Treatment of low-level glioma using midametinib

Abstract

The present disclosure relates to a method of treating a patient (e.g., a human patient) having low-grade glioma by administering (e.g., oral) midametinib or a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 321,042, filed on March 17, 2022, the entire contents of which are hereby incorporated by reference. Technical Field

[0002] The present disclosure relates to a method of treating a patient (eg, a human patient) having a low-grade glioma by administering (eg, orally) mirametinib or a pharmaceutically acceptable salt thereof to the patient. Background Art

[0003] Low-grade gliomas are brain tumors that originate from glial cells, which support and nourish neurons in the brain. Glial tumors, or gliomas, are classified into four grades based on how their cells look under a microscope. Grade 1 and 2 gliomas are considered low grade and account for about two-thirds of all pediatric tumors.

[0004] In addition to their grade, low-grade gliomas can be classified based on their location and by the type of glial cell from which they originate (astrocytes, oligodendrocytes, or ependymal cells).

[0005] Low-grade gliomas do not spread outside the brain but instead grow into normal brain tissue and cause symptoms as the tumor grows locally. This can damage connections between normal brain cells and also put pressure on nearby brain tissue. The brain cannot expand when a tumor grows inside the brain because it is confined to the skull. Therefore, even relatively small, slow-growing tumors can cause serious brain problems, especially if the tumor is in a critical area of ​​the brain.

[0006] Low-grade gliomas are slow-growing tumors. As they grow, they can press on surrounding healthy parts of the brain, affecting how well it can function. Therefore, the symptoms of a pediatric low-grade glioma depend on the size of the tumor and where it is in the brain. Some of the most common symptoms of a pediatric low-grade glioma may include:

[0007] Headache, especially in the morning

[0008] Severe or frequent vomiting without other signs of gastrointestinal illness;

[0009] Vision problems, such as double vision, blurred vision, or vision loss;

[0010] Difficulty walking or maintaining balance

[0011] ·epilepsy;

[0012] Weight gain or loss;

[0013] Early puberty;

[0014] ·clumsy;

[0015] confusion; and

[0016] Sleepiness.

[0017] In many people, seizures are the first sign of a low-grade glioma. Other conditions can cause seizures, which are caused by chaotic electrical activity in the brain. Seizures may cause loss of consciousness (passing out), involuntary movements (seizures or fits), and / or loss of total muscle control.

[0018] Robinson et al., Oncogene, 2011, 30(11): 1341-1350, describe mouse and human glioma cells treated with the MEK inhibitor PD0325901.

[0019] Improved treatment approaches for low-grade gliomas are needed. Furthermore, inadequate objective responses and disease recurrence after completion of therapy are common. Summary of the invention

[0020] In one aspect, the present invention relates to a method of treating a low-grade glioma in a patient (e.g., a human patient in need thereof), comprising administering (e.g., orally) midametinib or a pharmaceutically acceptable salt thereof to the patient. In one embodiment, the patient is a pediatric patient.

[0021] In another aspect, the present invention relates to a method for treating one or more symptoms associated with low-grade glioma in a patient (e.g., a human patient in need thereof), comprising administering (e.g., orally) midametinib or a pharmaceutically acceptable salt thereof to the patient. In certain embodiments, one or more symptoms associated with low-grade glioma include, but are not limited to, headache, vomiting, vision problems (such as diplopia, blurred vision, or loss of vision), difficulty walking or maintaining balance, epilepsy, weight gain or loss, premature puberty, clumsiness, confusion, drowsiness, and any combination of any of the foregoing. In one embodiment, the patient is a pediatric patient.

[0022] In some embodiments of any of the methods described herein, the patient has one or more BRAF, MYB, RAF1, NF1, or FGFR1 mutations (such as somatic gene rearrangements of BRAF, MYB, RAF1, NF1, or FGFR1).

[0023] In some embodiments of any of the methods described herein, the patient has a NF1 germline mutation.

[0024] In some embodiments of any of the methods described herein, the patient has metastatic disease.

[0025] In some embodiments of any of the methods described herein, a therapeutically effective amount of midametinib or a pharmaceutically acceptable salt thereof is administered. In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered at about 1 mg / m per day based on midametinib free base. 2 About 10 mg / m 2 The amount of application.

[0026] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof comprises about 0.1 mg / m based on midametinib free base. 2 About 10 mg / m 2 In some embodiments of any of the methods described herein, mirdametinib or a pharmaceutically acceptable salt thereof is administered in a single dosage form comprising about 0.1 mg to about 10 mg based on mirdametinib free base.

[0027] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered twice daily.

[0028] In one embodiment, the patient is orally administered 1 mg / m twice daily. 2 In another embodiment, the patient is orally administered 2.0 mg / m twice daily. 2 In yet another embodiment, the patient is orally administered 2.5 mg / m twice daily. 2 In yet another embodiment, the patient is orally administered 3.0 mg / m twice daily. 2 .

[0029] In one embodiment of any of the methods described herein,

[0030] (a) For a body with a surface area of ​​0.38 m 2 Up to 1.80m 2 Patients between 2 and 3 months old were initially treated with 3.0 mg / m 2 Midametinib twice (ie, a total of 6 mg per day),

[0031] (b) For a body with a surface area of ​​0.44 m 2 Up to 2.22m 2 Patients between 2 and 5 years old were initially treated with 2.0 mg / m2 orally daily. 2 Midametinib twice (ie, 4 mg total per day), and

[0032] (c) For a body with a surface area of ​​0.44 m 2 Up to 3.0m 2 Patients between 1 and 2 months of age were initially treated with 1.0 mg / m 2 Midametinib twice (ie, a total of 2 mg per day).

[0033] In one embodiment of any of the methods described herein,

[0034] (a) For a body surface area not exceeding 0.69 m 2 patients who were initially administered 1 mg of mitrametinib orally twice daily (i.e., a total of 2 mg per day),

[0035] (b) For body surface areas between 0.7 and 1.04 m 2 patients who were initially administered 2 mg of mitrametinib orally twice daily (i.e., a total of 4 mg per day),

[0036] (c) For a body surface area of ​​1.05 to 1.49 m 2 patients who were initially administered 3 mg of midametinib orally twice daily (i.e., a total of 6 mg per day), and

[0037] (d) For a body with a surface area of ​​at least 1.5 m 2 The patients were initially administered 4 mg of mitrametinib orally twice daily (ie, a total of 8 mg per day).

[0038] In another embodiment of any of the methods described herein, for a patient aged 2 to 10 years with a body surface area of ​​no more than 0.69 m 2 In yet another embodiment, for patients aged 2 to 8 years and with a body surface area of ​​no more than 0.69 m 2 In yet another embodiment, for patients aged 2 to 7 years and with a body surface area of ​​no more than 0.69 m 2 In yet another embodiment, for patients aged 2 to 6 years and with a body surface area of ​​no more than 0.69 m 2 In yet another embodiment, for patients aged 2 to 5 years and with a body surface area of ​​no more than 0.69 m 2Patients were initially administered 1 mg of mitrametinib orally twice daily (ie, a total of 2 mg per day).

[0039] In another embodiment of any of the methods described herein, the administered dose is reduced due to an adverse event, wherein the dose is reduced as follows:

[0040] (a) If the dose at the time of the event was 1 mg mitrametinib twice daily, the reduced daily dose was 1 mg mitrametinib in the morning only;

[0041] (b) If the dose at the time of the event was 2 mg mitrametinib twice daily, the reduced daily dose was 2 mg mitrametinib in the morning and 1 mg mitrametinib in the afternoon or evening;

[0042] (c) if the event occurred while taking 3 mg mirametinib twice daily, the reduced daily dose is 2 mg mirametinib twice daily; and

[0043] (d) If the event occurred while taking 4 mg mitramemtinib twice daily, the reduced daily dose will be 3 mg mitramemtinib twice daily.

[0044] In one embodiment, the adverse event leading to dose reduction is acneiform.

[0045] In another embodiment of any of the methods described herein, the method comprises orally administering 1 mg of mirametinib twice daily (ie, a total of 2 mg per day).

[0046] In another embodiment of any of the methods described herein, the maximum daily oral dose administered to the patient is 4 mg mirametinib twice daily (ie, a total of 8 mg per day).

[0047] In one embodiment of any of the methods described herein, about 2 mg / m is orally administered to the patient daily. 2 Midametinib twice.

[0048] In one embodiment of any of the methods described herein, within each four-week period, midametinib is administered for the first three weeks and is discontinued in the last week.

[0049] In some embodiments of any of the methods described herein, mirametinib or a pharmaceutically acceptable salt thereof exhibits high blood-brain barrier penetrability.

[0050] In some embodiments of any of the methods described herein, the patient is a human. In some embodiments of any of the methods described herein, the human is ≥2 and <25 years old.

[0051] In some embodiments of any of the methods described herein, the human has not been previously exposed to a MEK inhibitor.

[0052] In some embodiments of any method described herein, mitrametinib or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments of any method described herein, mitrametinib or a pharmaceutically acceptable salt thereof is dispersible in a drinking liquid or orodispersible in the patient's saliva. In some embodiments of any method described herein, mitrametinib or a pharmaceutically acceptable salt thereof is administered orally in a solid dosage form. In some embodiments of any method described herein, the solid dosage form is a tablet or a capsule. In some embodiments of any method described herein, the solid dosage form is a capsule.

[0053] In some embodiments of any of the methods described herein, mitrametinib or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat low-grade glioma or one or more symptoms associated therewith. In some embodiments of any of the methods described herein, mitrametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat low-grade glioma or one or more symptoms associated therewith. DETAILED DESCRIPTION

[0054] I. definition

[0055] To facilitate understanding of the disclosure described herein, a number of terms are defined below.

[0056] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0057] In this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly indicates otherwise. The term "a" (or "an") and the terms "one or more" and "at least one" may be used interchangeably herein. In some aspects, the term "a" or "an" refers to "single". In other aspects, the term "a" or "an" includes "two or more" or "multiple".

[0058] Furthermore, “and / or” when used herein should be considered as a specific disclosure of each of the two specified features or components, either together or not together with the other. Thus, the term “and / or” as used herein in phrases such as “A and / or B” is meant to include: “both A and B”; “A or B”; “A” (alone); and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0059] The term "midametinib" refers to a single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. Midametinib is an allosteric small molecule that targets mitogen-activated protein kinase kinase (MEK). The teachings about midametinib throughout the specification also apply to pharmaceutically acceptable salts of midametinib.

[0060] The term "mg / m 2 ” refers to mg / m 2 Dose based on patient body surface area.

[0061] The term "subject" refers to an animal, including but not limited to a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to, for example, a mammalian subject, such as a human subject.

[0062] The term "pediatric" refers to human subjects under the age of 21 at the time of treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (from birth to the first 28 days of life); infants (29 days to less than two years); toddlers (two years to less than 12 years); and adolescents (12 to 21 years (up to but not including the twenty-second birthday)). See, e.g., Berhman et al., Textbook of Pediatrics, 15th ed. Philadelphia: WB Saunders Company, 1996; Rudolp et al., Rudolph's Pediatrics, 21st ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd ed. Baltimore: Williams & Wilkins; 1994. In some additional embodiments, the pediatric patient is aged 2 to 21 years, 3 to 21 years, 2 to 16 years, 2 to 15 years, 2 to 8 years, 2 to 7 years, 2 to 6 years, or 2 to 5 years. In particular, younger pediatric patients, such as newborns, infants, and young children, may have difficulty swallowing a capsule or tablet whole.

[0063] As used herein, the term "dispersible" refers to a composition (e.g., tablet, powder, granule, tablet or pill) that disintegrates and / or dissolves when combined with water or another potable liquid (e.g., non-aqueous beverage), or disintegrates and / or dissolves when placed in a subject's mouth with or without agitation or temperature change. In some embodiments, 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 merging with water or another potable liquid. Such disintegration or dissolution need not be complete. For example, a dispersible tablet may be almost completely dissolved, but some undissolved particulate matter may remain.

[0064] The term "orodispersible" refers to a composition that, if administered orally, is capable of dissolving or disintegrating in the mouth of a subject (ie, dissolving or disintegrating in the saliva of a subject) without first having to be dissolved or disintegrated in a separate container.

[0065] As used herein, the terms "treat," "treated," and "treating" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (mitigate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Thus, patients in need of treatment include those who have been diagnosed with or suspected of having the disorder. Beneficial or desired clinical results include, but are not limited to, relief of symptoms; a reduction in the extent of the condition, disorder, or disease; stabilization of the condition, disorder, or disease state (i.e., not worsening); a delay in the onset or slowing of the progression of the condition, disorder, or disease; an improvement or remission (whether partial or complete) of the condition, disorder, or disease state, whether detectable or undetectable; an improvement in at least one measurable physical parameter that is not necessarily discernible by the patient; or an enhancement or improvement of the condition, disorder, or disease. Treatment includes inducing a clinically significant response without undue side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment. The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of, the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0066] In certain aspects, if the patient exhibits one or more of the following, the subject's tumor is successfully "treated" according to the methods described herein: reduction in tumor size; relief of one or more symptoms associated with a specific tumor; reduction in tumor volume; 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), reduction in progressive disease (PD), increased time to progression (TTP), or any combination thereof. In some aspects, nationally or internationally recognized standards for given tumor treatment outcomes can be used to determine whether a therapeutically effective amount of midametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0067] In certain aspects, if the patient exhibits one or more of the following, according to the methods described herein, the subject's cancer (e.g., low-grade glioma) is successfully "treated": tumor volume reduction; relief of one or more symptoms associated with a specified tumor; reduction or complete disappearance of the number of cancer cells; relief of one or more symptoms associated with a specified cancer; reduction of morbidity and mortality; improvement of quality of life; increase progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete remission (CR), minimal residual disease (MRD), partial remission (PR), disease stabilization (SD), disease progression (PD) reduction, progression time (TTP) extension, or any combination thereof. In some embodiments, nationally or internationally recognized standards for given cancer treatment outcomes can be used to determine whether an effective amount of midametinib meets any of these specific endpoints (e.g., CR, PFS, PR).

[0068] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th ed., Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd ed., Ash and Ash, eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson, ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0069] The term "pharmaceutically acceptable salt" refers to relatively nontoxic inorganic and organic acid addition salts of mitrametinib. These salts can be prepared in situ during the administration of the vehicle or the manufacture of the dosage form, or by reacting the purified compound of the present invention in the form of a free base with a suitable organic or inorganic acid alone, and separating the salts formed thereby in the subsequent purification process. Representative salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate and lauryl sulfonate. See, for example, Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, 1-19, 1977.

[0070] Pharmaceutically acceptable salts of Midametinib also include conventional non-toxic salts or quaternary ammonium salts of the compound, such as salts from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; and salts prepared from organic acids, such as, but not limited to, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid.

[0071] The term "about" or "approximately" means the acceptable error of a particular value determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0072] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are used with the clear understanding that they are to be construed as inclusive and not exclusive, and Applicant intends that each of these words be so construed in interpreting this patent, including the appended claims.

[0073] II. Treatment

[0074] Provided herein are methods for treating low-grade gliomas comprising administering mirdametinib or a pharmaceutically acceptable salt thereof to a patient (eg, a human patient in need thereof).

[0075] Provided herein are methods for treating one or more symptoms associated with low-grade gliomas, comprising administering mirdametinib or a pharmaceutically acceptable salt thereof to a patient (eg, a human patient in need thereof).

[0076] In some embodiments of any of the methods described herein, a therapeutically effective amount of mirdametinib or a pharmaceutically acceptable salt thereof is administered.

[0077] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered at about 1 mg / m per day based on midametinib free base. 2 About 10 mg / m 2 , based on midametinib free base, approximately 1.5 mg / m per day 2 To about 9.5mg / m 2 , based on midametinib free base, approximately 2 mg / m per day 2 About 9 mg / m 2 , based on midametinib free base, approximately 2.5 mg / m per day 2 To about 8.5mg / m 2 , based on midametinib free base, approximately 3 mg / m per day 2 About 8 mg / m 2 , based on midametinib free base, approximately 3.5 mg / m per day 2 To about 7.5mg / m 2 , based on midametinib free base, approximately 4 mg / m per day 2 About 7 mg / m 2 , based on midametinib free base, approximately 4.5 mg / m per day 2 To about 6.5mg / m 2 or approximately 5 mg / m2 per day based on midametinib free base 2 About 6 mg / m 2 In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg / m per day based on midametinib free base. 2 , based on midametinib free base, approximately 1.5 mg / m per day 2 , based on midametinib free base, approximately 2 mg / m per day 2 , based on midametinib free base, approximately 2.5 mg / m per day 2 , based on midametinib free base, approximately 3 mg / m per day 2, based on midametinib free base, approximately 3.5 mg / m per day 2 , based on midametinib free base, approximately 4 mg / m per day 2 , based on midametinib free base, approximately 4.5 mg / m per day 2 , based on midametinib free base, approximately 5 mg / m per day 2 , based on midametinib free base, approximately 5.5 mg / m per day 2 , based on midametinib free base, approximately 6 mg / m per day 2 , based on midametinib free base, approximately 6.5 mg / m per day 2 , based on midametinib free base, approximately 7 mg / m per day 2 , based on midametinib free base, approximately 7.5 mg / m per day 2 , based on midametinib free base, approximately 8 mg / m per day 2 , based on midametinib free base, approximately 8.5 mg / m per day 2 , based on midametinib free base, approximately 9 mg / m per day 2 , based on midametinib free base, approximately 9.5 mg / m per day 2 Or about 10 mg / m per day based on midametinib free base 2 The amount of application.

[0078] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof comprises about 0.1 mg / m based on midametinib free base. 2 About 10 mg / m 2 , based on midametinib free base, approximately 0.5 mg / m 2 To about 9.5mg / m 2 , based on midametinib free base, approximately 1 mg / m 2 About 9 mg / m 2 Based on midametinib free base, approximately 1.5 mg / m 2 To about 8.5mg / m 2 , based on midametinib free base, approximately 2 mg / m 2 About 8 mg / m 2 , based on midametinib free base, approximately 2.5 mg / m 2 To about 7.5mg / m 2 , based on midametinib free base, approximately 3 mg / m 2 About 7 mg / m 2 , based on midametinib free base, approximately 3.5 mg / m 2 To about 6.5mg / m 2 , based on midametinib free base, approximately 4 mg / m 2About 6 mg / m 2 or about 4.5 mg / m based on midametinib free base 2 To about 5.5mg / m 2 In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered in an amount comprising about 0.1 mg / m based on midametinib free base. 2 , based on midametinib free base, approximately 0.2 mg / m 2 , based on midametinib free base, approximately 0.3 mg / m 2 , based on midametinib free base, approximately 0.4 mg / m 2 , based on midametinib free base, approximately 0.5 mg / m 2 , based on midametinib free base, approximately 1 mg / m 2 Based on midametinib free base, approximately 1.5 mg / m 2 , based on midametinib free base, approximately 2 mg / m 2 , based on midametinib free base, approximately 2.5 mg / m 2 , based on midametinib free base, approximately 3 mg / m 2 , based on midametinib free base, approximately 3.5 mg / m 2 , based on midametinib free base, approximately 4 mg / m 2 , based on midametinib free base, approximately 4.5 mg / m 2 , based on midametinib free base, approximately 5 mg / m 2 , based on midametinib free base, approximately 5.5 mg / m 2 , based on midametinib free base, approximately 6 mg / m 2 Based on midametinib free base, approximately 6.5 mg / m 2 , based on midametinib free base, approximately 7 mg / m 2 Based on midametinib free base, approximately 7.5 mg / m 2 , based on midametinib free base, approximately 8 mg / m 2 Based on midametinib free base, approximately 8.5 mg / m 2 , based on midametinib free base, approximately 9 mg / m 2 , based on midametinib free base, approximately 9.5 mg / m 2 or about 10 mg / m based on midametinib free base 2 A single dosage form is administered.

[0079] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered once, twice, three times, or four times a day. In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered twice a day.

[0080] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered at about 0.5 mg / m based on midametinib free base. 2 About 10 mg / m 2 , based on midametinib free base, approximately 1 mg / m 2 To about 9.5mg / m 2 Based on midametinib free base, approximately 1.5 mg / m 2 About 9 mg / m 2 , based on midametinib free base, approximately 2 mg / m 2 To about 8.5mg / m 2 , based on midametinib free base, approximately 2.5 mg / m 2 About 8 mg / m 2 , based on midametinib free base, approximately 3 mg / m 2 To about 7.5mg / m 2 , based on midametinib free base, approximately 3.5 mg / m 2 About 7 mg / m 2 , based on midametinib free base, approximately 4 mg / m 2 To about 6.5mg / m 2 , based on midametinib free base, approximately 4.5 mg / m 2 About 6 mg / m 2 or about 5 mg / m based on midametinib free base 2 About 6 mg / m 2 In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 0.5 mg / m based on midametinib free base. 2 , based on midametinib free base, approximately 1 mg / m 2 Based on midametinib free base, approximately 1.5 mg / m 2 , based on midametinib free base, approximately 2 mg / m 2 , based on midametinib free base, approximately 2.5 mg / m 2 , based on midametinib free base, approximately 3 mg / m 2 , based on midametinib free base, approximately 3.5 mg / m 2, based on midametinib free base, approximately 4 mg / m 2 , based on midametinib free base, approximately 4.5 mg / m 2 , based on midametinib free base, approximately 5 mg / m 2 , based on midametinib free base, approximately 5.5 mg / m 2 , based on midametinib free base, approximately 6 mg / m 2 Based on midametinib free base, approximately 6.5 mg / m 2 , based on midametinib free base, approximately 7 mg / m 2 Based on midametinib free base, approximately 7.5 mg / m 2 , based on midametinib free base, approximately 8 mg / m 2 Based on midametinib free base, approximately 8.5 mg / m 2 , based on midametinib free base, approximately 9 mg / m 2 , based on midametinib free base, approximately 9.5 mg / m 2 or about 10 mg / m based on midametinib free base 2 The amount is applied twice daily.

[0081] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered as midametinib free base.

[0082] In one aspect, the invention relates to a method for treating a low-grade glioma in a patient (eg, a patient in need thereof), comprising administering midametinib free base to the patient.

[0083] In some embodiments of any of the methods described herein, a therapeutically effective amount of midametinib free base is administered.

[0084] In some embodiments of any of the methods described herein, midametinib free base is administered at about 1 mg / m per day. 2 About 10 mg / m 2 , about 1.5 mg / m per day 2 To about 9.5mg / m 2 , about 2 mg / m per day 2 About 9 mg / m 2 , about 2.5 mg / m per day 2 To about 8.5mg / m 2 , about 3 mg / m per day 2 About 8 mg / m 2 , about 3.5 mg / m per day 2 To about 7.5mg / m 2 , about 4 mg / m per day 2 About 7 mg / m2 , about 4.5 mg / m per day 2 To about 6.5mg / m 2 or about 5 mg / m per day 2 About 6 mg / m 2 In some embodiments of any of the methods described herein, midametinib free base is administered at about 1 mg / m per day. 2 , about 1.5 mg / m per day 2 , about 2 mg / m per day 2 , about 2.5 mg / m per day 2 , about 3 mg / m per day 2 , about 3.5 mg / m per day 2 , about 4 mg / m per day 2 , about 4.5 mg / m per day 2 , about 5 mg / m per day 2 , about 5.5 mg / m per day 2 , about 6 mg / m per day 2 , about 6.5 mg / m per day 2 , about 7 mg / m per day 2 , about 7.5 mg / m per day 2 , about 8 mg / m per day 2 , about 8.5 mg / m per day 2 , about 9 mg / m per day 2 , about 9.5 mg / m per day 2 or about 10 mg / m per day 2 The amount of application.

[0085] In some embodiments of any of the methods described herein, midametinib free base is present in an amount comprising about 0.1 mg / m 2 About 10 mg / m 2 , about 0.5mg / m 2 To about 9.5mg / m 2 , about 1mg / m 2 About 9 mg / m 2 , about 1.5mg / m 2 To about 8.5mg / m 2 , about 2mg / m 2 About 8 mg / m 2 , about 2.5mg / m 2 To about 7.5mg / m 2 , about 3mg / m 2 About 7 mg / m 2 , about 3.5mg / m 2 To about 6.5mg / m 2 , about 4mg / m 2 About 6 mg / m2 or about 4.5 mg / m 2 To about 5.5mg / m 2 In some embodiments of any of the methods described herein, midametinib free base is administered in a single dosage form comprising about 0.1 mg / m 2 , about 0.2mg / m 2 , about 0.3mg / m 2 , about 0.4mg / m 2 , about 0.5mg / m 2 , about 1mg / m 2 , about 1.5mg / m 2 , about 2mg / m 2 , about 2.5mg / m 2 , about 3mg / m 2 , about 3.5mg / m 2 , about 4mg / m 2 , about 4.5mg / m 2 , about 5mg / m 2 , about 5.5mg / m 2 , about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2 , about 8.5mg / m 2 , about 9mg / m 2 , about 9.5mg / m 2 or about 10 mg / m 2 A single dosage form is administered.

[0086] In some embodiments of any of the methods described herein, midametinib free base is administered once, twice, three times, or four times per day. In some embodiments of any of the methods described herein, midametinib free base is administered once per day. In some embodiments of any of the methods described herein, midametinib free base is administered twice per day.

[0087] In some embodiments of any of the methods described herein, midametinib free base is administered at about 0.5 mg / m 2 About 10 mg / m 2 , about 1mg / m 2 To about 9.5mg / m 2 , about 1.5mg / m 2 About 9 mg / m 2 , about 2mg / m 2 To about 8.5mg / m 2 , about 2.5mg / m 2About 8 mg / m 2 , about 3mg / m 2 To about 7.5mg / m 2 , about 3.5mg / m 2 About 7 mg / m 2 , about 4mg / m 2 To about 6.5mg / m 2 , about 4.5mg / m 2 About 6 mg / m 2 or 5 mg / m 2 About 6 mg / m 2 In some embodiments of any of the methods described herein, midametinib free base is administered at about 0.5 mg / m 2 , about 1mg / m 2 , about 1.5mg / m 2 , about 2mg / m 2 , about 2.5mg / m 2 , about 3mg / m 2 , about 3.5mg / m 2 , about 4mg / m 2 , about 4.5mg / m 2 , about 5mg / m 2 , about 5.5mg / m 2 , about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2 , about 8.5mg / m 2 , about 9mg / m 2 , about 9.5mg / m 2 or about 10 mg / m 2 The amount is applied twice daily.

[0088] In some embodiments of any of the methods described herein, mirametinib or a pharmaceutically acceptable salt thereof exhibits high blood-brain barrier penetrability.

[0089] In some embodiments of any of the methods described herein, the patient is a human.

[0090] In some embodiments of any of the methods described herein, the human is ≥2 and <25 years old.

[0091] In some embodiments of any of the methods described herein, the human has not been previously exposed to a MEK inhibitor. In some embodiments of any of the methods described herein, the human has not responded to previous treatment with one or more MEK inhibitors.

[0092] In some embodiments of any of the methods described herein, mitrametinib or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments of any of the methods described herein, mitrametinib or a pharmaceutically acceptable salt thereof is administered orally in a solid dosage form. In some embodiments of any of the methods described herein, the solid dosage form is a tablet or a capsule. In some aspects, the solid dosage form is a capsule. In some embodiments of any of the methods described herein, mitrametinib or a pharmaceutically acceptable salt thereof can be dispersed in a drinking liquid or can be orally dispersed in the patient's saliva.

[0093] In some embodiments of any of the methods described herein, midametinib or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat low-grade glioma or a symptom thereof.

[0094] In some embodiments of any of the methods described herein, mirdametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat low-grade glioma or a symptom thereof.

[0095] Example

[0096] Example 1: Single-dose sera for the treatment of children, adolescents and young adults with low-grade glioma (LGG) Dosage of mitrametinib (a brain-penetrant MEK1 / 2 inhibitor) I / II

[0097] Period Evaluation

[0098] A multi-arm phase I / II trial of midametinib is currently underway in patients with LGG aged ≥2 years and <25 years. Phase I requires participants to have no prior exposure to MEK inhibitors and to have recurrent / progressive disease with biopsy-proven evidence of MAPK pathway activation. Using a rolling 6 design, three escalating dose levels (2 mg / m 2 / dose BID, 2.5mg / m 2 / dose BID and 3mg / m 2 / dose BID).

[0099] The median age of patients enrolled in the study was 10 years (range, 3-21 years). Ten patients had somatic gene rearrangements (7BRAF, 1MYB, 1RAF1, 1FGFR1); 1 patient had a germline NF1 mutation; and 3 patients had metastatic disease. Dose level 1 (2 mg / m 2 ) did not cause dose-limiting toxicity, while dose level 2 (2.5 mg / m 2 ) data are not yet determined. Only grade 1 and 2 treatment-related adverse events were observed. No MEK-related retinopathy or heart disease was observed. Of the six patients who completed at least one follow-up disease assessment, four had a mild response (>25%-<50% reduction). No disease progression occurred.

[0100] Of the 11 patients with somatic gene rearrangements or NF1, 4 with BRAF and 1 with FGFR1 received 2 mg / m 2 The remaining 11 patients (3 BRAF, 1 MYB, 1 NF1, and 1 RAF1) received 2.5 mg / m 2 The results for the specific cut-off dates are shown in Table 1 below.

[0101] Table 1

[0102]

[0103] PR = 50%-75% reduction in tumor size; MR = 25%-50% reduction; SD - tumor size is stable or reduced by up to 25%.

[0104] To date, midametinib has been well tolerated and clinically promising when administered continuously in patients with recurrent / progressive pediatric LGG (pLGG).

[0105] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference in their entirety, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. When a term in this application is found to have a different definition in a document incorporated herein by reference, the definition provided herein serves as the definition of that term.

[0106] Although the invention has been described in conjunction with specific aspects thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any changes, uses or modifications following these principles in general, including such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains, and which may be applied to the essential features set forth above and which follow within the scope of the claims.

Claims

1. A method for treating low-grade glioma in a patient in need thereof, comprising administering to the patient midametinib or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the patient has one or more BRAF, MYB, RAF1 or FGFR1 mutations.

3. The method of claim 1 or 2, wherein a therapeutically effective amount of mirdametinib or a pharmaceutically acceptable salt thereof is administered.

4. The method of claim 1, wherein the dosage of midametinib or a pharmaceutically acceptable salt thereof is about 1 mg / m per day based on midametinib free base. 2 About 10 mg / m 2 Oral administration of the amount.

5. The method of any one of claims 1 to 3, wherein the dosage of midametinib or a pharmaceutically acceptable salt thereof is about 4 mg / m per day based on midametinib free base. 2 Oral administration of the amount.

6. The method of any one of claims 1 to 3, wherein the dosage of midametinib or a pharmaceutically acceptable salt thereof is about 5 mg / m per day based on midametinib free base. 2 Oral administration of the amount.

7. The method of any one of claims 1 to 3, wherein the dosage of midametinib or a pharmaceutically acceptable salt thereof is about 6 mg / m per day based on midametinib free base. 2 Oral administration of the amount.

8. The method of any one of claims 1 to 7, wherein the mirdametinib or a pharmaceutically acceptable salt thereof is orally administered once daily.

9. The method of any one of claims 1 to 7, wherein the mirdametinib or a pharmaceutically acceptable salt thereof is orally administered twice daily.

10. The method of any one of claims 1 to 3, wherein the amount of midametinib or a pharmaceutically acceptable salt thereof is about 2 mg / m based on midametinib free base. 2 The amount was administered orally twice daily.

11. The method of any one of claims 1 to 3, wherein the dosage of midametinib or a pharmaceutically acceptable salt thereof is about 2.5 mg / m based on midametinib free base. 2 The amount was administered orally twice daily.

12. The method of any one of claims 1 to 3, wherein the amount of midametinib or a pharmaceutically acceptable salt thereof is about 3 mg / m based on midametinib free base. 2 The amount was administered orally twice daily.

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

14. The method of any one of claims 1 to 3, wherein (a) For a body with a surface area of ​​0.38 m 2 Up to 1.80m 2 Patients between 2 and 3 months old were initially treated with 3.0 mg / m2 of oral administration daily. 2 Midametinib twice, (b) For a body with a surface area of ​​0.44 m 2 Up to 2.22m 2 Patients between 2 and 5 years old were initially treated with 2.0 mg / m2 orally daily. 2 Midametinib twice, and (c) For a body with a surface area of ​​0.44 m 2 Up to 3.0m 2 Patients between 1 and 2 months of age were initially treated with 1.0 mg / m 2 Midametinib twice.

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

16. The method of claim 15, wherein the adverse event leading to the dose reduction is acneiform.

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

18. The method of any of the preceding claims, wherein the patient is ≥2 and <25 years old.

19. The method of any one of claims 1 to 17, wherein the patient is between 2 and 21 years old.

20. The method of any one of claims 1 to 17, wherein the patient is a pediatric patient.

21. The method of any one of claims 1 to 17, wherein the patient is between 2 and 15 years old.

22. The method of any one of the preceding claims, wherein the human has not been previously exposed to a MEK inhibitor.

23. The method of any one of the preceding claims, wherein the mirdametinib or a pharmaceutically acceptable salt thereof is administered as a monotherapy to treat the low-grade glioma.

24. The method of any one of claims 1 to 22, wherein the mirdametinib or a pharmaceutically acceptable salt thereof is administered in combination with another active ingredient and / or surgery to treat the low-grade glioma.

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