Ripretinib for the treatment of gastrointestinal stromal tumors

Abstract

This disclosure relates to a method of treating a subject with a gastrointestinal stromal tumor, comprising administering to the subject a therapeutically effective amount of ripretinib or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of Chinese patent application No. 2020800712739 (application date: August 12, 2020, invention title: Ripretinib for the treatment of gastrointestinal stromal tumors). Cross-references to related applications

[0002] This application claims priority to USSN 62 / 885,797, filed August 12, 2019; USSN 62 / 904,198, filed September 23, 2019; USSN 62 / 926,281, filed October 25, 2019; USSN 62 / 936,018, filed November 15, 2019; USSN 62 / 968,927, filed January 31, 2020; USSN 62 / 968,945, filed January 31, 2020; USSN 63 / 023,921, filed May 13, 2020; and USSN 63 / 023,936, filed May 13, 2020, each of which is incorporated herein by reference in its entirety. Background Technology

[0003] Gastrointestinal stromal tumors (GISTs) account for less than 1% of all gastrointestinal (GI) tumors, but constitute the most common mesenchymal tumors and soft tissue sarcomas of the gastrointestinal tract. They can occur anywhere in the gastrointestinal tract, but are most common in the stomach (60%) or small intestine (30%), and less common in the rectum, colon, or mesentery. In the United States, approximately 3,300 to 6,000 new GIST cases are diagnosed each year. The vast majority of cases are sporadic, and older age is a recognized risk factor. KIT and platelet-derived growth factor receptor α (PDGFRA) mutations have been found in more than 80% of all primary GISTs. Alterations in the neurofibroma type 1 (NF1) gene and the succinate dehydrogenase (SDH) complex (SDHC) gene, as well as methylation alterations in the SDHC promoter, have been described as oncogenic drivers of GIST in the absence of activated KIT or PDGFRA mutations, and are associated with familial and hereditary syndromes (NF1 and Carney-Stratakis syndrome).

[0004] Despite significant variability in tumor size, location, and histological subtype (spindle cell, epithelioid cell, and mixed), approximately 85% of GISTs have an oncogenic mutation in one of the two receptor tyrosine kinases (TKs): KIT or PDGFRA. Constitutive activation of these TKs plays a central role in GIST oncogenic behavior. Early characterization of GIST mutational status is important in both local and metastatic settings for identifying imatinib-resistant mutations (such as some primary KIT exon 17 mutations or PDGFRAD842V) or mutations requiring higher doses of imatinib. GIST patients lacking KIT or PDGFRA mutations typically do not benefit from imatinib, and standard treatment algorithms are largely inapplicable. However, other mutations may be present in these patients, with the largest group represented by SDH deficiency, often associated with Carney or Carney-Stratakis syndrome. Other subtypes have mutations in NF1 (often associated with neurofibromatosis type 1) or BRAF or KRAS. Recently, incidental cases of GIST-type tumors with NTRK ectopic sites have further expanded the range of molecular subtypes.

[0005] In the pre-tyrosine kinase inhibitor (TKI) era, GIST (often classified as gastric leiomyosarcoma or leiomyoblastoma) was treated in subtypes of unknown sarcoma trials with a lack of effective systemic therapies. However, a deeper understanding of the molecular pathogenesis and driving roles of the proto-oncogenes KIT and PDGFRA has transformed the treatment of both localized and metastatic disease. Localized and resectable tumors are treated surgically, which remains the primary curative treatment for localized disease. Resected high-risk GISTs are often treated adjuvantly with imatinib, while low-risk GISTs are treated surgically alone. Intermediate-risk GISTs are managed on a case-by-case basis. In advanced / metastatic settings, imatinib at 400 mg daily, with the dose increased to 800 mg upon progression, has been approved and has shown significant efficacy in disease control. Patients resistant to imatinib receive sunitinib as second-line therapy, and regorafenib as third-line therapy for those resistant to or intolerant of sunitinib.

[0006] At diagnosis, KIT gene mutations occur in 80% of GISTs, typically in exon 11 and less frequently in exon 9. Both mechanisms result in ligand-independent receptor activation, leading to uncontrolled cell growth and transformation. Primary mutations affect loss-of-function mutations within the JM region, causing a shift in the equilibrium towards KIT's type I active or on state conformation, away from its type II inactive or off state conformation. Primary exon 11 mutations are the most common mutations in GISTs (approximately 70% of cases) and have shown significant benefit with imatinib treatment in both adjuvant and metastatic settings, achieving nearly 90% 2-year recurrence-free survival in adjuvant settings and a median event-free survival of nearly 2 years in metastatic settings. Primary exon 9 mutations (in treatment-naïve patients) affect the extracellular domain of KIT, mimicking ligand-binding-induced conformational changes and triggering KIT receptor homodimerization. This dimerization leads to activation of specific intracellular signaling pathways, resulting in cancer cell proliferation, survival, and drug resistance. Although less common than exon 11 mutations, exon 9 mutations (accounting for 10% to 15% of newly diagnosed cases) are most common in GISTs originating from the small intestine. Unlike exon 11 mutations, they benefit less from imatinib in helper or metastatic settings.

[0007] Although outcomes have significantly improved compared to the pre-mutation-driven / TKI era, not all patients respond to imatinib. Most GIST patients eventually develop resistance to imatinib, most commonly due to secondary mutations in KIT. Secondary resistance mutations typically occur in the catalytic domain of the kinase: 1) at the switch pocket, usually in KIT exons 13 and 4 or PDGFRA exons 14 and 15, spatially disrupting drug binding or conformationally activating KIT; and 2) at the activation loop switch encoded by KIT exons 17 and 18 and PDGFRA exon 18. Activation loop mutations convert the kinase to an activated type I or initiation state conformation, which is less suitable for binding to any approved type II TKI drug. Although uncommon in primary GIST (accounting for 1% to 2% of newly diagnosed cases), exon 13, 14, and 17 mutations are often the cause of acquired imatinib resistance, with exon 17 mutations alone accounting for nearly 50% of acquired imatinib resistance cases, followed by sunitinib. There is a need for a TKI that can broadly inhibit clinically relevant KIT and PDGFRA mutations. Summary of the Invention

[0008] This article describes a method for treating gastrointestinal stromal tumors in patients in need, including administering a therapeutically effective amount of ripretinib or a pharmaceutically acceptable salt thereof to the patient.

[0009] For example, in one embodiment, this document describes a method of treating a patient with advanced gastrointestinal stromal tumor, comprising administering 100 mg to 300 mg (e.g., 150 mg) of riprinib daily to the patient, wherein the patient’s tumor has progressed since previous first-line administration of imatinib, or the patient is intolerant to previous first-line administration of imatinib.

[0010] For example, in one embodiment, this document describes a method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100 mg to 250 mg (e.g., 150 mg) of ripretinib to the patient, wherein the patient’s tumor has progressed since previous first-line administration of imatinib, or the patient is intolerant to previous first-line administration of imatinib.

[0011] In another embodiment, this document describes a method of treating a patient with advanced gastrointestinal stromal tumor, comprising administering 100 mg to 600 mg (e.g., 100 mg to 250 mg, e.g., 150 mg) of ripretinib orally to the patient daily, wherein the patient’s tumor has progressed since previous first-line administration of imatinib, or the patient is intolerant to previous first-line administration of imatinib.

[0012] In another embodiment, this document describes a method for treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering one or more tablets containing ripretinib (e.g., tablets containing 50 mg to 100 mg of ripretinib per tablet) daily to the patient, wherein the patient's tumor has progressed since prior first-line treatment with imatinib, or the patient is intolerant to prior first-line treatment with imatinib. In some instances, the tablet contains 50 mg of ripretinib. In some embodiments, the tablet contains 75 mg of ripretinib. In some embodiments, the tablet contains 100 mg of ripretinib.

[0013] In another embodiment, this document describes a method of treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering one or more tablets containing ripretinib (e.g., tablets containing 50 mg to 100 mg of ripretinib per tablet) daily to the patient, wherein the patient's tumor has progressed since prior first-line treatment with imatinib, prior second-line treatment with sunitinib, and prior third-line treatment with regorafenib, or wherein the patient is intolerant to prior first-line, second-line, and third-line treatment with imatinib, sunitinib, and / or regorafenib, or wherein the patient has a documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib. In some embodiments, the tablet contains 50 mg of ripretinib. In some instances, the tablet contains 75 mg of ripretinib. In some instances, the tablet contains 100 mg of ripretinib. In another embodiment, this document describes a method for treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100 mg to 250 mg of ripretinib (e.g., 150 mg) daily to the patient, wherein the patient’s tumor has progressed since first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or wherein the patient is intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or wherein the patient has a documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib.

[0014] In another embodiment, this document describes a method of treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering 100 mg to 600 mg of ripretinib (e.g., 100 mg to 250 mg, 100 mg to 500 mg, 100 mg to 250 mg, 150 mg) daily to the patient, wherein the patient’s tumor has progressed since first-line imatinib, second-line sunitinib, and third-line regorafenib, or wherein the patient is intolerant to first-line imatinib, second-line sunitinib, and third-line regorafenib, or wherein the patient has a documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib.

[0015] In another embodiment, this document describes a method of treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering one or more tablets daily, each containing ripretinib (e.g., tablets containing 50 mg to 100 mg of ripretinib), to the patient whose tumor has progressed since first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or whose patient is intolerant to first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or whose patient has a documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib. In some embodiments, the tablet contains 50 mg of ripretinib. In some embodiments, the tablet contains 75 mg of ripretinib. In some embodiments, the tablet contains 100 mg of ripretinib.

[0016] In another embodiment, this document describes a method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100 mg to 600 mg of ripretinib (e.g., 100 mg to 250 mg, 100 mg to 500 mg, 100 mg to 250 mg, 150 mg, 300 mg) to the patient daily, wherein at least two tyrosine kinase inhibitors have been previously administered to the patient prior to the administration of the ripretinib.

[0017] In another embodiment, this document describes a method for treating a patient with stage III gastrointestinal stromal tumors, comprising orally administering 150 mg of ripretinib to the patient once daily, wherein the patient has been previously administered at least two tyrosine kinase inhibitors prior to the administration of ripretinib.

[0018] In another embodiment, this document describes a method of treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering one or more tablets, each containing ripretinib, to the patient daily, for example, tablets containing 50 mg to 100 mg of ripretinib, wherein the patient has been previously administered at least two tyrosine kinase inhibitors prior to administration of said ripretinib. In some embodiments, the tablet contains 50 mg of ripretinib. In some embodiments, the tablet contains 75 mg of ripretinib. In some embodiments, the tablet contains 100 mg of ripretinib.

[0019] In another embodiment, this document describes a method for treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering 150 mg of ripretinib to the patient once daily, wherein the patient is pre-administered with three or more tyrosine kinase inhibitors prior to administration of said ripretinib. In some embodiments, after at least 4 weeks of daily administration of ripretinib, the patient has at least 5 months of progression-free survival, as measured using mRECIST v1.1. In some embodiments, orally administering 150 mg of ripretinib to the patient once daily comprises administering three tablets to the patient, each tablet containing 50 mg of ripretinib. In some embodiments, one of the three or more tyrosine kinase inhibitors is imatinib. In some embodiments, the patient is pre-administered with imatinib, sunitinib, and regorafenib.

[0020] In another embodiment, this document describes a method for treating a patient with advanced gastrointestinal stromal tumor, comprising administering 150 mg of ripretinib orally to the patient daily, wherein the patient’s tumor has progressed since first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or wherein the patient is intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib.

[0021] In another embodiment, this document describes a method for treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 150 mg of ripretinib to the patient once or twice daily, wherein the patient’s tumor has progressed since previous first-line treatment with imatinib, or the patient is intolerant to previous first-line treatment with imatinib.

[0022] In another embodiment, this article describes a method for achieving at least 5 months of progression-free survival as determined by mRECIST 1.1 in patients with advanced gastrointestinal stromal tumors, comprising orally administering 100, 150, 200, or 300 mg of ripretinib to the patient daily or twice daily for at least 28 days.

[0023] In another embodiment, this document describes a method for achieving at least 5 months of progression-free survival as determined by mRECIST 1.1 in patients with advanced gastrointestinal stromal tumors, comprising orally administering 100, 150, or 200 mg of ripretinib to the patient daily or twice daily for at least 28 days.

[0024] In another embodiment, this document describes a method for treating a patient with Grade 3 palmar-plantar erythema syndrome while administering 150 mg of ripretinib daily or twice daily, comprising discontinuing ripretinib for at least 7 days or until the patient reaches Grade 1 or lower palmar-plantar erythema syndrome, and then administering 100 mg of ripretinib daily (e.g., once daily) for at least 28 days.

[0025] In another embodiment, this document describes a method for treating a patient with grade 2 palmoplantar erythema syndrome following daily or twice-daily administration of 150 mg of ripretinib, comprising a) discontinuing ripretinib administration until the patient reaches grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib to the patient daily; or c) if the patient does not recover, administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0026] In another embodiment, this document describes a method for treating a patient with gastrointestinal stromal tumors in need, wherein the patient is concurrently receiving CYP3A4 inhibitor therapy, the method comprising: orally administering 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof to the patient once or twice daily, wherein, compared to administration of ripretinib without concurrent CYP3A4 inhibitor therapy, administration of ripretinib and a CYP3A4 inhibitor provides an 80% or greater increase in the area under the curve (AUC) of ripretinib plasma concentration in the patient. 0-inf Therefore, these patients have a higher risk of adverse events; and adverse events in these patients are monitored more frequently compared to patients who have not received CYP3A4 inhibitor treatment.

[0027] In another embodiment, this document describes a method for treating gastrointestinal stromal tumors in patients in need, wherein the patients are concurrently receiving proton pump inhibitor therapy, the method comprising: orally administering 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof to the patients once or twice daily; wherein, following administration of ripretinib and a proton pump inhibitor, no clinically significant difference was provided in the patients' plasma exposure to ripretinib compared to patients who received ripretinib without concurrent proton pump inhibitor therapy.

[0028] In another embodiment, this document describes a method for treating a patient with gastrointestinal stromal tumors, the method comprising orally administering 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof to the patient once or twice daily, wherein the ripretinib is administered to the patient with or without food. Attached Figure Description

[0029] Figure 1 A survival probability plot is depicted for progression-free survival (PFS) of patients who received ripretinib and patients who received placebo as described in Example 2.

[0030] Figure 2 A survival probability plot is described for overall survival (OS) of patients receiving ripretinib and patients receiving placebo, as described in Example 2.

[0031] Figure 3 A survival probability plot is described, showing the overall survival (OS) for patients receiving ripretinib, patients who crossed over from placebo to ripretinib, and patients who did not cross over.

[0032] Figure 4 This describes the progression-free survival (PFS) of GIST patients treated with 150 mg ripretinib once daily, based on the line of therapy.

[0033] Figure 5 The patient-reported outcomes using the EQ-VAS visual scale are described in the study of Example 2, administered at a dose of 150 mg ripretinib. Figure 5 A) and the change in scores used to assess these scores relative to the baseline ( Figure 5 B) and the corresponding patient percentage distribution ( Figure 5 C). In this study, 70 patients received ripretinib and 32 patients received placebo.

[0034] Figure 6 The study in Example 2 described the physical function problems of EORTC QLQ-C30 under 150 mg ripretinib QD. Figure 6 A) and the change in patient scores relative to baseline in response ( Figure 6 B) and the corresponding patient percentage distribution ( Figure 6 C). Patients taking ripretinib showed a mean improvement in physical function scores from baseline to a C2D1 of 1.6, compared to a mean decline in C2D1 of 8.9 observed in placebo patients (p=0.004). In this study, 71 patients received ripretinib and 32 patients received placebo.

[0035] Figure 7The role function of EORTC QLQ-C30 under 150 mg ripretinib QD was described in the study of Example 2. Figure 7 A) and the change in patient scores relative to baseline in response ( Figure 7 B) and the corresponding patient percentage distribution ( Figure 7 C). In the study, 70 patients received ripretinib, and 32 patients received a placebo.

[0036] Figure 8 This describes the change in patient scores relative to baseline in response to EORTC QLQ-C30 question C29 (“How would you rate your overall health over the past week?”) ranging from 1 (“Very poor”) to 7 (“Excellent”) at a 150 mg ripretinib QD study in Example 2. Figure 8 A) and percentage distribution ( Figure 8 B). In this study, 70 patients received ripretinib and 32 patients received placebo.

[0037] Figure 9 This describes the change in patient scores relative to baseline in response to the EORTC QLQ-C30 question C30 (“How would you rate your overall quality of life over the past week?”) ranging from 1 (“Very poor”) to 7 (“Excellent”) at a QD of 150 mg ripretinib in the study of Example 2. Figure 9 A) and the corresponding patient percentage distribution ( Figure 9 B). In this study, 70 patients received ripretinib and 32 patients received placebo.

[0038] Figure 10 Describes the mean change in baseline EQ-VAS scores at different time points from day 15 of cycle 1 to day 1 of cycle 15 in the intention-to-treat population with 150 mg ripretinib QD in Example 2 study.

[0039] Figure 11 A and Figure 11 B describes the mean changes in EORTC QLQ-C30 role function and EORTC QLQ-C30 baseline physical function scores at different time points from day 15 of cycle 1 to day 1 of cycle 15 in the intention-to-treat population with 150 mg ripretinib QD in Example 2.

[0040] Figure 12 A and Figure 12B describes the mean changes in baseline scores in the EORTC QLQ-C30 question C29 response and EORTC QLQ-C30 question C30 response at different time points from day 15 of cycle 1 to day 1 of cycle 15 in the intention-to-treat population with 150 mg ripretinib QD in Example 2.

[0041] Figure 13 Exemplary PFS data are described for patients who crossed over from placebo to ripretinib at a QD of 150 mg ripretinib in the study described in Example 2.

[0042] Figure 14 A and Figure 14 Figure 14C describes the progression-free survival (PFS) study in Example 2, comparing patients whose dose was increased from 150 mg ripretinib QD to 150 mg ripretinib BID during the double-blind and open-label periods. The median PFS data and other parameters from these PFS studies are illustrated in Figure 14C.

[0043] Figure 15 Exemplary PFS data from patients with wild-type KIT mutations in the study of Example 2 are shown.

[0044] Figure 16 A and 16B describe data on progression-free survival (PFS) and overall survival (OS) in patients with primary exon 11 mutations or non-exon 11 mutations at a QD of 150 mg ripretinib in Example 2.

[0045] Figure 17 A and 17B describe data on progression-free survival (PFS) and overall survival (OS) in patients with localized primary exon 11 or exon 9 mutations at a QD of 150 mg ripretinib in Example 2.

[0046] Figure 18 A and 18B describe data on progression-free survival (PFS) and overall survival (OS) in patients with primary exon 11 mutations or primary exon 9 mutations or other mutations, or wild-type (KIT and PDGFRA), at a QD of 150 mg ripretinib in Example 2.

[0047] Figure 19 A and Figure 19 B describes the progression-free survival (PFS) studies of patients with specific primary mutations (exon 9 or exon 11) and whose doses were increased from 150 mg QD ripretinib to 150 mg BID ripretinib during the double-blind and open-label periods, respectively, in the study of Example 2.

[0048] Figure 20 Exemplary progression-free survival data are shown for patients with other KIT mutations and PGDFR mutations in the study of Example 2, under a 150 mg ripretinib QD.

[0049] Figure 21 The median first occurrence and worst grade of hair loss and PPES in patients who received ripretinib in the study described in Example 2 are described.

[0050] Figure 22A The mean change in EORTC-QLQ-C30 results relative to baseline was described in patients receiving ripretinib in the study described in Example 2, with or without hair loss. Figure 22B The mean change from baseline in role function patients reported by patients receiving ripretinib in the study described in Example 2, with or without hair loss. Figure 22C The mean change from baseline in EORTC-QLQ-C30 results reported by patients receiving ripretinib in the study described in Example 2, in patients with / without palmoplantar erythema syndrome and who had lost sensation in their palms and soles. Figure 22D The mean change from baseline in role-function-reported EORTC-QLQ-C30 outcomes in patients receiving ripretinib in the study described in Example 2, with and without palmoplantar erythema syndrome.

[0051] Figure 23A The mean change from baseline in overall health status patient-reported EORTC-QLQ-C30 results in patients receiving ripretinib, with or without hair loss, is described in the study described in Example 2. Figure 23B The mean change from baseline in overall quality of life patient-reported EORTC-QLQ-C30 results in patients receiving ripretinib, with or without hair loss, is described in the study described in Example 2. Figure 23C The mean change from baseline in overall health patient-reported EORTC-QLQ-C30 results in patients receiving ripretinib in the study described in Example 2, with / without palmoplantar erythema syndrome. Figure 23D The study described in Example 2 describes the mean change from baseline in patients receiving ripretinib who reported EORTC-QLQ-C30 outcomes for quality of life in patients with / without palmoplantar erythema syndrome and who had lost sensation in their palms and soles.

[0052] Figure 24AThe mean change from baseline in EORTC-QLQ-C30 results reported by patients receiving ripretinib in the study described in Example 2, with or without hair loss. Figure 24B The mean change from baseline in EORTC-QLQ-C30 results reported by patients receiving ripretinib in the study described in Example 2, in patients with / without palmoplantar erythema syndrome and in patients with / without palmoplantar sensory loss syndrome.

[0053] Figure 25A and Figure 25B Exemplary PFS, PFS before dose escalation (PFS1), and PFS after dose escalation (PFS2) are described for subjects whose dose was increased to 150 mg BID.

[0054] Figure 26 A through D describe those with exon 9 ( Figure 26 A) Exon 11 ( Figure 26 B), Exon 13 ( Figure 26 C) or exon 17 ( Figure 26 D) Exemplary PFS comparison in subgroups of patients with KIT mutations. This exemplary data shows that ripretinib demonstrated a PFS benefit compared to placebo in all evaluated patient subgroups.

[0055] Figure 27 PFS data are shown for second- and third-line patients with symptomatic KIT mutations in exons 9, 11, 13, or 17. The data indicate that patients with these various KIT mutations have similar PFS in both the second- and third-line populations. Detailed Implementation

[0056] Features and other details of this disclosure will now be described in more specific terms. Certain terms used in the specification, embodiments, and appended claims are collected herein. These definitions should be read in light of the remainder of this disclosure and 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 one of ordinary skill in the art.

[0057] definition As used herein, “repretinib” is a compound represented by the following structure: As used herein, “sunitinib” is a compound represented by the following structure: As used herein, “imatinib” is a compound represented by the following structure: As used herein, “regorafenib” is a compound represented by the following structure: As used herein, “compound A” is a compound represented by the following structure: The terms “individual,” “patient,” or “subject” are used interchangeably herein and include any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, 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 domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Ideally, the mammals treated in the methods described herein are those requiring treatment for the conditions described herein, such as humans.

[0058] As used herein, the term "pharmaceutically acceptable salt" refers to a salt containing an acidic or basic group that may be present in the compound used in the composition. Compounds that are inherently basic and are included in the compositions of this invention are capable of forming a variety of salts with various inorganic and organic acids. The pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to: malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannins, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate).

[0059] As used in this article, “treatment” includes any effect that causes improvement of symptoms, disease, condition, etc., such as reducing, decreasing, regulating, or eliminating them.

[0060] "Therapeuticly effective amount" refers to the amount of the subject compound that will elicit a biological or medical response in a tissue, system, animal, or human sought by a researcher, veterinarian, physician, or other clinician. The compounds described herein (e.g., riprinib) are administered in a therapeutically effective amount to treat the conditions described herein, such as gastrointestinal stromal tumors. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect, such as an amount that results in the prevention or reduction of symptoms associated with the condition.

[0061] As used in this article, "AUC" 0-24h "AUC" refers to the area under the plasma concentration-time curve of the compound described herein from time 0 to 24 hours. As used herein, "AUC" is... 0-无限时间 "C" refers to the area under the plasma concentration-time curve for the compound described herein, from time zero to infinity. As used herein, "C" max "" refers to the maximum plasma concentration of the compound described in this article.

[0062] The compounds described herein (e.g., ripretinib) can be formulated into pharmaceutical compositions using pharmaceutically acceptable carriers and administered via a variety of routes. In some embodiments, such compositions are for oral administration. In some embodiments, compositions formulated for oral administration are provided in tablet form. In some embodiments, such compositions are for parenteral (by injection) administration (e.g., formulations for local injection at tumor sites (e.g., diffuse giant cell tumors)). In some embodiments, such compositions are for percutaneous administration. In some embodiments, such compositions are for local 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 methods of preparing them are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro et al., eds., 19th edition, Mack Publishing Co., 1995).

[0063] Treatment This document describes a method for treating gastrointestinal stromal tumors (GISTs) in patients of need. For example, this disclosure relates to a method for treating a patient with advanced GIST, comprising orally administering 100 mg or more (e.g., 100 mg to 5000 mg, 100 mg to 500 mg, 100 mg to 250 mg, 150 mg, etc.) of ripretinib daily to the patient, wherein the patient's tumor has progressed since prior first-line treatment with imatinib, or the patient is intolerant to prior first-line imatinib treatment. In some embodiments, the method comprises administering 110 mg of ripretinib daily to the patient. In some embodiments, the method comprises administering 120 mg of ripretinib daily to the patient. In some embodiments, the method comprises administering 130 mg of ripretinib daily to the patient. In some embodiments, the method comprises administering 140 mg of ripretinib daily to the patient. In some embodiments, the method comprises administering 150 mg of ripretinib daily to the patient. In some embodiments, the method includes administering 200 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 250 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 300 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 350 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 400 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 450 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 500 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 550 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 600 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 650 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 700 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 750 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 800 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 850 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 900 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 950 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 1000 mg of ripretinib to the patient daily.In some embodiments, the method includes administering 150 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 200 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 250 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 300 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 350 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 400 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 450 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 500 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 550 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 600 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 650 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 700 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 750 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 800 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 850 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 900 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 950 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 1000 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 150 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 200 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 250 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 300 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 350 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 400 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 450 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 500 mg of ripretinib to the patient twice daily.

[0064] In some implementations, the patient has previously received only first-line imatinib treatment, for example, imatinib was administered to the patient without any other therapeutic compounds before administering ripretinib. For example, the patient has not previously received sunitinib and / or regorafenib, such as having not previously received second-line sunitinib therapy and / or third-line regorafenib therapy.

[0065] In some embodiments, the patient has non-lymph node neoplasia with a length greater than or equal to 1.0 cm on the long axis, or with a length greater than or equal to twice the slide thickness, within 21 days prior to the first dose of ripretinib. The anticipated treatment regimen includes administration of ripretinib in 42-day cycles, comprising daily administration of ripretinib without sunitinib. Following at least one 42-day cycle including daily administration of ripretinib, the patient may have progression-free survival, as measured using mRECIST v1.1. In some embodiments, patients treated with daily ripretinib have significantly longer progression-free survival (e.g., approximately 3 months or longer, such as approximately 6 months) compared to a 42-day cycle of second-line administration of 50 mg sunitinib daily for four weeks followed by a two-week discontinuation of daily administration, where the patient's tumor has progressed since previous first-line administration of imatinib, or the patient is intolerant to previous first-line imatinib administration.

[0066] The intended treatment with ripretinib is to treat a broad spectrum of KIT and PDGFRA mutations. For example, a patient's tumor may have a KIT exon 9 mutation, a PDGFRA exon 18 mutation, a PDGFRA exon 12 mutation, or a PDGFRA exon 18 activation loop mutation. For example, the patient's tumor mutation is the PDGFRA D842V mutation.

[0067] In some embodiments, the patient's tumor has an imatinib resistance mutation selected from the following: KIT exon 17 activation loop mutation, KIT exon 18 activation loop mutation, KIT exon 13 mutation, KIT exon 14 mutation, KIT exon 18 mutation, PDGFRA exon 12 mutation, PDGFRA exon 14 mutation, PDGFRA exon 15 mutation, and PDGFRA exon 18 activation loop mutation. For example, the imatinib resistance mutation is the PDGFRA D842V mutation.

[0068] In some embodiments, the patient's tumor has an imatinib resistance mutation selected from the following: KIT exon 13 or 14 mutation, PDGFRA exon 14 or 15 mutation, KIT 17 or 18 activation loop mutation, and PDGFRA 18 activation loop mutation. For example, the patient's tumor has an imatinib resistance KIT exon 17 mutation.

[0069] This article also describes a method for treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering 100 mg or more (e.g., up to about 600 mg, e.g., up to about 250 mg, e.g., 100 mg or 150 mg) of ripretinib daily to the patient, wherein the patient's tumor has progressed since first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or wherein the patient is intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or wherein the patient has documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib. The anticipated treatment regimen comprises orally administering 100 mg, 150 mg or more of ripretinib daily for 42 days without sunitinib administration. In some embodiments, the method comprises administering 110 mg of ripretinib daily to the patient. In some embodiments, the method comprises administering 120 mg of ripretinib daily to the patient. In some embodiments, the method includes administering 130 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 140 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 150 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 200 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 250 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 300 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 350 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 400 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 450 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 500 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 550 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 600 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 650 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 700 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 750 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 800 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 850 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 900 mg of ripretinib to the patient daily.In some embodiments, the method includes administering 950 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 1000 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 150 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 200 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 250 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 300 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 350 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 400 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 450 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 500 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 550 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 600 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 650 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 700 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 750 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 800 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 850 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 900 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 950 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 1000 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 150 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 200 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 250 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 300 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 350 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 400 mg of ripretinib to the patient twice daily.In some embodiments, the method includes administering 450 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 500 mg of ripretinib to the patient twice daily.

[0070] In some embodiments, a method of treating a patient with advanced gastrointestinal stromal tumors includes orally administering 100 mg or more (e.g., up to about 600 mg, e.g., 100 mg to 250 mg, e.g., 100 mg to 500 mg, e.g., 100 mg to 250 mg, e.g., 150 mg) of ripretinib daily to the patient, taking into account prior treatment with at least two tyrosine kinase inhibitors. A contemplated treatment regimen includes orally administering 100 mg, 150 mg or more of ripretinib daily for 42 days without the administration of sunitinib. In some embodiments, the method includes administering 110 mg of ripretinib daily to the patient. In some embodiments, the method includes administering 120 mg of ripretinib daily to the patient. In some specific embodiments, the method includes administering 130 mg of ripretinib daily to the patient. In some embodiments, the method includes administering 140 mg of ripretinib daily to the patient. In some embodiments, the method includes administering 150 mg of ripretinib daily to the patient. In some embodiments, the method includes administering 200 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 250 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 300 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 350 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 400 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 450 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 500 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 550 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 600 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 650 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 700 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 750 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 800 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 850 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 900 mg of ripretinib to the patient daily. In some embodiments, the method includes administering 950 mg of ripretinib to the patient daily. In some embodiments, the method includes 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 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 includes administering 600 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 650 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 700 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 750 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 800 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 850 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 900 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 950 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 1000 mg of ripretinib to the patient once daily. In some embodiments, the method includes administering 150 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 200 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 250 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 300 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 350 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 400 mg of ripretinib to the patient twice daily. In some embodiments, the method includes administering 450 mg of ripretinib to the patient twice daily.In some embodiments, the method includes administering 500 mg of ripretinib to the patient twice daily. In some embodiments, the patient has previously been administered two separate tyrosine kinase inhibitors, each selected from imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, valsartanib, cranolab, and pharmaceutically acceptable salts thereof. In some embodiments, each tyrosine kinase inhibitor is independently selected from imatinib, sunitinib, and regorafenib. In some embodiments, each tyrosine kinase inhibitor is independently selected from imatinib mesylate, sunitinib malate, and regorafenib.

[0071] In some embodiments of the methods described herein, one or more tablets containing ripretinib are orally administered to the patient. For example, the disclosed methods include treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering one or more tablets containing ripretinib (e.g., each containing 50 mg to 100 mg of ripretinib) to the patient daily, wherein the patient's tumor has progressed since prior first-line treatment with imatinib, or the patient is intolerant to prior first-line treatment with imatinib. In some embodiments, one tablet containing ripretinib is administered to the patient. In some embodiments, one tablet containing 50 mg of ripretinib is administered to the patient. In some embodiments, one tablet containing 50 mg of ripretinib is administered to the patient once daily. In some embodiments, two tablets each containing 50 mg of ripretinib are administered to the patient. In some embodiments, two tablets each containing 50 mg of ripretinib are administered to the patient once daily. In some embodiments, three tablets each containing 50 mg of ripretinib are administered to the patient. In some embodiments, the patient is given three tablets, each containing 50 mg of ripretinib, once daily. In some embodiments, the patient is given four tablets, each containing 50 mg of ripretinib. In some embodiments, the patient is given four tablets, each containing 50 mg of ripretinib, once daily. In some embodiments, the patient is given five tablets, each containing 50 mg of ripretinib. In some embodiments, the patient is given five tablets, each containing 50 mg of ripretinib, once daily. In some embodiments, the patient is given six tablets, each containing 50 mg of ripretinib. In some embodiments, the patient is given six tablets, each containing 50 mg of ripretinib, once daily.

[0072] Additionally, the disclosed methods include methods for treating patients with advanced gastrointestinal stromal tumors, comprising orally administering one or more tablets containing ripretinib (e.g., tablets containing 50 mg to 100 mg of ripretinib) to the patient daily, wherein the patient's tumor has progressed since first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient is intolerant to first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient has documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib. In some embodiments, one tablet containing ripretinib is administered to the patient. In some embodiments, one tablet containing 50 mg of ripretinib is administered to the patient. In some embodiments, one tablet containing 50 mg of ripretinib is administered to the patient once daily. In some embodiments, two tablets containing 50 mg of ripretinib are administered to the patient. In some embodiments, the patient is given two tablets, each containing 50 mg of ripretinib, once daily. In some embodiments, the patient is given three tablets, each containing 50 mg of ripretinib. In some embodiments, the patient is given three tablets, each containing 50 mg of ripretinib, once daily.

[0073] In some embodiments, a method of treating a patient with advanced gastrointestinal stromal tumors is provided, comprising orally administering to the patient once daily one or more tablets, each containing ripretinib, for example, tablets containing 50 mg to 100 mg of ripretinib, wherein the patient has been administered at least two tyrosine kinase inhibitors prior to administration of the ripretinib. In some embodiments, the patient is administered one tablet containing ripretinib. In some embodiments, the patient is administered one tablet containing 50 mg of ripretinib. In some embodiments, the patient is administered one tablet containing 50 mg of ripretinib once daily. In some embodiments, the patient is administered two tablets, each containing 50 mg of ripretinib. In some embodiments, the patient is administered two tablets, each containing 50 mg of ripretinib, once daily. In some embodiments, the patient is administered three tablets, each containing 50 mg of ripretinib. In some embodiments, the patient is administered three tablets, each containing 50 mg of ripretinib, once daily. In some embodiments, the patient has previously been administered two separate tyrosine kinase inhibitors, each selected from imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, vatalanib, cranolab, and pharmaceutically acceptable salts thereof. In some embodiments, each tyrosine kinase inhibitor is independently selected from imatinib, sunitinib, and regorafenib. In some embodiments, each tyrosine kinase inhibitor is independently selected from imatinib mesylate, sunitinib malate, and regorafenib.

[0074] In another specific embodiment, this document describes a method for treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering 150 mg of ripretinib to the patient once daily, wherein the patient has been administered three or more tyrosine kinase inhibitors prior to administration of ripretinib. In some embodiments, the patient has at least 5 months of progression-free survival, as measured using mRECIST v1.1, after at least 4 weeks of daily administration of ripretinib. In some embodiments, orally administering 150 mg of ripretinib to the patient once daily comprises administering three tablets, each containing 50 mg of ripretinib. In some embodiments, one of the three or more tyrosine kinase inhibitors is imatinib. In some embodiments, the patient has been previously administered imatinib, sunitinib, and regorafenib.

[0075] In some embodiments, if the patient develops grade 3 palmoplantar anesthesia erythema syndrome after administration of ripretinib, the method further includes a) discontinuing administration of ripretinib for at least 7 days or until the patient has grade 1 or lower palmoplantar anesthesia erythema syndrome, and then administering 100 mg of ripretinib to the patient daily (e.g., 100 mg once daily) for at least 28 days.

[0076] In some embodiments, if the patient develops grade 2 palmoplantar erythema syndrome after administration of ripretinib, the method further comprises a) discontinuing ripretinib administration for at least 7 days or until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib to the patient daily; or c) if the patient does not recover, administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0077] In another embodiment, this document describes a method for treating a patient with advanced gastrointestinal stromal tumor, comprising administering 150 mg of ripretinib orally to the patient daily, wherein the patient’s tumor has progressed since first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or wherein the patient is intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib.

[0078] In some embodiments, if the patient develops grade 3 palmoplantar anesthesia erythema syndrome after administration of ripretinib, the method further includes a) discontinuing administration of ripretinib for at least 7 days or until the patient has grade 1 or lower palmoplantar anesthesia erythema syndrome, and then administering 100 mg of ripretinib to the patient daily (e.g., 100 mg once daily) for at least 28 days.

[0079] In some embodiments, if the patient develops grade 2 palmoplantar erythema syndrome after administration of ripretinib, the method further includes a) discontinuing ripretinib administration until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib to the patient daily; or c) if the patient does not recover, administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0080] In another specific embodiment, this document describes a method for treating a patient with advanced gastrointestinal stromal tumors, comprising orally administering 150 mg of ripretinib once or twice daily to the patient, wherein the patient's tumor has progressed since prior first-line treatment with imatinib, or the patient is intolerant to prior first-line treatment with imatinib. In some embodiments, if the patient develops grade 3 palmoplantar erythema syndrome after administration of ripretinib, the method further comprises a) discontinuing ripretinib administration for at least 7 days or until the patient has grade 1 or lower palmoplantar erythema syndrome, and then administering 100 mg of ripretinib daily (e.g., 100 mg once daily) to the patient for at least 28 days. In some embodiments, if the patient develops grade 3 palmoplantar erythema syndrome after administration of ripretinib, the method further comprises a) discontinuing ripretinib administration for at least 7 days or until the patient has grade 1 or lower palmoplantar erythema syndrome, and then administering 100 mg of ripretinib daily (e.g., 100 mg once daily) to the patient for at least 28 days. In some embodiments, if the patient develops grade 2 palmoplantar erythema syndrome after administration of ripretinib, the method further comprises a) discontinuing ripretinib administration until the patient has grade 1 or lower palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib daily to the patient; or c) if the patient does not recover, administering 100 mg of ripretinib daily to the patient for at least 28 days. In some embodiments, if the patient develops a grade 3 adverse condition selected from arthralgia or myalgia after administration of ripretinib, the method further comprises: a) discontinuing ripretinib administration until the patient has a grade 1 adverse condition or lower, and then administering 100 mg of ripretinib daily (e.g., 100 mg once daily) to the patient for at least 28 days. In some embodiments, if the patient develops grade 3 hypertension after administration of ripretinib, the method further comprises discontinuing ripretinib administration until the patient's blood pressure is controlled, and if the patient's blood pressure is grade 1 or lower, administering 150 mg of ripretinib daily; or if the patient's blood pressure is grade 1 or higher, administering 100 mg of ripretinib daily (e.g., 100 mg once daily).

[0081] In another embodiment, this document describes a method for achieving at least 5 months of progression-free survival as determined by mRECIST 1.1 in a patient with advanced gastrointestinal stromal tumors, comprising orally administering 100, 150, 200, or 300 mg of ripretinib once or twice daily for at least 28 days. In some embodiments, at least one prior kinase inhibitor has been administered to the patient. In some embodiments, at least three prior kinase inhibitors have been administered to the patient. In some embodiments, the at least one prior kinase inhibitor is imatinib. In some embodiments, the method includes orally administering 100, 150, or 200 mg of ripretinib once or twice daily for at least 4 months.

[0082] In another embodiment, this document describes a method for achieving at least 5 months of progression-free survival as determined by mRECIST 1.1 in a patient with advanced gastrointestinal stromal tumors, 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, at least one prior kinase inhibitor has been administered to the patient. In some embodiments, at least three prior kinase inhibitors have been administered to the patient. In some embodiments, the at least one prior kinase inhibitor is imatinib. In some embodiments, the method comprises orally administering 100, 150, or 200 mg of ripretinib to the patient daily or twice daily for at least 4 months.

[0083] In another embodiment, this document describes a method for treating a patient with grade 3 palmoplantar anesthesia erythema syndrome while administering 150 mg of ripretinib daily or twice daily, comprising discontinuing ripretinib for at least 7 days or until the patient has grade 1 or lower palmoplantar anesthesia erythema syndrome, and then administering 100 mg of ripretinib daily (e.g., once daily) to the patient for at least 28 days.

[0084] In another embodiment, this document describes a method for treating patients with grade 2 palmoplantar erythema syndrome following daily or twice-daily administration of 150 mg of ripretinib, comprising a) discontinuing ripretinib administration until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib to the patient daily; or c) if the patient does not recover, administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0085] In another embodiment, this document describes a method for treating a patient with gastrointestinal stromal tumors in need, wherein the patient is concurrently receiving CYP3A4 inhibitor therapy, the method comprising: orally administering 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof to the patient once or twice daily, wherein, compared to administration of ripretinib without concurrent CYP3A4 inhibitor therapy, administration of ripretinib and a CYP3A4 inhibitor provides an 80% or greater increase in the area under the curve (AUC) of ripretinib plasma concentration in the patient. 0-inf Therefore, these patients have a higher risk of adverse events; and adverse events in these patients are monitored more frequently compared to patients who have not received CYP3A4 inhibitor therapy. In some embodiments, if the patient has a grade 3 palmoplantar erythema syndrome adverse event, the method further includes a) discontinuing administration of ripretinib for at least 7 days or until the patient has a grade 1 or lower palmoplantar erythema syndrome, and then administering 100 mg of ripretinib to the patient daily for at least 28 days. In some embodiments, if the patient develops grade 2 palmoplantar erythema syndrome after administration of ripretinib, the method further comprises a) discontinuing ripretinib administration until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib daily to the patient; or c) if the patient does not recover, administering 100 mg of ripretinib daily to the patient for at least 28 days. In some embodiments, the CYP3A4 inhibitor is selected from itraconazole, ketoconazole, clarithromycin, and indinavir. In some embodiments, the CYP3A4 inhibitor is itraconazole. In some embodiments, the patient has previously been administered one or more tyrosine kinase inhibitors, each selected from imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, valtaranib, crenoranib, and pharmaceutically acceptable salts thereof.

[0086] In another embodiment, this document describes a method for treating a patient with gastrointestinal stromal tumors in need, wherein the patient is concurrently receiving proton pump inhibitor (PPI) therapy, the method comprising: orally administering 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof to the patient once or twice daily; wherein, following administration of ripretinib and the PPI, no clinically significant difference was provided in the patient's plasma exposure to ripretinib compared to a patient receiving ripretinib without concurrent PPI therapy. In some embodiments, the PPI is selected from pantoprazole, omeprazole, lansoprazole, rabeprazole, esomeprazole, and dextrolansoprazole. In some embodiments, the PPI is pantoprazole. In some embodiments, the patient concurrently receives 40 mg of the PPI once daily.

[0087] In another embodiment, this document describes a method for treating gastrointestinal stromal tumors in patients in need, the method comprising orally administering 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof to the patient once or twice daily, wherein ripretinib is administered to the patient with or without food. In some embodiments, the food comprises a high-fat meal (as described herein).

[0088] In some embodiments, the therapeutic efficacy of ripretinib is determined by progression-free survival in patients after independent radiological examination using the Responsive Evaluation Criteria for Solid Tumors (RECIST). In some embodiments, the therapeutic efficacy of ripretinib is determined by progression-free survival in patients after independent radiological review using the modified Responsive Evaluation Criteria for Solid Tumors (mRECIST). In some embodiments, the therapeutic efficacy of ripretinib is determined by objective response rate (ORR), time to progression (TTP), or overall survival (OS) in patients after independent radiological examination using mRECIST. In some embodiments, the therapeutic efficacy of ripretinib is determined by investigator-assessed progression-free survival. In some embodiments, the therapeutic efficacy of ripretinib is determined by the quality of life of patients according to the European Organization for Research and Treatment of Cancer Cancer Quality of Life Questionnaire 30 (EORTC-QLQ-C30) and the EuroQol 5-dimensional 5-level (EQ-5D-5L) questionnaire. In some embodiments, the therapeutic efficacy of ripretinib is determined by the disease control rate of said patients. In some embodiments, the therapeutic efficacy of ripretinib is determined by the duration of response in patients.

[0089] After at least one month, two months (e.g., 42 days or more) of treatment with ripretinib, the patients may have progression-free survival as measured using mRECIST v1.1. As another example, compared to placebo, after at least 4 weeks of daily administration of ripretinib and / or, for example, after at least 4 weeks of daily administration of ripretinib, the patients may have a progression-free survival of at least 5 or 6 months, significantly reducing the risk of disease progression or death by 85%.

[0090] In some embodiments, the patient has at least one measurable tumor lesion according to a modified RECIST version 1.1 within 21 days prior to the first dose of ripretinib. In some embodiments, the patient has a non-lymph node tumor lesion with a length greater than or equal to 1.0 cm on the long axis, or with a length greater than or equal to twice the sliding thickness on the long axis, within 21 days prior to the first dose of ripretinib.

[0091] In some embodiments, the patient's tumor has a KIT exon 9 mutation, a PDGFRA exon 18 mutation, a PDGFRA exon 12 mutation, or a PDGFRA exon 18 activation loop mutation. For example, the patient's tumor mutation is a PDGFRAD842V mutation.

[0092] In some embodiments, the patient's tumor has a mutation selected from imatinib resistance, sunitinib resistance, and / or regorafenib resistance: KIT exon 17 activation loop mutation, KIT exon 18 activation loop mutation, KIT exon 13 mutation, KIT exon 14 mutation, KIT exon 18 mutation, PDGFRA exon 12 mutation, PDGFRA exon 14 mutation, PDGFRA exon 15 mutation, and PDGFRA exon 18 activation loop mutation. For example, the anti-mutation is the PDGFRA D842V mutation.

[0093] In some embodiments, the patient's tumor has a drug-resistant mutation selected from the following: KIT exon 13 or 14 mutation, PDGFRA exon 14 or 15 mutation, KIT exon 17 or 18 activation loop mutation, and PDGFRA exon 18 activation loop mutation. For example, the tumor has a drug-resistant KIT exon 17 mutation.

[0094] Dosage adjustment Due to adverse events experienced by the patient, dose adjustments may be made in the manner of administration of ripretinib described herein. In some embodiments, the dose adjustment is a dose interruption. In some embodiments, the dose adjustment is a permanent cessation of administration. In some embodiments, the dose adjustment is a dose reduction. In some embodiments, the dose of ripretinib administered to the patient is reduced from 150 mg once daily (e.g., three tablets each containing 50 mg of ripretinib) to 100 mg once daily (e.g., two tablets each containing 50 mg of ripretinib). In some embodiments, the dose of ripretinib administered to the patient is reduced from 150 mg once daily (e.g., three tablets each containing 50 mg of ripretinib) to 50 mg once daily (e.g., one tablet each containing 50 mg of ripretinib). In some embodiments, the adverse reactions are selected from hand-foot skin reactions (e.g., palmoplantar erythema syndrome), hypertension, arthralgia, and myalgia.

[0095] In some implementations, adverse reactions are graded according to the National Cancer Institute's General Terminology Standard for Adverse Events, version 4.03 (e.g., baseline, grade 1, grade 2, grade 3, or grade 4). In some implementations, the dose adjustment is due to a grade 2 adverse event resulting in a dose interruption (e.g., a dose interruption of at least 7 days). In some implementations, if the adverse event decreases to grade 1 or baseline within a first time period (e.g., within 7 days), administration continues at the same dose level before the dose interruption. In some implementations, if the adverse event decreases to grade 1 or baseline after a first time period (e.g., after 7 days), administration continues at a reduced dose level before the dose interruption. In some implementations, if the adverse event decreases to grade 1 or baseline after a first time period (e.g., after 28 days) but remains at grade 1 or baseline after a second time period, the reduced dose level is increased back to the dose level before the dose interruption. In some implementations, the dose adjustment is due to a grade 3 adverse event resulting in a dose interruption (e.g., a dose interruption of at least 7 days to a maximum of 28 days). In some implementations, administration continues at a reduced level after the dose interruption. In some implementations, the dose adjustment is due to permanent discontinuation of dosing caused by a grade 4 adverse event (e.g., grade 4 hypertension).

[0096] Additional treatment may be administered to patients in response to or to prevent adverse events. In some embodiments, a topical composition (e.g., an emollient) is applied to a patient with an adverse skin reaction (e.g., hand-foot skin reaction, such as palmoplantar erythema anesthesia syndrome) to treat the adverse skin reaction. In some embodiments, a topical composition (e.g., an emollient) is applied to a patient based on the severity of the adverse skin reaction (e.g., grade 2, grade 3 adverse skin reaction, such as grade 1, grade 2, or grade 2 hand-foot skin reaction, such as grade 1, grade 2, or grade 3 palmoplantar erythema anesthesia 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 concurrently with a dose of ripretinib (e.g., a reduced dose of ripretinib).

[0097] Additional treatment may also be administered to a patient before or during administration of ripretinib, as described herein, to prevent or improve adverse events. In some embodiments, a topical composition (e.g., an emollient) may be administered to the patient before and / or during administration of ripretinib to prevent or improve the onset of adverse skin reactions (e.g., hand-foot skin reactions, such as palmoplantar erythema syndrome).

[0098] Example Example 1. An open-label randomized study to compare the efficacy of ripretinib versus sunitinib in patients with advanced GIST who had previously received imatinib.

[0099] Study Design. Approximately 358 eligible patients were randomly assigned in a 1:1 ratio to two groups: one group received 150 mg of ripretinib daily for 42 consecutive days (179 patients); the other group received 50 mg of sunitinib daily for 4 weeks over a 42-day period, followed by a 2-week break (179 patients).

[0100] Given the mutation-driven natural history of GIST and the well-described relationship between secondary mutations and the emergence of resistance to first- and second-line TKIs, the results of this study will evaluate ripretinib versus sunitinib as second-line treatment for GIST patients following imatinib therapy.

[0101] The primary endpoint of this study was progression-free survival (PFS) of ripretinib assessed using the modified Solid Tumor Response Evaluation Criteria version 1.1 (mRECIST v1.1) via blinded independent central assessment (BICR). Key secondary efficacy endpoints included objective response rate (ORR) assessed via BICR using mRECIST v1.1 and overall survival (OS).

[0102] Statistical analysis. PFS was defined as the time from randomization to the date of first documented disease progression or death from any cause, assessed based on the primary endpoint using BICR. OS was defined as the time from randomization to the date of death from any cause. OS and PFS at 95% CI were summarized using the Kaplan-Meier method, and point estimates of hazard ratios were obtained from a Cox regression model. Objective response was defined as CR or PR assessed using mRECIST v1.1 via BICR.

[0103] Example 2. A randomized, double-blind, placebo-controlled, international multicenter study was conducted to evaluate the safety, tolerability, and efficacy of ripretinib compared with placebo in patients with advanced GIST who had previously received treatment with imatinib, sunitinib, and regorafenib.

[0104] This was a randomized (2:1), double-blind, placebo-controlled, international multicenter study to evaluate the safety, tolerability, and efficacy of ripretinib compared to placebo in 129 patients with advanced GIST who had previously received at least imatinib, sunitinib, and regorafenib. Patients were randomized 2:1 to receive ripretinib 150 mg once daily or placebo. The primary efficacy endpoint was progression-free survival (PFS) as determined by independent radiological review using the Modified Response Evaluation Criteria for Solid Tumors (RECIST). Secondary endpoints determined by independent radiological review using RECIST included objective response rate (ORR), time to progression (TTP), and overall survival (OS).

[0105] Results. This study achieved the major endpoint of improved PFS, which was determined by blinded independent central radiological review using the modified response evaluation criteria for solid tumors (RECIST) version 1.1.

[0106] Compared to the placebo control group (1.0 month, 4.1 weeks), ripretinib demonstrated a median progression-free survival (PFS) of 6.3 months (27.6 weeks), representing a significant 85% reduction in the risk of disease progression or death compared to placebo (HR = 0.15, p < 0.0001). The 6-month PFS rate for ripretinib was 51% (95% CI: 39.4, 61.4), while that for placebo was 3.2% (95% CI: 0.2, 13.8). The survival probabilities corresponding to PFS in patients receiving ripretinib and those receiving placebo are illustrated in the figure below. Figure 1 middle.

[0107] For the key secondary endpoint of objective response rate (ORR) determined by blinded independent assessment center radiology review using the modified RECIST version 1.1, ripretinib showed an ORR of 9.4%, compared to 0% for placebo (p=0.0504), which was not statistically significant. Compared to placebo, ripretinib demonstrated a clinically meaningful improvement in the secondary endpoint of overall survival (OS) in this study (median OS 15.1 months vs. 6.6 months, HR = 0.36, nominal p=0.0004; 12-month OS rate for ripretinib was 65.4% (95% CI: 51.6, 76.1), compared to 25.9% for placebo (95% confidence interval: 7.2, 49.9)); however, because the ORR did not reach statistical significance, a hypothesis test for OS was not formally performed. The survival probabilities corresponding to OS in patients receiving ripretinib and placebo are illustrated in the figure below. Figure 2 In accordance with the stratified test procedure for pre-specified endpoints, a hypothesis test for OS could not be formally performed unless the ORR test was statistically significant. OS data for the placebo group included patients who received placebo and then crossed over to ripretinib after disease progression. A graph showing the survival probabilities corresponding to OS for patients receiving ripretinib, patients who crossed over from placebo to ripretinib, and patients who did not cross over is shown below. Figure 3 The survival probabilities of PFS for patients receiving ripretinib, patients who crossed over from placebo to ripretinib, and patients who did not cross over are shown in the figure. Figure 13 Furthermore, compared to patients receiving placebo, more patients receiving ripretinib had stable disease (SD) lasting 12 weeks (40 [47.1%] vs. 2 [4.5%]) and fewer cases of progression-progression (PD) (16 [18.8%] vs. 28 [63.6%]). The majority of patients with stable disease (SD) receiving ripretinib is noteworthy because progression-free survival is considered a key indicator of benefit from GIST treatment. Unlike many other advanced solid tumors, progression-free survival (whether partial response (PR) or SD) predicts PFS and OS benefit in advanced patients.

[0108] Tumors in patients who successfully crossed over from placebo were smaller than those in non-crossover patients (median sum of maximum target lesion diameters: 119.4 mm vs. 183.3 mm). Furthermore, the median age of crossover patients was higher than that of non-crossover patients (68.0 years vs. 58.0 years), with none having a baseline Eastern Cooperative Oncology Group (ECOG) score of 2, compared to 3 patients in the non-crossover group with an ECOG score of 2. The median PFS in crossover patients was 20.0 weeks [95% CI, 8.0–NE], compared to a median PFS of 27.6 weeks in the initial ripretinib group and 4.1 weeks in the initial placebo group. The median OS in crossover patients was 11.6 months, compared to a median OS of 15.1 months in patients initially randomized to ripretinib and 1.8 months in non-crossover patients receiving placebo. TEAEs during the crossover period indicated no safety issues compared to the safety profile of patients initially assigned to ripretinib.

[0109] Ripretinib was generally well tolerated, and adverse event outcomes were consistent with data from the previously submitted Phase 1 study. In the ripretinib group, 42 patients (49%) experienced grade 3 or 4 treatment-emergent adverse events (TEAEs), compared to 19 patients (44%) in the placebo group. In the ripretinib group, grade 3 or 4 TEAEs >5% occurred in anemia (9%; n=8), abdominal pain (7%; n=6), and hypertension (7%; n=6). In the placebo group, grade 3 or 4 TEAEs >5% occurred in anemia (14%; n=6). Table 1 lists the TEAEs >15% in the ripretinib group compared to the placebo group.

[0110] Table 1. Adverse events that occurred when patients were treated with ripretinib or placebo.

[0111] In Table 1, (1) represents the safety group, which includes 128 patients. One patient was randomly assigned to the placebo group but did not receive the study drug.

[0112] Patient-reported results Patient-reported outcomes were assessed using the EQ-5D-5L Visual Analogue Scale (VAS) and the EORTC QLQ-C30, which provides a physical and role function scale. The EQ-5D-5L VAS (or EQ-VAS) records the respondent's current overall health status on a vertical visual analog scale and provides a quantitative measure of the patient's perception of overall health status. These outcomes were reported over a 28-day cycle of receiving either 150 mg QD ripretinib or placebo.

[0113] Figure 5Patient-reported outcomes via EQ-VAS are described, showing the visual scales used to assess scores ( Figure 5 A) Change in score relative to baseline ( Figure 5 B) and the corresponding patient percentage distribution ( Figure 5 C). Patients receiving ripretinib showed a mean improvement in EQ-VAS score from baseline to 3.7 on cycle 2, day 1 (C2D1), compared to a mean decrease of 8.9 observed in placebo patients (p=0.004). 70 patients received ripretinib, and 32 patients received placebo.

[0114] The EORTC QLQ-C30 is an assessment of treatment function and symptoms in cancer patients and is not specific to any particular cancer. The EORTC QLQ-C30 consists of 30 questions plus an overall health status assessment, including 5 functional scales, 3 symptom scales, and an overall health status assessment.

[0115] Figure 6 Describes the physical function problems of EORTC QLQ-C30 ( Figure 6 A) Changes in patient scores relative to baseline in response ( Figure 6 B) and the corresponding patient percentage distribution ( Figure 6 C). Patients taking ripretinib showed a mean improvement in physical function scores from baseline to C2D1 of 1.6, compared to a mean decline in C2D1 of 8.9 observed in placebo patients (p=0.004). 71 patients received ripretinib, and 32 patients received placebo.

[0116] Figure 7 Describes the role functionality issues of EORTC QLQ-C30 ( Figure 7 A) Changes in patient scores relative to baseline in response ( Figure 7 B) and the corresponding patient percentage distribution ( Figure 7 C). The role function score of patients taking ripretinib improved from baseline to a mean C2D1 of 3.5, while the observed decline in C2D1 to 17.1 was observed in placebo patients (p=0.001). 70 patients received ripretinib, and 32 patients received placebo.

[0117] Figure 8 This describes the change in patient scores relative to baseline in response to EORTC QLQ-C30 question C29 (“How would you rate your overall health over the past week?”) ranging from 1 (“Very Poor”) to 7 (“Excellent”). Figure 8 A) and the corresponding patient percentage distribution ( Figure 8B). The C29 score improved by 0.20 in the ripretinib group, while it decreased by 0.78 in the placebo group (p=0.001). 70 patients received ripretinib, and 32 patients received placebo.

[0118] Figure 9 This describes the change in patient scores relative to baseline in response to the EORTC QLQ-C30 question C30 (“How would you rate your overall quality of life over the past week?”) ranging from 1 (“Very poor”) to 7 (“Excellent”). Figure 9 A) and the corresponding patient percentage distribution ( Figure 9 B). The score improved by 0.28 in the riprinib group and decreased by 0.76 in the placebo group (p=0.001). 70 patients received riprinib and 32 patients received placebo.

[0119] Figure 10 The mean changes in EQ-VSA baseline scores at different time points from day 15 of cycle 1 to day 1 of cycle 15 are described. Figure 11 A and Figure 11 B describes the mean changes in EORTC QLQ-C30 role function and EORTC QLQ-C30 physical function baseline scores at different time points from day 15 of cycle 1 to day 1 of cycle 15 in the intention-to-treat population. Figure 12 A and Figure 12 B describes the mean changes in baseline scores in the EORTC QLQ-C30 question C29 response and EORTC QLQ-C30 question C30 response at different time points from day 15 of cycle 1 to day 1 of cycle 15 in the intention-to-treat population.

[0120] Open-label phase and dose increase Patients whose disease progressed during the double-blind phase of the study had their dose increased to 150 mg BID riprecitinib and continued at a 150 mg QD dose or had their dose interrupted during the open-label phase of the study. Table 8 shows a comparison of patients receiving 150 mg QD riprecitinib at the data cutoff point in the double-blind phase versus the data cutoff point in the open-label phase. The data in Table 8 indicate that at 9 months following the initial double-blind analysis, the riprecitinib group showed improved median overall survival (mOS) and similar median progression-free survival (mPFS).

[0121] In this study, at least 31 patients had their dose increased to 150 mg BID riprecitinib during the open-label phase of disease progression. The progression-free survival (PFS) results for these patients during the double-blind and open-label phases are described separately. Figure 14 A and Figure 14 In B, Figure 14 C describes the midpoint PFS data.

[0122] Wild-type (KIT and PDGFRA) mutations PFS data were further evaluated in patients with wild-type KIT or PDGFRA mutations using a 150 mg ripretinib QD. PFS data for patients with these wild-type KIT and PDGFRA mutations were shown in... Figure 15 middle.

[0123] Additional mutation analysis Data on progression-free survival (PFS) and overall survival (OS) in patients with primary exon 11 mutations or non-exon 11 mutations, administered via a 150 mg ripretinib QD, were presented in [data missing]. Figure 16 In A (PFS) and 16B (OS), data showed that regardless of the primary mutation, whether it was a primary exon 11 mutation or a non-exon 11 primary mutation, GIST patients received similar benefits from ripretinib compared to placebo.

[0124] Data on progression-free survival (PFS) and overall survival (OS) in patients with primary exon 11 mutations or primary exon 9 mutations administered via 150 mg ripretinib QD were presented in... Figure 17 In A (PFS) and 17B (OS), data showed that, regardless of the primary mutation, GIST patients with exon 11 and exon 9 received similar benefits from ripretinib compared to placebo.

[0125] Furthermore, data on progression-free survival (PFS) and overall survival (OS) in patients with primary exon 11 mutations, primary exon 9 mutations, or other mutations, as well as wild-type (KIT and PDGFRA) patients on a 150 mg ripretinib QD regimen were presented. Figure 18 In A(PFS) and 19B(OS).

[0126] PFS studies in patients with specific primary mutations (exon 9 or exon 11) and whose dose was increased to 150 mg BID of ripretinib during the double-blind and open-label periods showed [data missing]. Figure 19 In A and 19B.

[0127] also, Figure 20 Exemplary progression-free survival data for patients with other KIT mutations and PGDFR mutations in the study of Example 2 are shown for 150 mg ripretinib QD.

[0128] Figure 26 A through D describe those with exon 9 ( Figure 26 A) Exon 11 ( Figure 26 B), Exon 13 ( Figure 26 C) or exon 17 ( Figure 26 D) Exemplary PFS comparison in subgroups of patients with KIT mutations. This exemplary data shows that ripretinib demonstrated a PFS benefit compared to placebo in all evaluated patient subgroups.

[0129] Example 3. Clinical study results of riprinib in patients with second- to fourth-line treatment plus GIST.

[0130] Results. Table 2 lists data from 178 GIST patients who received ripretinib at a dose >100 mg daily. The table includes objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) as assessed by the investigator based on best response, all of which were determined according to the Responsive Criteria for Solid Tumor Response (RECIST) version 1.1.

[0131] Table 2. Results / Clinical Studies of Ripretinib

[0132] In Table 2, (1) represents the total number of patients (n=178), which is the same as the previous data presented at ESMO 2018; based on additional data cleaning, one patient each from second-line and fourth-line / ≥ fourth-line were reclassified as third-line patients; (2) refers to the median duration of treatment: second-line = 44 weeks, third-line = 48 weeks, fourth-line = 46 weeks, and ≥ fourth-line = 29 weeks; (3) refers to the 60 patients who chose to increase their intra-patient dose from 150 mg QD to 150 mg BID; and (4) refers to the number of patients, which includes the 60 fourth-line patients.

[0133] Ripretinib was generally well tolerated, and the updated adverse events were consistent with previously presented Phase 1 data in GIST patients. Grade 3 or 4 treatment-acting adverse events (TEAEs) in >5% of patients included increased lipase (18%; n=33), anemia (11%; n=20), hypertension (7%; n=13), and abdominal pain (6%; n=11). 13% of patients (n=24) experienced TEAEs leading to study discontinuation, 17% (n=31) experienced TEAEs leading to dose reduction, and 49% (n=88) experienced TEAEs leading to study drug interruption. Table 3 lists TEAEs >10% in GIST patients treated with >100 mg ripretinib daily.

[0134] Table 3. Adverse events in patients receiving 100 mg ripretinib daily.

[0135] In Table 3, (1) refers to a patient who participated only in the food effect portion of a Phase 1 study; and (2) indicates that a dermatology skin test was performed to better assess skin lesions.

[0136] Example 4. Clinical study results of administering 150 mg QD ripretinib to patients receiving second- to fourth-line treatment plus GIST.

[0137] This study presents efficacy and safety results from the escalation and expansion phases of a Phase 1 study in patients with GIST treated with 150 mg QD ripretinib as the starting dose over a 28-day cycle. Patients were assessed every two cycles according to the Local Investigator Assessment Criteria for Solid Tumor Response version 1.1 (RECIST 1.1). In the expansion group, patients who progressed according to RECIST 1.1 were allowed to escalate the dose to 150 mg BID.

[0138] Of the 142 GIST patients in the ascending and expanding phases, 150 mg QD was administered. The number of patients receiving the second line of treatment was as follows: 31 second-line patients, 28 third-line patients, and 83 ≥ fourth-line patients. 135 patients (95.1%) had KIT-mutated GIST, and 7 patients (4.9%) had PDGFRA-mutated GIST.

[0139] Efficacy results for GIST patients receiving 150 mg QD ripretinib at the number of lines of treatment are presented in Table 4. For example, confirmed complete response (CR), partial response (PR), stable disease, and disease progression are presented in Table 4. Objective response rate data in Table 4 are related to the proportion of CR+PR patients. Median PFS data in Table 4 refer to investigator-assessed progression-free survival based on the number of lines of treatment. A PFS plot based on the number of lines of treatment is also shown. Figure 4 middle.

[0140] Table 4: Efficacy of treatment lines in patients receiving 150 mg QD riprecitinib.

[0141] In Table 4: a In the 150 mg QD group of GIST patients, 64 subjects escalated to 150 mg BID. CR, confidence interval; CR, complete response; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, standard deviation. Local (investigator) response assessment.

[0142] In subjects whose dose was increased to 150 mg BID, PFS before dose escalation (PFS1) and PFS after dose escalation (PFS2) were assessed and displayed separately. Figure 25A and25B The data supports the conclusion that, regardless of the treatment regimen, patients experienced additional clinical benefit as assessed by investigators after escalating the dose to 150 mg BID.

[0143] Mutation analysis Figure 27 PFS data are shown for exemplary second- and third-line patients with KIT mutations in exons 9, 11, 13, or 17. The data show that patients with these various KIT mutations have similar PFS in both the second- and third-line populations.

[0144] Example 5. Dosage adjustment protocol for ripretinib due to adverse reactions.

[0145] If a dose adjustment for ripretinib is necessary due to adverse reactions, the following regimen should be adopted: reduce the dose in increments of 50 mg (one tablet); the minimum recommended dose of ripretinib is 50 mg once daily. A summary of ripretinib dose reductions for adverse reactions is shown in Table 5.

[0146] Table 5: Recommended dose reduction for adverse reactions

[0147] For certain toxicities, dosing may be reduced, interrupted, or discontinued. See Table 6 for dosage adjustment guidelines.

[0148] Table 6: Recommended Dosage Adjustment for Ripretinib

[0149] Example 6. Safety of ripretinib and its impact on patient-reported outcomes in patients with alopecia and palmoplantar erythema syndrome (PPES).

[0150] The safety profile of ripretinib and the impact of alopecia and palmoplantar erythema syndrome (PPES) on patient-reported outcomes (PROs) in patients treated in the study described in Example 2 are described. In the Example 2 trial, ripretinib demonstrated a favorable overall safety and tolerability profile. When stratified according to alopecia and PPES, patient-reported assessments of function, overall health, and overall quality of life remained constant over time. For both alopecia and PPES, the onset and most severe episodes occurred almost simultaneously, indicating that these events do not typically worsen gradually. Overall, these results suggest that alopecia and PPES are manageable and that ripretinib treatment offset any negative effects associated with these AEs.

[0151] Patient-reported outcomes (PROs) were assessed using questions from the EuroQol 5D (EQ 5D 5L) and the European Organization for Research and Treatment of Cancer (EORTC) Cancer Quality of Life Questionnaire (EORTC QLQ C30).

[0152] The generalized estimating equation (GEE) model was used for statistical analysis, where: a repeated measures model across visits was used, with the result being 1 of 5 PROs; the model was only applicable to patients on ripretinib; for patients with alopecia, periods 1 and 2 were excluded to explain the median time to alopecia onset; covariates were sex, alopecia / PPES (present / absent), and baseline Eastern Cooperative Oncology Group (ECOG) score; when AEs did not have an end date, they were appropriately coded as extended to the last visit during the double-blind period.

[0153] In the ripretinib group, the most common treatment-emergent adverse event (TEAE) was alopecia (51.8%), and the most common grade 3 / 4 TEAE was anemia (9.4%). The highest severity classification for alopecia was grade 2; therefore, no patients in either group experienced grade 3 / 4 alopecia. In the ripretinib group, alopecia was slightly more common in women than in men (56.8% vs. 43.2%). In the ripretinib group, 21.2% of patients reported PPES; no patients had grade 3 PPES (grade 3 being the highest severity classification for PPES). No serious adverse events of alopecia or PPES were reported. In the ripretinib group, 7.1%, 23.5%, and 5.9% of patients experienced TEAEs leading to dose reduction, dose interruption, or death, respectively, compared to 2.3%, 20.9%, and 23.3% in the placebo group. In patients receiving ripretinib, the median worst grade of alopecia occurred shortly after the median first occurrence. Figure 21 In patients receiving ripretinib, the median first and worst PPRS grades occurred simultaneously. Figure 21 ).

[0154] Table 7 summarizes the GEE analysis of the correlation between alopecia and PPES with the five PRO measures in patients taking ripretinib. In the repeated measures analysis, the five PRO measures in patients with alopecia showed a trend of progressive improvement (Table 7). The presence of alopecia was associated with better self-reported overall quality of life (Table 7). This was statistically significant at P < 0.01, but did not exceed the threshold for meaningful change. There was no correlation between PPES and the five PRO measures (Table 7).

[0155] Table 7. Summary of GEE analysis of the correlation between alopecia and PPES and the five PRO measurements in patients taking ripretinib.

[0156] The longitudinal graph up to day 1 of cycle 10 shows that for patients receiving ripretinib who experienced hair loss or PPES, and for those who did not, the mean trend of change in 5 PROs was similar to baseline. Figure 22A , 22B 22C, 22D, 23A, 23B, 23C, 23D, 24A, and 24B).

[0157] Table 8. Comparison of cutoff time periods for double-blind and open-label data.

[0158] Example 7. Study of ripretinib and compound A with potent CYP3A inhibitors.

[0159] Concomitant administration of 150 mg QD ripretinib and a potent CYP3A inhibitor increases exposure to ripretinib and its active metabolite (compound A), which may increase the risk of adverse reactions. Concomitant administration of ripretinib and itraconazole (a potent CYP3A inhibitor and also a P-gp inhibitor) increased the Cmax of ripretinib by 36% and AUC... 0-inf It increases by 99%, and also increases the AUC of compound A. 0-inf It increases by 99%, while its Cmax remains unchanged.

[0160] Example 8. Study of ripretinib and proton pump inhibitors.

[0161] The effect of proton pump inhibitors (PPIs) on ripretinib exposure was evaluated. No clinically significant difference in plasma exposure was observed between ripretinib and compound A when ripretinib was co-administered with the PPI pantoprazole. Despite ripretinib's pH-dependent solubility, co-administration of 40 mg QD pantoprazole and 150 mg QD ripretinib did not affect ripretinib exposure.

[0162] Example 9. Study on the effects of food on exposure to ripretinib and compound A.

[0163] The effect of a high-fat breakfast on exposure to ripretinib and compound A was evaluated. High-fat diets consisted of approximately 150, 250, and 500–600 calories of protein, carbohydrates, and fat, respectively. The AUC of ripretinib was assessed after administration of ripretinib at a dose of 150 mg in conjunction with a high-fat diet. 0至24h The Cmax values ​​were 30% and 22% higher, respectively. For metabolite compound A, the AUC was significantly higher. 0至24h The Cmax and Cmax were 47% and 66% higher, respectively. Based on exposure-response analysis, the food effect was not considered clinically significant. Therefore, ripretinib can be taken daily at approximately the same time, with or without food.

[0164] This application includes the following implementation methods: 1. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100 mg to 300 mg of ripretinib to the patient daily, wherein the patient’s tumor has progressed since prior first-line administration of imatinib, or the patient is intolerant to prior first-line administration of imatinib.

[0165] 2. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100 mg to 600 mg of ripretinib to the patient daily, wherein the patient’s tumor has progressed since prior first-line administration of imatinib, or the patient is intolerant to prior first-line administration of imatinib.

[0166] 3. The method as described in item 1 or 2, wherein 150 mg of ripretinib is administered to the patient daily.

[0167] 4. The method as described in item 2, wherein 500 mg of ripretinib is administered to the patient daily.

[0168] 5. The method as described in item 1 or 2, wherein 150 mg of ripretinib is administered to the patient once daily.

[0169] 6. The method as described in item 2, wherein 150 mg of ripretinib is administered to the patient twice daily.

[0170] 7. The method as described in item 2, wherein 250 mg of ripretinib is administered to the patient twice daily.

[0171] 8. The method of any one of items 1 to 7, wherein the patient has previously been treated with imatinib as a first-line treatment only.

[0172] 9. The method as described in item 8, wherein the patient has not previously received second-line sunitinib treatment and / or third-line regorafenib treatment.

[0173] 10. The method of any one of items 1 to 9, wherein the patient has a non-lymph node neoplastic lesion with a length axis greater than or equal to 1.0 cm, or with a length axis greater than or equal to twice the sliding thickness, within 21 days prior to the first dose of riprinib.

[0174] 11. The method of any one of items 1 to 10, wherein the administration of ripretinib is in a 42-day cycle, comprising daily administration of ripretinib without administration of sunitinib.

[0175] 12. The method of claim 11, wherein after at least one 42-day cycle, the patient has progression-free survival as measured using mRECIST v1.1.

[0176] 13. The method as described in item 11 or 12, wherein the patient has significant progression-free survival compared to a 42-day cycle of second-line administration of 50 mg sunitinib daily for four weeks followed by a two-week cessation of daily administration, wherein the patient's tumor has progressed since the previous first-line administration of imatinib, or the patient is intolerant to the previous first-line administration of imatinib.

[0177] 14. The method of any one of claims 1 to 13, wherein the tumor has a KIT exon 9 mutation, a PDGFRA exon 18 mutation, a PDGFRA exon 12 mutation, or a PDGFRA exon 18 activation loop mutation.

[0178] 15. The method as described in item 14, wherein the mutation is the PDGFRA D842V mutation.

[0179] 16. The method of any one of claims 1 to 15, wherein the tumor has an imatinib resistance mutation selected from the following: KIT exon 17 activation loop mutation, KIT exon 18 activation loop mutation, KIT exon 13 mutation, KIT exon 14 mutation, KIT exon 18 mutation, PDGFRA exon 12 mutation, PDGFRA exon 14 mutation, PDGFRA exon 15 mutation, and PDGFRA exon 18 activation loop mutation.

[0180] 17. The method of claim 16, wherein the imatinib resistance mutation is the PDGFRA D842V mutation.

[0181] 18. The method of claim 16 or 17, wherein the tumor has an imatinib resistance mutation selected from the following: KIT exon 13 or 14 mutation, PDGFRA exon 14 or 15 mutation, KIT exon 17 or 18 activation loop mutation, and PDGFRA exon 18 activation loop mutation.

[0182] 19. The method of any one of items 15 to 18, wherein the tumor has an imatinib-resistant KIT exon 17 mutation.

[0183] 20. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100 mg to 250 mg of ripretinib to the patient daily, wherein the patient’s tumor has progressed since first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient is intolerant to first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient is known to be intolerant to one or more of imatinib, sunitinib, and / or regorafenib.

[0184] 21. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100 mg to 600 mg of ripretinib to the patient daily, wherein the patient's tumor has progressed since first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient is intolerant to first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient is known to be intolerant to one or more of imatinib, sunitinib, and / or regorafenib.

[0185] 22. The method as described in item 20 or 21, wherein 150 mg of ripretinib is administered to the patient daily.

[0186] 23. The method as described in item 21, wherein 500 mg of ripretinib is administered to the patient daily.

[0187] 24. The method as described in item 20 or 21, wherein 150 mg of ripretinib is administered to the patient once daily.

[0188] 25. The method as described in item 21, wherein 150 mg of ripretinib is administered to the patient twice daily.

[0189] 26. The method of item 21, wherein 250 mg of ripretinib is administered to the patient twice daily.

[0190] 27. The method of any one of items 20 to 26, wherein the patient has at least one measurable tumor lesion according to the modified RECIST version 1.1 within 21 days prior to the first dose of ripretinib.

[0191] 28. The method of any one of items 20 to 27, wherein the patient has a non-lymph node neoplastic lesion with a length greater than or equal to 1.0 cm or a length greater than or equal to twice the sliding thickness within 21 days prior to the first dose of riprinib.

[0192] 29. The method of any one of claims 20 to 28, wherein the tumor has a KIT exon 9 mutation, a PDGFRA exon 18 mutation, a PDGFRA exon 12 mutation, or a PDGFRA exon 18 activation loop mutation.

[0193] 30. The method as described in item 29, wherein the mutation is the PDGFRA D842V mutation.

[0194] 31. The method of any one of claims 20 to 30, wherein the tumor has a mutation selected from imatinib resistance, sunitinib resistance and / or regorafenib resistance: KIT exon 17 activation loop mutation, KIT exon 18 activation loop mutation, KIT exon 13 mutation, KIT exon 14 mutation, KIT exon 18 mutation, PDGFRA exon 12 mutation, PDGFRA exon 14 mutation, PDGFRA exon 15 mutation and PDGFRA exon 18 activation loop mutation.

[0195] 32. The method of claim 31, wherein the resistance mutation is the PDGFRA D842V mutation.

[0196] 33. The method of claim 31 or 32, wherein the tumor has a drug resistance mutation selected from the following: KIT exon 13 / 14 mutation, PDGFRA exon 14 or 15 mutation, KIT exon 17 or 18 activation loop mutation and PDGFRA exon 18 activation loop mutation.

[0197] 34. The method of any one of items 20 to 33, wherein the tumor has a drug-resistant KIT exon 17 mutation.

[0198] 35. The method of any one of items 20 to 34, wherein the administration of ripretinib is in a 42-day cycle, comprising daily administration of ripretinib without the administration of sunitinib.

[0199] 36. The method of claim 35, wherein after at least one 42-day cycle, the patient has progression-free survival as measured using mRECIST v1.1.

[0200] 37. The method of any one of items 20 to 36, wherein after daily administration of ripretinib for at least 4 weeks, the patient has a progression-free survival of at least 5 or 6 months compared to placebo.

[0201] 38. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering one or more tablets containing ripretinib to the patient daily, wherein the patient’s tumor has progressed since prior first-line administration of imatinib, or the patient is intolerant to prior first-line administration of imatinib.

[0202] 39. The method of claim 38, wherein three tablets containing 50 mg of ripretinib are administered to the patient once daily.

[0203] 40. The method of claim 38, wherein two tablets, each containing 50 mg of ripretinib, are administered to the patient once daily.

[0204] 41. The method of claim 38, wherein a tablet containing 50 mg of ripretinib is administered to the patient once daily.

[0205] 42. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering one or more tablets containing ripretinib to the patient daily, wherein the patient's tumor has progressed since first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient is intolerant to first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient is known to be intolerant to one or more of imatinib, sunitinib, and / or regorafenib.

[0206] 43. The method of claim 42, wherein three tablets, each containing 50 mg of ripretinib, are administered to the patient once daily.

[0207] 44. The method of claim 42, wherein two tablets, each containing 50 mg of ripretinib, are administered to the patient once daily.

[0208] 45. The method of claim 42, wherein a tablet containing 50 mg of ripretinib is administered to the patient once daily.

[0209] 46. ​​A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100 mg to 600 mg of ripretinib to the patient daily, wherein the patient has been previously administered at least two tyrosine kinase inhibitors prior to administration of ripretinib.

[0210] 47. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 150 mg of ripretinib to the patient once daily, wherein the patient has been previously administered at least two tyrosine kinase inhibitors prior to administration of ripretinib.

[0211] 48. A method for treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering one or more tablets each containing ripretinib, for example, tablets each containing 50 mg to 100 mg of ripretinib, to the patient prior to administration of ripretinib, wherein at least two tyrosine kinase inhibitors have been previously administered to the patient.

[0212] 49. The method of claim 48, wherein three tablets, each containing 50 mg of ripretinib, are administered to the patient once daily.

[0213] 50. The method of any one of items 46 to 49, wherein the patient has previously been administered two separate tyrosine kinase inhibitors, each selected from imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, valtaranib, crenoranib, and pharmaceutically acceptable salts thereof.

[0214] 51. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 150 mg of ripretinib to the patient once daily, wherein the patient has been previously administered three or more kinase inhibitors prior to administration of ripretinib.

[0215] 52. The method of claim 51, wherein, after daily administration of ripretinib for at least 4 weeks, the patient has at least 5 months of progression-free survival as measured using mRECIST v1.1.

[0216] 53. The method of claim 51 or 52, wherein oral administration of 150 mg of ripretinib to the patient once daily comprises administering three tablets to the patient, each tablet containing 50 mg of ripretinib.

[0217] 54. The method of any one of claims 51 to 53, wherein one of the three or more kinase inhibitors is imatinib.

[0218] 55. The method of any one of items 51 to 54, wherein the patient has previously been administered imatinib, sunitinib, and regorafenib.

[0219] 56. The method of any one of claims 51 to 55, wherein if the patient has grade 3 palmoplantar anesthesia syndrome after administration of ripretinib, the method further comprises a) discontinuing administration of ripretinib for at least 7 days or until the patient has grade 1 or lower palmoplantar anesthesia syndrome, and then administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0220] 57. The method of any one of claims 51 to 55, wherein if the patient has grade 2 palmoplantar erythema syndrome after administration of ripretinib, the method further comprises a) discontinuing administration of ripretinib until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib to the patient daily; or c) if the patient does not recover, administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0221] 58. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising administering 150 mg of ripretinib orally to the patient daily, wherein the patient’s tumor has progressed since first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib, or wherein the patient is intolerant to first-line treatment with imatinib, second-line treatment with sunitinib, and third-line treatment with regorafenib.

[0222] 59. The method of claim 58, wherein if the patient has grade 2 palmoplantar anesthesia syndrome after administration of ripretinib, the method further comprises a) discontinuing administration of ripretinib for at least 7 days or until the patient has grade 1 or lower palmoplantar anesthesia syndrome, and then administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0223] 60. The method of claim 58, wherein if the patient develops grade 2 palmoplantar erythema syndrome after administration of ripretinib, the method further comprises a) discontinuing administration of ripretinib until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib to the patient daily; or c) if the patient does not recover, administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0224] 61. A method of treating a patient with advanced gastrointestinal stromal tumor, comprising orally administering 150 mg of ripretinib to the patient once or twice daily, wherein the patient’s tumor has progressed since prior first-line administration of imatinib, or the patient is intolerant to prior first-line administration of imatinib.

[0225] 62. The method of claim 61, wherein if the patient has grade 3 palmoplantar anesthesia syndrome after administration of ripretinib, the method further comprises a) discontinuing administration of ripretinib for at least 7 days or until the patient has grade 1 or lower palmoplantar anesthesia syndrome, and then administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0226] 63. The method of any one of claims 3 to 20, wherein if the patient has grade 3 palmoplantar anesthesia syndrome after administration of ripretinib, the method further comprises a) discontinuing administration of ripretinib for at least 7 days or until the patient has grade 1 or lower palmoplantar anesthesia syndrome, and then administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0227] 64. The method of any one of claims 3 to 20, wherein if the patient develops grade 2 palmoplantar erythema syndrome after administration of ripretinib, the method further comprises a) discontinuing administration of ripretinib until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib to the patient daily; or c) if the patient does not recover, administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0228] 65. The method of any one of items 3 to 20, wherein if the patient suffers from a grade 3 adverse condition selected from arthralgia or myalgia after administration of ripretinib, the method further comprises: a) discontinuing administration of ripretinib until the patient has a grade 1 adverse condition or lower, and then administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0229] 66. The method of any one of claims 3 to 20, wherein if the patient has grade 3 hypertension after administration of ripretinib, the method further comprises discontinuing administration of ripretinib until the patient's blood pressure is controlled, administering 150 mg of ripretinib to the patient daily if the patient's blood pressure is below or equal to grade 1, or administering 100 mg of ripretinib to the patient daily if the patient's blood pressure is above grade 1.

[0230] 67. A method for achieving at least 5 months of progression-free production as determined by mRECIST 1.1 in a patient with advanced gastrointestinal stromal tumor, comprising orally administering 100, 150, 200, or 300 mg of ripretinib to said patient daily or twice daily for at least 28 days.

[0231] 68. The method of claim 67, wherein at least one prior kinase inhibitor has been administered to the patient.

[0232] 69. The method of any one of items 67 to 68, wherein at least three prior kinase inhibitors have been administered to the patient.

[0233] 70. The method of claim 68 or 69, wherein the at least one prior kinase inhibitor is imatinib.

[0234] 71. The method of any one of items 67 to 70, comprising administering 100, 150, or 200 mg of ripretinib orally to the patient once daily or twice daily for at least 4 months.

[0235] 72. A method of treating a patient with grade 3 palmoplantar erythema syndrome while administering 150 mg of ripretinib daily or twice daily, comprising discontinuing ripretinib for at least 7 days or until the patient has grade 1 or lower palmoplantar erythema syndrome, and then administering 100 mg of ripretinib daily to the patient for at least 28 days.

[0236] 73. A method of treating a patient with grade 2 palmoplantar erythema syndrome following administration of 150 mg of ripretinib daily or twice daily, comprising a) discontinuing ripretinib administration until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib daily to the patient; or c) if the patient does not recover, administering 100 mg of ripretinib daily to the patient for at least 28 days.

[0237] 74. A method for treating a patient with a gastrointestinal stromal tumor, wherein the patient is simultaneously receiving CYP3A4 inhibitor therapy, the method comprising: 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof shall be administered orally to the patients once or twice daily, wherein, compared with administration of ripretinib without concurrent CYP3A4 inhibitor therapy, administration of ripretinib and a CYP3A4 inhibitor provides an 80% or greater increase in the area under the curve (AUC) of ripretinib plasma concentration in the patients. 0-inf Therefore, these patients have a higher risk of adverse events; and Adverse events in these patients were monitored more frequently compared to patients who did not receive CYP3A4 inhibitor therapy.

[0238] 75. The method of claim 74, wherein if the patient has a grade 2 palmoplantar erythema syndrome adverse event, the method further comprises a) discontinuing administration of ripretinib for at least 7 days or until the patient has a grade 1 or lower palmoplantar erythema syndrome, and then administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0239] 76. The method of claim 75, wherein if the patient has grade 2 palmoplantar erythema syndrome at the time of administration of ripretinib, the method further comprises a) discontinuing administration of ripretinib until the patient has grade 1 palmoplantar erythema syndrome or baseline; b) if the patient recovers from palmoplantar erythema syndrome within 7 days of discontinuation, administering 150 mg of ripretinib to the patient daily; or c) if the patient does not recover, administering 100 mg of ripretinib to the patient daily for at least 28 days.

[0240] 77. The method of any one of items 74 to 76, wherein the CYP3A4 inhibitor is selected from itraconazole, ketoconazole, clarithromycin and indinavir.

[0241] 78. The method of any one of items 74 to 77, wherein the CYP3A4 inhibitor is itraconazole.

[0242] 79. The method of any one of items 74 to 78, wherein the patient has previously been administered one or more tyrosine kinase inhibitors, each selected from imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, valtaranib, crenoranib, and pharmaceutically acceptable salts thereof.

[0243] 80. A method for treating a patient with a gastrointestinal stromal tumor in need, wherein the patient is concurrently receiving proton pump inhibitor therapy, the method comprising: orally administering 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof to the patient once or twice daily; wherein, following administration of ripretinib and the proton pump inhibitor, no clinically significant difference was provided in the patient's plasma exposure to ripretinib compared to a patient receiving ripretinib without concurrent proton pump inhibitor therapy.

[0244] 81. The method of claim 80, wherein the proton pump inhibitor is selected from pantoprazole, omeprazole, lansoprazole, rabeprazole, esomeprazole and dextrorotatory lansoprazole.

[0245] 82. The method of claim 80 or 81, wherein the proton pump inhibitor is pantoprazole.

[0246] 83. The method of any one of claims 80 to 82, wherein the patient receives 40 mg of the proton pump inhibitor once daily.

[0247] 84. A method for treating a patient with a gastrointestinal stromal tumor, the method comprising orally administering 100 mg or 150 mg of ripretinib or a pharmaceutically acceptable salt thereof to the patient once or twice daily, wherein the ripretinib is administered to the patient with or without food.

[0248] 85. The method as described in item 83, wherein the food comprises a high-fat diet.

[0249] equivalent Using only conventional experiments, those skilled in the art will recognize or be able to identify many equivalents of the particular embodiments specifically described herein. All such equivalents are included within the scope of the appended claims.

Claims

1. Use of the compound represented by the following formula in the preparation of a medicament for treating gastrointestinal stromal tumors in patients who are concurrently receiving CYP3A4 inhibitor therapy and who require such treatment. in Compared with administration of the compound without concurrent CYP3A4 inhibitor treatment, administration of the compound and a CYP3A4 inhibitor provided an 80% or greater increase in the area under the plasma concentration curve (AUC). 0-inf );and The drug is a tablet containing 50 mg of the compound.

2. The use as described in claim 1, wherein the patient has a higher risk of adverse events.

3. The method of claim 1 or 2, wherein the CYP3A4 inhibitor is selected from itraconazole, ketoconazole, clarithromycin, and indinavir.

4. The use as described in any one of claims 1 to 3, wherein the CYP3A4 inhibitor is itraconazole.

5. The use as described in any one of claims 1 to 4, wherein the tumor has been previously treated with one or more tyrosine kinase inhibitors, each tyrosine kinase inhibitor being selected from imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, vastarabine, crenoranib, and pharmaceutically acceptable salts thereof.

6. The use as claimed in any one of claims 1 to 5, wherein the tumor has been previously treated with three or more kinase inhibitors prior to the administration of the compound.

7. The use as described in claim 5, wherein the tumor was previously treated with imatinib only as a first-line therapy.

8. The use as described in claim 7, wherein the tumor has not previously been treated with second-line sunitinib and / or third-line regorafenib.

9. The use as described in claim 6, wherein one of the three or more kinase inhibitors is imatinib.

10. The use as described in claim 9, wherein the tumor has been previously treated with imatinib, sunitinib, and regorafenib.

11. The use as described in claim 10, wherein the tumor progressed after first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib.

12. The use according to any one of claims 1 to 11, wherein the tumor is at least one measurable tumor lesion according to a modified RECIST version 1.1 within 21 days prior to the first dose of the compound.

13. The use according to any one of claims 1 to 12, wherein the tumor is a non-lymph node tumor lesion having a length axis greater than or equal to 1.0 cm or having a length axis greater than or equal to twice the sliding thickness within 21 days prior to the first dose of the compound.

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