Ripretinib for Treating Melanoma

Abstract

The present disclosure relates to a method of treating melanoma in a patient in need thereof, the method comprising administering to the subject a therapeutically effective amount of ripretinib, or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] (cross reference) This application claims priority to U.S. Provisional Patent Application No. 63 / 187,903, filed May 12, 2021, U.S. Provisional Patent Application No. 63 / 231,384, filed August 10, 2021, and U.S. Provisional Patent Application No. 63 / 313,570, filed February 24, 2022, the contents of each of which are incorporated by reference in their entirety herein. [Background technology]

[0002] c-KIT (also known as KIT, CD117, and stem cell factor receptor) is a 145 kDa transmembrane tyrosine kinase protein that acts as a type III receptor. The c-KIT proto-oncogene, located on chromosome 4q11-21, encodes the c-KIT receptor, whose ligands are stem cell factor (SCF), hematopoietic stem cell factor, kit ligand, and mast cell growth factor). The receptor has tyrosine protein kinase activity, and binding of the ligand SCF leads to autophosphorylation of c-KIT and association of c-KIT with substrates such as phosphatidylinositol 3-kinase (PI3K), which activates the PI3K / AKT signaling pathway and also the RAS / MAPK signaling pathway through RAF, MEK, and ERK kinases. Oncogenic mutations in cKIT or overexpression of wild-type KIT result in dysregulation of KIT signaling, allowing uncontrolled activation of cKIT independent of control by activating ligands such as SCF. Tyrosine phosphorylation by protein tyrosine kinases is particularly important in cell signaling and can mediate signals for key intracellular processes such as proliferation, survival, differentiation, apoptosis, adhesion, invasion, and migration. Deficiency of c-KIT is the cause of focal albinism, an autosomal dominant inherited developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. Activating mutations in the receptor tyrosine kinase KIT have been identified in multiple cancer types, including melanoma. Furthermore, aberrant wild-type KIT overexpression is found in melanoma.

[0003] There is a need for therapeutic agents that can broadly inhibit clinically relevant KIT mutations for the treatment of melanoma. Summary of the Invention

[0004] Described herein is a method of treating melanoma in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of ripretinib, or a pharma- ceutical acceptable salt thereof.

[0005] In one embodiment, described herein is a method of treating KIT-driven melanoma in a patient in need of such treatment, comprising orally administering to the patient between 100 mg and 600 mg of ripretinib daily.

[0006] In another embodiment, described herein is a method of treating KIT-driven melanoma in a patient in need of such treatment, comprising orally administering to the patient one or more tablets containing between 100 mg and 600 mg of ripretinib daily.

[0007] In another embodiment, described herein is a method of treating KIT-driven melanoma in a patient in need of such treatment, comprising orally administering to the patient between 100 mg and 600 mg of ripretinib daily, wherein the patient has not previously been administered one or more tyrosine kinase inhibitors prior to administration of ripretinib.

[0008] In another embodiment, described herein is a method of treating KIT-driven melanoma in a patient in need of such treatment, comprising orally administering to the patient between 100 mg and 600 mg of ripretinib daily, wherein the patient has previously been administered at least one tyrosine kinase inhibitor prior to administration of ripretinib.

[0009] In one embodiment, described herein is a method of treating KIT-driven melanoma in a patient in need of such treatment, comprising orally administering to the patient daily one or more tablets each containing ripretinib (e.g., tablets each containing 50 mg to 100 mg of ripretinib), wherein the patient has previously been administered at least one tyrosine kinase inhibitor prior to administration of ripretinib.

[0010] In one embodiment, described herein is a method of treating melanoma in a patient in need of such treatment, comprising orally administering to the patient 100 mg to 600 mg of ripretinib daily and one or more additional therapeutic agents. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows an exemplary plot of survival probability for progression-free survival (PFS) for KIT-driven melanoma patients receiving ripretinib treatment. [Diagram 2] FIG. 2 shows an exemplary plot depicting progression-free survival (PFS) between previously TKI-naive (non-TKI) and previously TKI-treated (TKI) ripretinib-treated KIT-driven melanoma patients. [Diagram 3] FIG. 3 shows the duration of treatment with ripretinib in melanoma patients in the study of Example 1. [Figure 4] Figure 4 shows the best overall response in individual patients after ripretinib treatment and the respective percentage change in target lesions from baseline from the study in Example 1. Abbreviations: PD: progressive disease, SD: stable disease, PR: partial response, CR: complete response. [Diagram 5] FIG. 5 shows spider plots of target lesion changes in individual patients with respect to treatment period from the study of Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The features and other details of the present disclosure will now be described in more detail.Specific terms employed in this specification, examples and appended claims are summarized here.These definitions should be read in light of the remaining parts of this disclosure as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0013] definition "Ripretinib," as used herein, is a compound represented by the following structure: [ka]

[0014] As used herein, "Compound A" is a compound represented by the following structure: [ka]

[0015] "Individual", "patient" or "subject" are used interchangeably herein and include any animal, including mammals, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans. The compounds described herein can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, such as pets (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the methods described herein is preferably a mammal (e.g., a human) for which treatment of a disorder described herein is desired.

[0016] As used herein, the term "pharmaceutical acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids which may be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0017] As used herein, "treating" includes any effect, eg, attenuation, reduction, modulation, or elimination, that results in the improvement of a condition, disease, disorder, or the like.

[0018] "Therapeutically effective amount" includes the amount of the subject compound that induces the biological or medical response of a tissue, system, animal or human that is desired by a researcher, veterinarian, physician or other clinician. The compounds described herein, such as ripretinib, are administered in a therapeutically effective amount to treat the conditions described herein, such as melanoma. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or prophylactic effect, such as an amount that results in the prevention or reduction of symptoms associated with a condition.

[0019] As used herein, "AUC 0-24h " refers to the area under the plasma concentration-time curve from time 0 to 24 hours for the compounds described herein. As used herein, "AUC0-inf " refers to the area under the plasma concentration-time curve from time 0 to infinity for the compounds described herein. max " refers to the maximum plasma concentration of the compounds described herein.

[0020] The compounds described herein, such as ripretinib, can be formulated as pharmaceutical compositions using pharma- ceutically acceptable carriers and can be administered by a variety of routes. In some embodiments, such compositions are for oral administration. In some embodiments, compositions formulated for oral administration are provided as tablets. In some embodiments, such compositions are for parenteral (by injection) administration (e.g., compositions formulated for local injection at the site of a tumor, such as diffuse giant cell tumor). In some embodiments, such compositions are for transdermal administration. In some embodiments, such compositions are for topical administration. In some embodiments, such compositions are for intravenous (IV) administration. In some embodiments, such compositions are for intramuscular (IM) administration. Such pharmaceutical compositions and the processes for their preparation are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro et al., eds., 19th ed., Mack Publishing Co., 1995).

[0021] "Combination therapy" is a treatment that includes administration of two or more therapeutic agents to a patient. The two or more therapeutic agents may be delivered simultaneously (e.g., in separate pharmaceutical compositions or in the same pharmaceutical composition), or the two or more therapeutic agents may be delivered at different times. For example, the two or more therapeutic agents may be delivered simultaneously or during overlapping periods of time, and / or one therapeutic agent may be delivered before or after the other therapeutic agent. Combination therapy treatment may include treatment with either single agent preceded or followed by a period of simultaneous treatment with both agents. However, it is intended that an effective amount of the two or more therapeutic agents will be present in the patient's body during some period of time.

[0022] Treatment method Described herein is a method for treating KIT-driven melanoma in a patient who needs to treat KIT-driven melanoma.In one embodiment, provided herein is a method for treating a patient suffering from melanoma, comprising administering to the patient a therapeutically effective amount of ripretinib or its pharmaceutically acceptable salt.

[0023] The melanoma described herein may be cutaneous or non-cutaneous melanoma. In some embodiments, the melanoma described herein is cutaneous melanoma. In some embodiments, the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, amelanotic and desmoplastic melanoma. In some embodiments, the melanoma described herein is non-cutaneous (non-skin) melanoma. In some embodiments, the non-cutaneous melanoma is selected from intraocular melanoma or mucosal melanoma. In some embodiments, the non-cutaneous melanoma is intraocular melanoma. In some embodiments, the non-cutaneous melanoma is mucosal melanoma. In some embodiments, the melanoma described herein is acral lentiginous melanoma. In some embodiments, the melanoma described herein is associated with chronic sun damage of the patient's skin.

[0024] In one embodiment, the disclosure provides a method of treating melanoma in a patient in need thereof, the method comprising, for example, orally administering to the patient 100 mg or more of ripretinib daily, for example 100 mg to 5000 mg, for example 100 mg to 600 mg, for example 100 mg to 500 mg, for example 100 mg to 300 mg, for example 100 mg to 250 mg, for example 150 mg. In some embodiments, the melanoma is a KIT-activated melanoma. In some embodiments, the KIT-activated melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation. In some embodiments, after at least one 42-28 day cycle, the patient has a progression-free survival as measured using RECIST 1.1. In some embodiments, the method comprises administering to the patient 110 mg of ripretinib daily. In some embodiments, the method comprises administering 120 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 130 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 140 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 400 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient daily.In some embodiments, the method comprises administering 650 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 800 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 850 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 1000 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 150 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 200 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 400 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 800 mg of ripretinib to the patient once daily.In some embodiments, the method comprises administering 850 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 1000 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 150 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 200 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 250 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 300 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 350 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 400 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 450 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 500 mg of ripretinib twice daily to the patient.

[0025] In one embodiment, the disclosure provides a method of treating melanoma in a patient in need of treatment thereof, the method comprising, for example, orally administering to the patient 100 mg or more of ripretinib daily, for example 100 mg to 5000 mg, for example 100 mg to 600 mg, for example 100 mg to 500 mg, for example 100 mg to 300 mg, for example 100 mg to 250 mg, for example 150 mg. In some embodiments, the melanoma is KIT-driven melanoma. In some embodiments, the KIT-driven melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation. In some embodiments, the KIT-driven melanoma is caused by overexpression of wild-type KIT. In some embodiments, after at least one 28-day cycle, the patient has progression-free survival as measured using RECIST 1.1. In some embodiments, the method comprises administering 110 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 120 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 130 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 140 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 400 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient daily.In some embodiments, the method comprises administering 600 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 800 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 850 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 1000 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 400 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient once daily.In some embodiments, the method comprises administering 800 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 850 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 1000 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient twice daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient twice daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient twice daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient twice daily. In some embodiments, the method comprises administering 350 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 400 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 450 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 500 mg of ripretinib twice daily to the patient.

[0026] In one embodiment, a method of treating a patient suffering from melanoma is contemplated, comprising orally administering to the patient 100 mg or more of ripretinib daily, for example up to about 600 mg, for example 100 mg to 250 mg, for example 100 mg to 500 mg, for example 100 mg to 300 mg, for example 100 mg to 250 mg, for example 150 mg, and the patient has previously been administered at least one tyrosine kinase inhibitor. In some embodiments, the melanoma is KIT-driven melanoma. In some embodiments, the KIT-activated melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation. In some embodiments, the KIT-driven melanoma is caused by overexpression of wild-type KIT. In some embodiments, the at least one previously administered tyrosine kinase inhibitor is selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, avapritinib, AZD3229, and pharma- ceutically acceptable salts thereof. In some embodiments, the patient has previously administered two, three, four, or five distinct tyrosine kinase inhibitors. In some embodiments, after at least one 28-day cycle, the patient has a progression-free survival measured using RECIST 1.1. In some embodiments, the method comprises administering 110 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 120 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 130 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 140 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient daily.In some embodiments, the method comprises administering 400 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 800 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 850 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 1000 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 100 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 400 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient once daily.In some embodiments, the method comprises administering 550 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 800 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 850 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 1000 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 150 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 200 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 250 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 300 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 350 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 400 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 450 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 500 mg of ripretinib twice daily to the patient.

[0027] In one embodiment, a method of treating a patient suffering from melanoma is contemplated, comprising orally administering to the patient 100 mg or more of ripretinib daily, for example up to about 600 mg, for example 100 mg to 250 mg, for example 100 mg to 500 mg, for example 100 mg to 300 mg, for example 100 mg to 250 mg, for example 150 mg, wherein the patient has not previously been administered one or more tyrosine kinase inhibitors. In some embodiments, the melanoma is KIT-driven melanoma. In some embodiments, the KIT-activated melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation. In some embodiments, the KIT-driven melanoma is caused by overexpression of wild-type KIT. In some embodiments, the at least one previously administered tyrosine kinase inhibitor is selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, avapritinib, AZD3229, and pharma- ceutically acceptable salts thereof. In some embodiments, the patient has previously administered two, three, four, or five distinct tyrosine kinase inhibitors. In some embodiments, after at least one 28-day cycle, the patient has a progression-free survival measured using RECIST 1.1. In some embodiments, the method comprises administering 110 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 120 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 130 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 140 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient daily.In some embodiments, the method comprises administering 400 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 800 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 850 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 1000 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 100 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 400 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient once daily.In some embodiments, the method comprises administering 550 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 800 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 850 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 1000 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 150 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 200 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 250 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 300 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 350 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 400 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 450 mg of ripretinib twice daily to the patient. In some embodiments, the method comprises administering 500 mg of ripretinib twice daily to the patient.

[0028] In one embodiment, the patient is orally administered one or more tablets comprising ripretinib. For example, the disclosed methods include a method of treating melanoma in a patient in need of treatment for melanoma, comprising orally administering to the patient one or more tablets comprising ripretinib, for example, tablets each comprising 50 mg to 100 mg of ripretinib, daily. In some embodiments, the melanoma is a KIT-activated melanoma. In some embodiments, the KIT-driven melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation. In some embodiments, the KIT-driven melanoma is caused by overexpression of wild-type KIT. In some embodiments, after at least one 28-day cycle, the patient has a progression-free survival as measured using RECIST 1.1. In some embodiments, the method comprises orally administering to the patient one tablet comprising ripretinib. In some embodiments, the method comprises orally administering to the patient one tablet comprising 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient one tablet containing 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient two tablets each containing 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient two tablets each containing 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient three tablets each containing 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient three tablets each containing 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient four tablets each containing 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient four tablets each containing 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient five tablets each containing 50 mg of ripretinib. In some embodiments, the methods involve orally administering to the patient five tablets each containing 50 mg of ripretinib once daily.In some embodiments, the method comprises orally administering to the patient six tablets each containing 50 mg of ripretinib.In some embodiments, the method comprises orally administering to the patient six tablets each containing 50 mg of ripretinib once daily.

[0029] In one embodiment, provided is a method of treating melanoma in a patient in need thereof, comprising orally administering to the patient one or more tablets each containing ripretinib (e.g., tablets each containing 50 mg to 100 mg of ripretinib) daily, wherein the patient has previously been administered at least one tyrosine kinase inhibitor prior to administration of ripretinib. In some embodiments, the melanoma is KIT-driven melanoma. In some embodiments, the KIT-driven melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation. In some embodiments, the KIT-driven melanoma is caused by overexpression of wild-type KIT. In some embodiments, after at least one 28-day cycle, the patient has progression-free survival as measured using RECIST 1.1. In some embodiments, the at least one previously administered tyrosine kinase inhibitor is selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, avapritinib, AZD3229, and pharma- ceutically acceptable salts thereof. In some embodiments, the patient has previously administered two, three, four, or five distinct tyrosine kinase inhibitors. In some embodiments, the method comprises orally administering to the patient one tablet comprising ripretinib. In some embodiments, the method comprises orally administering to the patient one tablet comprising 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient one tablet comprising 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient two tablets each comprising 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient two tablets each comprising 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient three tablets each containing 50 mg of ripretinib.In some embodiments, the method comprises orally administering to the patient three tablets each containing 50 mg of ripretinib once daily.

[0030] In another embodiment, described herein is a method of treating melanoma in a patient in need of treatment thereof, comprising orally administering to the patient 100 mg to 600 mg of ripretinib daily and one or more additional therapeutic agents. In some embodiments, the melanoma is KIT-driven melanoma. In some embodiments, the KIT-driven melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation. In some embodiments, the KIT-driven melanoma has a baseline genomic abnormality that causes overexpression of wild-type KIT. In some embodiments, after at least one 42-28 day cycle, the patient has a progression-free survival as measured using RECIST 1.1. In some embodiments, the patient has previously been administered at least one tyrosine kinase inhibitor prior to receiving ripretinib. In some embodiments, the at least one previously administered tyrosine kinase inhibitor is selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, avapritinib, and pharma- ceutically acceptable salts thereof. In some embodiments, the patient has previously been administered two, three, four, or five distinct tyrosine kinase inhibitors. In some embodiments, the method comprises orally administering to the patient one tablet comprising ripretinib. In some embodiments, the method comprises orally administering to the patient one tablet comprising 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient one tablet comprising 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient two tablets each comprising 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient two tablets each comprising 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient three tablets each containing 50 mg of ripretinib.In some embodiments, the method comprises orally administering to the patient three tablets each containing 50 mg of ripretinib once daily.

[0031] In another embodiment, described herein is a method of treating melanoma in a patient in need of treatment thereof, comprising orally administering to the patient 100 mg to 600 mg of ripretinib daily and one or more additional therapeutic agents. In some embodiments, the melanoma is a KIT-driven melanoma. In some embodiments, the KIT-driven melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation. In some embodiments, the KIT-driven melanoma has a baseline genomic abnormality that causes overexpression of wild-type KIT. In some embodiments, after at least one 28-day cycle, the patient has a progression-free survival as measured using RECIST 1.1. In some embodiments, the patient was previously administered at least one tyrosine kinase inhibitor prior to receiving ripretinib. In some embodiments, the at least one previously administered tyrosine kinase inhibitor is selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, avapritinib, and pharma- ceutically acceptable salts thereof. In some embodiments, the patient has previously been administered two, three, four, or five distinct tyrosine kinase inhibitors. In some embodiments, the method comprises orally administering to the patient one tablet comprising ripretinib. In some embodiments, the method comprises orally administering to the patient one tablet comprising 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient one tablet comprising 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient two tablets each comprising 50 mg of ripretinib. In some embodiments, the method comprises orally administering to the patient two tablets each comprising 50 mg of ripretinib once daily. In some embodiments, the method comprises orally administering to the patient three tablets each containing 50 mg of ripretinib.In some embodiments, the method comprises orally administering to the patient three tablets each containing 50 mg of ripretinib once daily.

[0032] In some embodiments, if the patient suffers from Grade 3 palmar-plantar erythrodysesthesia syndrome after administration of ripretinib, the method further comprises a) withholding administration of ripretinib for at least 7 days or until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome, and then administering 100 mg daily (e.g., 100 mg once daily) of ripretinib to the patient for at least 28 days.

[0033] In some embodiments, if the patient suffers from Grade 2 palmar-plantar erythrodysesthesia syndrome after administration of ripretinib, the method further comprises: a) withholding administration of ripretinib until the patient has palmar-plantar erythrodysesthesia syndrome of Grade 1 or less or baseline; b) if the patient recovers from palmar-plantar erythrodysesthesia syndrome within 7 days of withholding administration, then administering 150 mg of ripretinib daily to the patient; or c) if the patient has not recovered, then administering 100 mg of ripretinib daily to the patient for at least 28 days.

[0034] In another embodiment, described herein is a method for achieving progression-free survival of at least 5 months as determined by RECIST 1.1 in patients with melanoma, comprising orally administering 100, 150, 200, or 300 mg of ripretinib daily or twice daily for at least 28 days. In some embodiments, the patient has been administered at least one previous kinase inhibitor. In some embodiments, the patient has been administered at least three previous kinase inhibitors. In some embodiments, the at least one previous kinase inhibitor is imatinib. In some embodiments, the patient has been administered at least 100, 150, or 200 mg of ripretinib daily or twice daily for at least 4 months.

[0035] In another embodiment, described herein is a method for achieving progression-free survival of at least 5 months as determined by RECIST 1.1 in patients with melanoma, comprising orally administering 100, 150, or 200 mg of ripretinib to the patient daily or twice daily for at least 28 days. In some embodiments, the patient has not received a previous kinase inhibitor. In some embodiments, the patient has received at least one previous kinase inhibitor. In some embodiments, the patient has received at least three previous kinase inhibitors. In some embodiments, the at least one previous kinase inhibitor is imatinib. In some embodiments, the patient has orally administered 100, 150, or 200 mg of ripretinib to the patient daily or twice daily for at least 4 months.

[0036] In another embodiment, described herein is a method of treating melanoma in a patient in need of such treatment, wherein the patient is being concomitantly treated with a CYP3A4 inhibitor, the method comprising orally administering to the patient 100 mg or 150 mg of ripretinib, or a pharma- ceutical acceptable salt thereof, once or twice daily, wherein the patient has an 80% or greater area under the curve (AUC) following administration of ripretinib and a CYP3A4 inhibitor compared to administration of ripretinib without concomitant treatment with a CYP3A4 inhibitor. 0-inf) providing an increased ripretinib area in the bloodstream and thus the patient is at higher risk for an adverse event, and monitoring the patient more frequently for adverse events as compared to patients not treated with a CYP3A4 inhibitor. In some embodiments, if the patient suffers from a Grade 3 palmar-plantar erythrodysesthesia syndrome adverse event, the method further comprises a) withholding administration of ripretinib for at least 7 days or until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome, and then administering 100 mg of ripretinib daily to the patient for at least 28 days. In some embodiments, if the patient suffers from Grade 2 palmar-plantar erythrodysesthesia syndrome after administration of ripretinib, the method further comprises: a) withholding administration of ripretinib until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome or baseline; b) if the patient recovers from palmar-plantar erythrodysesthesia syndrome within 7 days of withholding administration, then administering 150 mg of ripretinib daily to the patient; or c) if the patient has not recovered, then administering 100 mg of ripretinib daily to the patient for at least 28 days. In some embodiments, the CYP3A4 inhibitor is selected from the group consisting of itraconazole, ketoconazole, clarithromycin, and indinavir. In some embodiments, the CYP3A4 inhibitor is itraconazole. In some embodiments, the patient has previously received one or more tyrosine kinase inhibitors selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, avapritinib, each of which is a pharmaceutical acceptable salt thereof.

[0037] In another embodiment, described herein is a method for treating melanoma in a patient in need of treatment thereof, wherein the patient is concurrently treated with a proton pump inhibitor, the method comprising orally administering 100 mg or 150 mg of ripretinib, or a pharma- ceutically acceptable salt thereof, once or twice daily to the patient, wherein administering ripretinib and a proton pump inhibitor to the patient does not provide a clinically significant difference in the plasma exposure of ripretinib in the patient compared to administering ripretinib without concurrent treatment with a proton pump inhibitor.In some embodiments, the proton pump inhibitor is selected from the group consisting of pantoprazole, omeprazole, lansoprazole, rabeprazole, esomeprazole, and dexlansoprazole.In some embodiments, the proton pump inhibitor is pantoprazole.In some embodiments, the patient is concurrently treated with a proton pump inhibitor at a dose of 40 mg once daily.

[0038] In another embodiment, described herein is a method of treating melanoma in a patient in need of such treatment, the method comprising orally administering to the patient 100 mg or 150 mg of ripretinib, or a pharma- ceutically acceptable salt thereof, once or twice daily, wherein the ripretinib is administered to the patient with or without food. In some embodiments, the food comprises a high-fat meal (e.g., a high-fat meal described herein).

[0039] In some embodiments, the therapeutic efficacy of ripretinib is determined by the progression-free survival of patients after independent radiological review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. In some embodiments, the therapeutic efficacy of ripretinib is determined by the objective response rate (ORR), tumor progression-free time (TTP) or overall survival (OS) of patients after independent radiological review using RECIST 1.1. In some embodiments, the therapeutic efficacy of ripretinib is determined by the progression-free survival of patients based on investigator's assessment.

[0040] After at least one month, two months, e.g., 28 days or more, of treatment with ripretinib, the patient may have progression free survival as measured using RECIST 1.1.

[0041] Dose modification Dose modification may be performed in the methods of administering ripretinib described herein as a result of adverse events experienced by the patient. In some embodiments, the dose modification is a dose interruption. In some embodiments, the dose modification is a permanent cessation in dosing. In some embodiments, the dose modification is a dose reduction. In some embodiments, the dose of ripretinib administered to the patient is reduced from 150 mg, e.g., 3 tablets each containing 50 mg of ripretinib once daily to 2 tablets each containing 100 mg, e.g., 50 mg of ripretinib once daily. In some embodiments, the dose of ripretinib administered to the patient is reduced from 150 mg, e.g., 3 tablets each containing 50 mg of ripretinib once daily to 1 tablet containing 50 mg, e.g., 50 mg of ripretinib once daily. In some embodiments, the adverse reaction is selected from the group consisting of hand-foot skin reactions (e.g., palmar-plantar erythrodysesthesia syndrome), hypertension, arthralgia, and muscle pain.

[0042] In some embodiments, the adverse event is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (e.g., baseline, grade 1, grade 2, grade 3, or grade 4). In some embodiments, the dose modification is a dose interruption (e.g., dose interruption for at least 7 days) as a result of a grade 2 adverse event. In some embodiments, if the adverse event declines to grade 1 or baseline within a first time period (e.g., within 7 days), dosing is resumed at the same dose level before dose interruption. In some embodiments, if the adverse event declines to grade 1 or baseline after a first time period (e.g., after 7 days), dosing is resumed at the reduced dose level before dose interruption. In some embodiments, if the adverse event declines to grade 1 or baseline after a first time period but remains as a grade 1 or baseline adverse event after a second time period (e.g., after 28 days), the reduced dose level is re-escalated to the dose level before dose interruption. In some embodiments, the dose modification is a dose interruption (e.g., a dose interruption for at least 7 days and up to 28 days) as a result of a grade 3 adverse event. In some embodiments, dosing is continued at a reduced level after dose interruption. In some embodiments, the dose modification is a permanent cessation of dosing as a result of a grade 4 adverse event (e.g., grade 4 hypertension).

[0043] The patient may be administered additional treatment in response to an adverse event or to prevent the occurrence of an adverse event. In some embodiments, a patient suffering from an adverse dermatological reaction, such as a palmar-plantar erythrodysesthesia syndrome, is administered a topical composition (e.g., an emollient) to treat the adverse dermatological reaction. In some embodiments, the patient is administered a topical composition (e.g., an emollient) based on the severity of the adverse dermatological reaction, such as a grade 2, grade 3 adverse dermatological reaction, such as a grade 1, grade 2, or grade 3 palmar-plantar erythrodysesthesia syndrome, such as a grade 1, grade 2, or grade 3 palmar-plantar erythrodysesthesia syndrome. In some embodiments, the topical composition (e.g., an emollient) is administered to the patient during a dose interruption of ripretinib. In some embodiments, the topical composition (e.g., an emollient) is administered to the patient contemporaneously with a dose of ripretinib, such as a reduced dose of ripretinib.

[0044] The patient may also be administered an additional treatment prior to or during administration of ripretinib in accordance with the methods described herein to prevent or ameliorate adverse events. In some embodiments, the patient is administered a topical composition (e.g., an emollient) prior to and / or during administration of ripretinib to prevent or ameliorate the development of adverse dermatological reactions, e.g., hand-foot skin reactions, e.g., palmar-plantar erythrodysesthesia syndrome.

[0045] Combination therapy In one embodiment, the present disclosure describes a combination therapy comprising administration of ripretinib, or a composition comprising ripretinib, and one or more therapeutic agents.The combination therapy described herein can be used by itself or further combined with one or more additional therapeutic agents (e.g., one or more additional therapeutic agents described below).For example, the compound of formula (I) or a composition comprising the compound of formula (I) in amorphous form can be administered with a cancer targeting agent, a cancer targeting biologic, an immune checkpoint inhibitor, or a chemotherapeutic agent.The therapeutic agent can be administered with another therapeutic agent described herein in combination therapy or sequentially with the therapeutic agent.

[0046] Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately, or combination therapy can be achieved by administering two or more therapeutic agents in a single formulation.

[0047] Other combinations are also included in combination therapy. While two or more drugs in combination therapy can be administered at the same time, it is not necessary. For example, the administration of a first drug (or combination of drugs) can precede the administration of a second drug (or combination of drugs) by minutes, hours, days, or weeks. Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or more of each other. In some cases, even longer intervals are possible. In many cases, it is desirable, but not necessary, for two or more drugs used in combination therapy to be present in the patient's body at the same time.

[0048] Combination therapy can also include more than one administration of one or more of the agents used in the combination with the component agents in a different order, for example, when agent X and agent Y are used in the combination, they can be administered one or more times sequentially in any combination, for example in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0049] In some embodiments, additional therapeutic agents that may be administered in accordance with the present disclosure include cytotoxic agents, cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-trifluoroethylene, 1,2-difluoropropanediol ...5-Tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alpha-2b, pegylated interferon alpha-2b, aromatase combination drugs, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6 -Mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, propionate Dromostanolone acetate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, amphetamine, thiazolidinone ... These include, but are not limited to, nastrazole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, and valrubicin.

[0050] In some embodiments, additional therapeutic agents that can be administered include DNA damaging agents (or DNA alkylating agents), AKT inhibitors, alkylating agents, all-trans-retinoic acid, antiandrogens, azacytidine, BCL2 inhibitors, BCL-XL inhibitors, BCR-ABL inhibitors, BTK inhibitors, BTK / LCK / LYN inhibitors, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitors, CDK4 / 6 inhibitors, CDK9 inhibitors, CBP / p300 inhibitors, EGFR inhibitors (e.g., afatinib, neratinib), endothelin receptor blockers, RAF inhibitors, MEK (mitogen-activated protein kinase) inhibitors, ERK inhibitors. , farnesyltransferase inhibitors, FLT3 inhibitors, glucocorticoid receptor agonists, HDM2 inhibitors, histone deacetylase inhibitors, IKKβ inhibitors, immunomodulatory drugs (IMiDs), ingenol, ITK inhibitors, JAK1 / JAK2 / JAK3 / TYK2 inhibitors, MTOR inhibitors, PI3 kinase inhibitors, dual PI3 kinase / MTOR inhibitors, proteasome inhibitors, protein kinase C agonists, SUV39H1 inhibitors, TRAIL, VEGFR2 inhibitors, Wnt / β-catenin signaling inhibitors, decitabine, anti-CD20 monoclonal antibodies.

[0051] In certain embodiments, the additional therapeutic agent is a CTLA4 inhibitor (such as, but not limited to, ipilimumab and tremelimumab), a PD1 inhibitor (such as, but not limited to, pembrolizumab and nivolumab), a PDL1 inhibitor (such as, but not limited to, atezolizumab (formerly MPDL3280A), durvalumab (formerly MEDI4736), avelumab, PDR001), 4 1BB or 4 1BB ligand inhibitors (such as but not limited to urelumab and PF-05082566), OX40 ligand agonists (such as but not limited to MEDI6469), GITR agents (such as but not limited to TRX518), CD27 inhibitors (such as but not limited to varlilumab), TNFRSF25 or TL1A inhibitors, CD40 agonists (such as but not limited to CP-870893), HVEM or LIGHT or LTA or BTLA or CD160 inhibitors, LAG3 inhibitors (such as but not limited to BMS-986016), TIM3 inhibitors, Siglecs inhibitors, ICOS or ICOS ligand agonists, B7 H3 inhibitors (such as but not limited to MGA271), B7 H4 inhibitors, VISTA inhibitors, HHLA2 or TMIGD2 inhibitors, butyrophilin inhibitors (including BTNL2 inhibitors), CD244 or CD48 inhibitors, inhibitors of TIGIT and PVR family members, KIR inhibitors (such as, but not limited to, lirilumab), inhibitors of ILT and LIR, NKG2D and NKG2A inhibitors (such as, but not limited to, IPH2201), inhibitors of MICA and MICB, CD244 inhibitors, CSF1R inhibitors (such as, but not limited to, bimsertinib), , emacutuzumab, cavirarizumab, pexidartinib, ARRY382, BLZ945, etc., IDO inhibitors (such as but not limited to INCB024360), thalidomide, lenalidomide, TGFβ inhibitors (such as but not limited to galunisertib), adenosine or CD39 or CD73 inhibitors, CXCR4 or CXCL12 inhibitors (urocupulumab and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H,16H-pi and immunomodulatory agents selected from the group consisting of methylprednisolone (MMP) (such as, but not limited to, methylprednisolone), ...

[0052] In some embodiments, the additional therapeutic agent is an antitubulin agent (paclitaxel, paclitaxel protein-bound particles for injectable suspension (nab-paclitaxel, eribulin, docetaxel, ixabepilone, taxitereme, vincristine or vinorelbine), vinorelbine, LHRH antagonists (including but not limited to leuprolide, goserelin, triptorelin, or histrelin), antiandrogens (including but not limited to abiraterone, flutamide, bicalutamide, nilutamide, cyproterone acetate, enzalutamide, and apalutamide), antiestrogens (tamoxifen, fulvescin, The chemotherapeutic agent is selected from the group consisting of chemotherapeutic agents including, but not limited to, tetracycline, anastrozole, letrozole, and exemestane, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacitadine, gemcitabine, bortezomib, carfilzomib, and methotrexate.

[0053] In some embodiments, the additional therapeutic agent is selected from the group consisting of paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, docetaxel, ixabepilone, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide, doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, epirubicin, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacitadine, gemcitabine, methotrexate, erlotinib, gefitinib, lapatinib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelasib, quizartinib, tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, prednisone, dexamethasone, irinotecan, camptothecin, topotecan, etoposide, etoposide phosphate, mitoxantrone, vorinostat, romidepsin, panobinostat, valproic acid, belinostat, DZNep The agent is selected from the group consisting of 5-aza-2'-deoxycytidine, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, ravlolizumab, nivolumab, MPDL3280A, bevacizumab, aflibercept, brentuximab vedotin, ado-trastuzumab emtansine, radiation therapy, and sipuleucel-T.

[0054] In some embodiments, the additional therapeutic agent is a kinase inhibitor selected from the group consisting of erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalisib, and quizartinib.

[0055] In some embodiments, the additional therapeutic agent is an anti-PD1 therapeutic agent. Examples of anti-PD1 therapeutic agents that can be administered in combination with the compound of formula (I) or a pharma- ceutically acceptable salt thereof, or the composition comprising the compound of formula (I) or a pharma-ceutically acceptable salt thereof described herein, include, but are not limited to, nivolumab, pidilizumab, cemiplimab, tislelizumab, AMP-224, AMP-514, and pembrolizumab.

[0056] In some embodiments, the additional therapeutic agent is selected from the group consisting of immunomodulatory agents, including, but not limited to, anti-PD-L1 therapeutics, including atezolizumab, durvalumab, BMS-936559, and avelumab, anti-TIM3 therapeutics, including TSR-022 and MBG453, anti-LAG3 therapeutics, including leratolimab, LAG525, and TSR-033, CD40 agonist therapeutics, including SGN-40, CP-870,893, and RO7009789, anti-CD47 therapeutics, including Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, other immunomodulatory therapeutics, including thalidomide, lenalidomide, pomalidomide, prednisone, dexamethasone. In some embodiments, the additional therapeutic agent is avelumab.

[0057] In some embodiments, the additional therapeutic agent is a targeted therapeutic agent (kinase inhibitors erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, idelalisib, quizartinib, avapritinib, BL U-667, BLU-263, Loxo292, latrorectinib, and quizartinib), antiestrogens (including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane), antiandrogens (including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, and cyproterone acetate), steroids (including but not limited to prednisone and dexamethasone), and PARP inhibitors (including but not limited to nephrectomycin, erythropoietinib, and erythrostatinib). topoisomerase I inhibitors (including but not limited to irinotecan, camptothecin, topotecan), topoisomerase II inhibitors (including but not limited to etoposide, etoposide phosphate, mitoxantrone), histone deacetylase (HDAC) inhibitors (including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, belinostat), DNA methylation inhibitors (DZNep and 5-aza-2'-deoxycytidine), proteasome inhibitors (including but not limited to bortezomib and carfilzomib), thalidomide, lenalidomide, pomalidomide, biologics (including but not limited to trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, tremelimumab), vaccines (including but not limited to sipuleucel-T), and radiation therapy.

[0058] In some embodiments, the additional therapeutic agent is selected from the group consisting of KIT inhibitors.In some embodiments, the additional therapeutic agent is selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, avapritinib.In some embodiments, the additional therapeutic agent is selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, avapritinib, and AZD3229.

[0059] In some embodiments, the additional therapeutic agent is selected from the group consisting of inhibitors of TIE2 immune kinase, including revastinib or ARRY-614.

[0060] In some embodiments, the additional therapeutic agent is selected from the group consisting of an inhibitor of TIE2 immune kinase, including revastinib or ARRY-614, and an anti-PD1 therapeutic agent.

[0061] In some embodiments, the additional therapeutic agent is selected from the group consisting of angiogenesis inhibitors, including AMG386, bevacizumab, aflibercept, and antibody drug conjugates (ADCs), including brentuximab vedotin, trastuzumab emtansine, and antibody drug conjugates (ADCs) comprising a payload, such as a derivative of camptothecin, a pyrrolobenzodiazepine dimer (PBD), an indolinobenzodiazepine dimer (IGN), DM1, DM4, MMAE, or MMAF.

[0062] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone releasing hormone (LHRH) analogs, including goserelin and leuprolide.

[0063] In some embodiments, the additional therapeutic agent is everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, butabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, jamatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanton, LY 317615, neuradiab, vitespam, rta 744, sdx 102, talampanel, atrasentan, xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib, PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)- ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005,Acetate of [D-Ser(Bu t)6, Azgly 10] (Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18Oi4-(C2H4O2)x (where x=1-2.4)], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, furutanide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib, amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951 , aminoglutethimide, amsacrine, anagrelide, L-asparaginase, sterile bovine tuberculosis (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, Fludrocortisone, fluoxymesterone, flutamide, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, prilosporin, rifabut ... Kamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine,Deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, vomitoxin, Lutezimibe, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and Erbitux, Cremophor-free paclitaxel, Epithilon B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene,Tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium 89, casopitant, netupitant, NK1 receptor blockers, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, and avapritinib.

[0064] In some embodiments, the additional therapeutic agent is an HSP90 inhibitor (e.g., AT13387). In some embodiments, the additional therapeutic agent is cyclophosphamide. In some embodiments, the additional therapeutic agent is an AKT inhibitor (e.g., perifosine). In some embodiments, the additional therapeutic agent is a BCR-ABL inhibitor (e.g., nilotinib). In some embodiments, the additional therapeutic agent is an mTOR inhibitor (e.g., RAD001). In some embodiments, the additional therapeutic agent is an FGFR inhibitor (e.g., erdafitinib, KO947, or BGJ398). In some embodiments, the additional therapeutic agent is an anti-PDL1 therapeutic agent. In some embodiments, the additional therapeutic agent is a Bcl2 inhibitor (e.g., venetoclax). In some embodiments, the additional therapeutic agent is an autophagy inhibitor (e.g., hydroxychloroquine). In some embodiments, the additional therapeutic agent is a MET inhibitor.

[0065] In some embodiments, the additional therapeutic agent is an inhibitor of the MAPK pathway. In some embodiments, the additional therapeutic agent is a RAF inhibitor. In some embodiments, the additional therapeutic agent is a RAF inhibitor selected from the group consisting of berbarafenib, LXH-254, lifirafenib (BGB-283), AZ-268, TAK-632, sorafenib, LY3009120, vemurafenib, dabrafenib, encorafenib, and PLX8394. In some embodiments, the additional therapeutic agent is a MEK inhibitor. In some embodiments, the additional therapeutic agent is a MEK inhibitor selected from the group consisting of binimetinib, cobimetinib, selumetinib, trametinib, pimisertib, and PD-0325901. In some embodiments, the additional therapeutic agent is an ERK inhibitor. In some embodiments, the additional therapeutic agent is an ERK inhibitor selected from the group consisting of GDC-0994, KO-947, LY-3214996, Vtx-11e, SCH-772984, MK-8253, and ulixertinib.

[0066] In some embodiments, the additional therapeutic agent is an inhibitor of the PI3K pathway. In some embodiments, the additional therapeutic agent is a p110 inhibitor. In some embodiments, the additional therapeutic agent is a p110 inhibitor selected from the group consisting of alpelisib, copanlisib, duvelisib, idelalisib, GDC-0077, and taselisib. In some embodiments, the additional therapeutic agent is an AKT inhibitor. In some embodiments, the additional therapeutic agent is an AKT inhibitor and is ipatasertib. In some embodiments, the additional therapeutic agent is an mTOR inhibitor. In some embodiments, the additional therapeutic agent is an mTOR inhibitor selected from the group consisting of everolimus and temsirolimus. EXAMPLES

[0067] Example 1. Phase I study of the treatment of melanoma with Ripretinib. This is a phase I study evaluating the efficacy of ripretinib in treating patients with melanoma. An efficacy cohort of 26 patients was enrolled. Each patient received ripretinib 150 mg daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. Patients with disease progression on ripretinib 150 mg QD were allowed to escalate to 150 mg twice daily (BID) after completion of cycle 2. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to optimal response (TBR), and progression-free survival (PFS) as determined by radiological review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

[0068] Results. The median duration of treatment with ripretinib 150 mg QD was 4.4 months (range, 0.5-33.6 months). Figure 3 shows the duration of treatment with ripretinib in individual patients. Ripretinib demonstrated a median PFS of 7.3 months. A plot of survival probability with respect to PFS for patients on ripretinib is shown in Figure 1. For the secondary endpoint of objective response rate (ORR), ripretinib demonstrated a confirmed ORR of 23.1% (6 of 26 patients) as determined by radiological review using RECIST version 1.1. In addition, ripretinib demonstrated a confirmed and unconfirmed ORR of 30.8%. For the secondary endpoint of duration of response (DOR), ripretinib demonstrated a median DOR (mDOR) of 9.1 months. Ripretinib dose was escalated to 150 mg BID after progressive disease (PD) at 150 mg QD in four (15%) patients.

[0069] Analysis of Prior Tyrosine Kinase Inhibitor (TKI) Treatment. The efficacy of ripretinib among efficacy cohort members who had previously received TKI treatment, and among those who had not received prior TKI treatment, was evaluated. Seventeen of the 25 members of the cohort had not received prior TKI treatment, and among these members, the mPFS was determined to be 10.2 months and the ORR was determined to be 29.4% (5 of 17 members). Eight of the 25 members had received TKI treatment prior to receiving ripretinib, and among these members, the mPFS was determined to be 2.9 months and the ORR was determined to be 11% (1 of 9 members). A plot illustrating the mPFS in the cohort members who had not previously received TKI treatment (non-TKI) and the cohort members who had previously received TKI treatment (TKI) is provided in Figure 2.

[0070] Additionally, overall response results as determined by investigator assessment across cohort populations are provided in Table 1 below. [Table 1]

[0071] Additionally, Figure 4 shows the best overall response and the respective percentage change in target lesions from baseline after ripretinib treatment in individual patients. Figure 5 shows spider plots of the change in target lesions in individual patients with respect to treatment period.

[0072] Mutation Analysis. An analysis of ripretinib efficacy based on baseline melanoma mutations among efficacy cohorts was performed. Table 2 shows exemplary overall response results for observed baseline exon mutations. L576P (exon 11), K642E (exon 13), and N822K / Y (exon 17) were determined to be the most prevalent baseline mutations in this cohort. [Table 2]

[0073] Additionally, the confirmed ORR in exon 11 and exon 17 patients was 44% and 18%, respectively. The median duration of response in exon 11 and exon 17 patients was 10.5 months (range: 8.3 months to 31.3 months) and 8.1 months (range: 6.9 months to 9.2 months), respectively. The median PFS in exon 11 and exon 17 patients was 10.2 months (95% CI: 0.6 months not assessed) and 13.6 months (95% CI: 1.8 months not assessed), respectively.

[0074] Furthermore, the median time to confirmed response (range) in exon 11 and exon 17 patients was 1.9 months (1.8-2.0 months) and 1.7 months (1.4-1.9 months), respectively.

[0075] The above data indicate that melanoma patients in this phase I study responded well to ripretinib treatment at the mutational level with respect to KIT inhibition.

[0076] Example 2. Study of ripretinib and compound A, a potent CYP3A inhibitor. Coadministration of 150mg QD ripretinib with a strong CYP3A inhibitor may increase the exposure of ripretinib and its active metabolite (compound A) and increase the risk of adverse reactions. Coadministration of ripretinib with itraconazole (a strong CYP3A inhibitor and P-gp inhibitor) increased ripretinib Cmax by 36% and AUC0-inf by 99% and increased the AUC0-inf of compound A by 99%, without changing its Cmax.

[0077] Example 3. Study of Ripretinib with Proton Pump Inhibitors. The effect of proton pump inhibitors on ripretinib exposure was evaluated. No clinically significant differences in plasma exposure to ripretinib and Compound A were observed when ripretinib was co-administered with pantoprazole (a proton pump inhibitor). Although ripretinib has pH-dependent solubility, co-administration of 40 mg QD pantoprazole with 150 mg QD ripretinib did not affect ripretinib exposure.

[0078] Example 4. Study of food effects on ripretinib and Compound A exposure. The effect of a high-fat breakfast on ripretinib and Compound A exposure was evaluated. The high-fat meal consisted of approximately 150 calories from protein, approximately 250 calories from carbohydrates, and approximately 500-600 calories from fat. Following administration of ripretinib with a high-fat meal at a dose of 150 mg, the AUC of ripretinib was 0-24h and C max were 30% and 22%, respectively. For metabolite compound A, AUC 0-24h and C max were 47% and 66% higher, respectively. The food effect was not considered clinically significant based on the exposure-response analysis. Thus, ripretinib can be taken with or without food at approximately the same time each day.

[0079] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. A pharmaceutical composition for use in the treatment of melanoma in a patient in need thereof, comprising a compound represented by: 【Chemistry 1】 13. A pharmaceutical composition comprising:

2. A pharmaceutical composition for use in treating melanoma in a patient in need thereof, comprising a compound represented by: 【Chemistry 2】 wherein said patient is orally administered 100 mg to 600 mg of said compound daily.

3. The composition for use described in claim 2, wherein the patient is orally administered 100 mg to 300 mg of the compound daily.

4. A composition for use as described in claim 2 or claim 3, wherein the patient is orally administered 150 mg of the compound daily.

5. A pharmaceutical composition for use in treating melanoma in a patient in need thereof, comprising a compound represented by: 【Chemistry 3】 wherein said patient is orally administered one or more tablets daily containing 100 mg to 600 mg of said compound.

6. The composition for use according to claim 5, wherein the patient is orally administered three tablets, each containing 50 mg of the compound, once daily.

7. The composition for use according to claim 5, wherein the patient is orally administered two tablets, each containing 50 mg of the compound, once daily.

8. The composition for use according to claim 5, wherein the patient is orally administered one tablet containing 50 mg of the compound twice daily.

9. A pharmaceutical composition for use in treating melanoma in a patient in need thereof, comprising a compound represented by: 【Chemistry 4】 wherein said patient is orally administered 100 mg to 600 mg of said compound daily, and said patient has not previously been administered one or more tyrosine kinase inhibitors prior to administration of said compound.

10. A pharmaceutical composition for use in treating melanoma in a patient in need thereof, comprising a compound represented by: 【Chemistry 5】 wherein said patient is orally administered 100 mg to 600 mg of said compound daily, and said patient has previously been administered at least one tyrosine kinase inhibitor prior to administration of said compound.

11. A composition for use as described in claim 9 or claim 10, wherein the patient is orally administered 100 mg to 300 mg of the compound daily.

12. A composition for use as described in claim 9 or claim 10, wherein the patient is orally administered 150 mg of the compound daily.

13. A composition for use as described in claim 9 or claim 10, wherein the patient had previously been administered at least two, three, four, or five tyrosine kinase inhibitors prior to administration of the compound.

14. A composition for use as described in claim 9 or claim 10, wherein the at least one previously administered tyrosine kinase inhibitor is selected from the group consisting of imatinib, sunitinib, regorafenib, lapatinib, dasatinib, crizotinib, gefitinib, erlotinib, vatalanib, crenolanib, and pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition for use in treating melanoma in a patient in need thereof, comprising a compound represented by: 【Chemistry 6】 wherein said patient is orally administered one or more tablets daily, each comprising said compound, and wherein said patient has previously been administered at least one tyrosine kinase inhibitor prior to administration of said compound.

16. The composition for use according to claim 15, wherein the patient is administered three tablets, each containing 50 mg of the compound, once daily.

17. A composition for use as described in claim 15 or claim 16, wherein the at least one previously administered tyrosine kinase inhibitor is selected from the group consisting of imatinib, sunitinib, regorafenib, lapatinib, dasatinib, crizotinib, gefitinib, erlotinib, vatalanib, crenolanib, and pharmaceutically acceptable salts thereof.

18. A composition for use as described in any one of claims 1 to 3, 5 to 10, 15 or 16, wherein the patient has previously been administered imatinib.

19. The composition for use according to any one of claims 1 to 3, 5 to 10, 15 or 16, wherein the melanoma is KIT-driven melanoma.

20. The composition for use according to claim 19, wherein the KIT-driven melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation.

21. The composition for use according to claim 19, wherein the KIT-driven melanoma is caused by overexpression of wild-type KIT.

22. A composition for use according to any one of claims 1 to 3, 5 to 10, 15 or 16, wherein after at least one 28-day cycle, the patient has progression-free survival as measured using RECIST 1.

1.

23. A pharmaceutical composition for use in treating melanoma in a patient in need thereof, comprising a compound represented by: 【Chemistry 7】 wherein said patient is orally administered 100 mg to 600 mg of said compound daily, and one or more additional therapeutic agents.

24. The composition for use according to claim 23, wherein the patient is orally administered 100 mg to 300 mg of the compound daily.

25. A composition for use as described in claim 23 or claim 24, wherein the patient is orally administered 150 mg of the compound daily.

26. The composition for use according to claim 23 or claim 24, wherein the melanoma is KIT-driven melanoma.

27. The composition for use according to claim 23 or claim 24, wherein the KIT-driven melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation.

28. The composition for use according to claim 23, wherein the KIT-driven melanoma is caused by overexpression of wild-type KIT.

29. The composition for use according to any one of claims 1 to 3, 5 to 10, 15, 16, 23 or 28, wherein the melanoma is cutaneous melanoma.

30. The composition for use according to claim 29, wherein the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, amelanotic melanoma, and desmoplastic melanoma.

31. The composition for use according to any one of claims 1 to 3, 5 to 10, 15, 16, 23 or 28, wherein the melanoma is a non-cutaneous melanoma.

32. The composition for use according to claim 31, wherein the non-cutaneous melanoma is selected from intraocular melanoma and mucosal melanoma.

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