib Capsules (for example, each capsule contains 1 mg or 2 mg mirdametinib): Patients are to swallow mirdametinib capsules whole. Do not open, break or chew capsules . Do not administer to patients who are unable to swallow a whole capsule.
  • Mirdametinib tablets for oral suspension for example, each capsule contains 1 mg mirdametinib
  • mirdametinib tablets for oral suspension can be swallowed whole or can be dispersed in drinking water and administered orally as liquid.
  • dosing as an oral suspension, patients are to fully disperse the prescribed number of tablet(s) in a small amount of drinking water (about 5 to 10 mL) in a dosing cup. Gently swirl the liquid until no lumps remain and administer the dose within 30 minutes of preparation. Alternatively, the liquid can be drawn into an oral syringe and administered. After swallowing the suspension from the dosing cup or oral syringe, rinse the dosing cup (or syringe) with an additional small amount of drinking water ( ⁇ 5 to 10 mL) and administer to ensure the full dose is taken. Only use water to prepare the dose.
  • Advise females of reproductive potential to use highly effective contraception during treatment with mirdametinib and for 1 week after the last dose Advise women not to breastfeed during treatment with mirdametinib and for 1 week after the last dose. Advise males with female partners of reproductive potential to use highly effective contraception during treatment with mirdametinib and for 1 week after the last dose.
  • All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

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Abstract

La présente divulgation concerne des méthodes de traitement de certains types de tumeurs ou de cancers, tels que les neurofibromes plexiformes (PN), les neurofibromes plexiformes associées à la neurofibromatose de type 1 (NF1-PN), par administration à un patient en ayant besoin de mirdamétinib ou d'un sel pharmaceutiquement acceptable de celui-ci, tel que selon un certain schéma posologique.
PCT/US2025/033463 2024-06-25 2025-06-13 Schéma posologique pour traitement par mirdamétinib Pending WO2026006011A1 (fr)

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