Ripretinib for treating gastrointestinal stromal tumors

Abstract

To provide methods of treating gastrointestinal stromal tumors to a subject in need of treatment of the gastrointestinal stromal tumors.SOLUTION: A method of treating a patient suffering from an advanced gastrointestinal stromal tumor comprises orally administering to the patient 100 mg to 300 mg of ripretinib daily, where the patient's tumor has progressed from, or the patient was intolerant to, a previous first line administration of imatinib.SELECTED DRAWING: Figure 1

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Patent No. 62 / 885,797, filed August 12, 2019, U.S. Patent No. 62 / 904,198, filed September 23, 2019, U.S. Patent No. 62 / 926,281, filed October 25, 2019, U.S. Patent No. 62 / 936,018, filed November 15, 2019, U.S. Patent No. 62 / 968,927, filed January 31, 2020, U.S. Patent No. 62 / 968,945, filed January 31, 2020, U.S. Patent No. 63 / 023,921, filed May 13, 2020, and U.S. Patent No. 63 / 023,936, filed May 13, 2020, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Gastrointestinal stromal tumors (GISTs) comprise less than 1% of all gastrointestinal (GI) tumors but constitute the most common mesenchymal tumors and soft tissue sarcomas of the GI tract. They can occur anywhere along the GI tract but are most often found in the stomach (60%) or small intestine (30%), and are less frequently found in the rectum, colon, or mesentery. Approximately 3,300 to 6,000 new cases of GIST are diagnosed each year in the United States. The majority of cases are sporadic, and older age is a recognized risk factor. Mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA) are found in more than 80% of all primary GISTs. Alterations in the neurofibromatosis type 1 gene (NF1) and succinate dehydrogenase (SDH) complex (SDHC) genes, as well as altered methylation of the SDHC promoter, have been described as oncogenic drivers in GISTs without activating mutations in KIT or PDGFRA, which are associated with familial and genetic syndromes (NF1 and Carney-Stratakis syndrome).

[0003] Despite wide variation in tumor size, location, and histological subtype (spindle cell, epithelioid, and mixed), approximately 85% of all GISTs share oncogenic mutations in one of two receptor tyrosine kinases (TKs): KIT or PDGFRA. Constitutive activation of either of these TKs plays a central role in the oncogenic behavior of GISTs. Early characterization of GIST mutational status is important in both localized and metastatic settings to identify imatinib-resistant mutations (such as some primary KIT exon 17 mutations or PDGFRA D842V) or mutations requiring higher doses of imatinib. Patients with GISTs 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, the largest group being represented by SDH deficiency, often associated with Carney or Carney-Stratakis syndrome. Other subtypes harbor mutations in NF1 (usually associated with neurofibromatosis type 1) or BRAF or KRAS. More recently, speculative cases of GIST-like tumors harboring NTRK translocations have further expanded the spectrum of molecular subtypes.

[0004]

[0004] In the era before tyrosine precursor kinase inhibitors (TKIs), GISTs (often classified as gastric leiomyosarcoma or leiomyoblastoma) were treated within the agnostic subtype of sarcoma and lacked effective systemic therapies. However, a deeper understanding of the molecular pathogenesis and driving role of the proto-oncogenes KIT and PDGFRA has transformed the treatment of both localized and metastatic disease. Localized and resectable tumors are often treated surgically. Although it is commonly treated with imatinib, it remains the mainstay of curative therapy for localized disease. Resected high-risk GISTs are typically treated with adjuvant imatinib, whereas low-risk GISTs are managed with surgery alone. Intermediate-risk GISTs are managed on a case-by-case basis. In the advanced / metastatic setting, imatinib 400 mg daily, with dose escalation to 800 mg at progression, has been approved and has shown dramatic results in disease control. Imatinib-refractory patients are treated with sunitinib as second-line therapy and regorafenib as third-line therapy for resistance or intolerance to sunitinib.

[0005] At diagnosis, mutations in the KIT gene occur in 80% of GISTs, usually found in exon 11 and less commonly in exon 9. Both mechanisms result in ligand-independent receptor activation, which leads to uncontrolled cell growth and transformation. Primary mutations affect loss-of-function mutations in the JM domain, resulting in a shift in equilibrium toward the type I active or on-state conformation of KIT and away from the type II inactive or off-state conformation of KIT. Exon 11 primary mutations are most commonly found in GISTs (approximately 70% of cases) and lead to significant benefit from treatment with imatinib in both the adjuvant and metastatic setting, achieving a 2-year recurrence-free survival rate of approximately 90% in the adjuvant setting and a median event-free survival of just under 2 years in the metastatic setting. Primary exon 9 mutations (in treatment-naive patients) affect the extracellular domain of KIT, mimicking the conformational change induced by ligand binding and inducing KIT receptor homodimerization. This dimerization leads to the activation of specific intracellular signaling pathways, which may result in cancer cell proliferation, survival, and resistance. Although less common than exon 11 mutations, exon 9 mutations (10%–15% of newly diagnosed cases) are most commonly found in GISTs arising from the small intestine. Unlike exon 11 mutations, they do not significantly benefit from imatinib in both the adjuvant and metastatic settings.

[0006] Despite significant improvements in outcomes compared to the previous era of mutation-driven / TKI therapy, not all patients experience a response to imatinib, and most patients with GIST eventually develop resistance to imatinib, most commonly due to the development of secondary mutations in KIT. Secondary resistance mutations usually occur in the catalytic domain of the kinase: 1) in the switch pocket, which typically occurs in KIT exons 13 and 14 or PDGFRA exons 14 and 15 and sterically disrupts drug binding or conformationally activates KIT, and 2) in the activation loop switch encoded by KIT exons 17 and 18 and PDGFRA exons 18. Activation loop mutations act by shifting the kinase into an activated type I or on-state conformation that is less amenable to drug binding by any of the approved type II TKIs. Although rare in primary GIST (1%-2% of newly diagnosed cases), mutations in exons 13, 14, and 17 are often the cause of acquired imatinib resistance, with exon 17 mutations alone accounting for 50% of cases of acquired resistance to imatinib and later sunitinib. There is a need for TKIs that can broadly inhibit clinically relevant KIT and PDGFRA mutations. Summary of the Invention

[0007]

[0007] Described herein is a method for treating gastrointestinal stromal tumors in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of ripretinib or a pharmaceutically acceptable salt thereof.

[0008] For example, in one embodiment, described herein is a method of treating a patient suffering from an advanced gastrointestinal stromal tumor, comprising administering to the patient 100 mg to 300 mg, e.g., 1 The method involves administering 50 mg of ripretinib orally daily, and the patient's tumor has progressed from or the patient is intolerant to a previous first-line dose of imatinib.

[0009] For example, in one embodiment, described herein is a method of treating a patient suffering from an advanced gastrointestinal stromal tumor, comprising orally administering to the patient 100 mg to 250 mg, e.g., 150 mg, of ripretinib daily, wherein the patient's tumor has progressed on or the patient is intolerant to a previous first-line dose of imatinib.

[0010]

[00010] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient with rituximab, comprising orally administering to the patient 100 mg to 600 mg, e.g., 100 mg to 250 mg, e.g., 150 mg, of ripretinib daily, wherein the patient's tumor has progressed from or the patient was intolerant to a previous first-line dose of imatinib.

[0011]

[00011] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis, comprising daily orally administering to the patient one or more tablets containing ripretinib, e.g., tablets each containing 50 mg to 100 mg of ripretinib, wherein the patient's tumor has progressed from or the patient is intolerant to a previous first-line administration of imatinib. 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.

[0012]

[00012] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis, comprising daily orally administering to the patient one or more tablets containing ripretinib, e.g., tablets each containing 50 mg to 100 mg of ripretinib, wherein the patient's tumor has progressed from or the patient was intolerant to a previous first-line administration of imatinib, a previous second-line administration of sunitinib, and a previous third-line administration of regorafenib, or 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 examples, the tablet contains 75 mg of ripretinib. In some examples, the tablet contains 100 mg of ripretinib. In another embodiment, described herein is a method of treating a patient suffering from an advanced gastrointestinal stromal tumor, comprising orally administering to the patient 100 mg to 250 mg of ripretinib daily, for example 150 mg, wherein the patient's tumor has progressed from or the patient has been intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or the patient has documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib.

[0013]

[00013] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient with rituximab, comprising orally administering to the patient 100 mg to 600 mg of ripretinib daily, for example 100 mg to 250 mg, for example 100 mg to 500 mg, for example 100 mg to 250 mg, for example 150 mg, wherein the patient's tumor has progressed from or the patient was intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or the patient has documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib.

[0014]

[00014] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rituximab, comprising daily oral administration of one or more tablets each containing ripretinib, for example, tablets each containing 50 mg to 100 mg of ripretinib, to the patient, wherein the patient's tumor has progressed from or the patient was intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or the patient has 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.

[0015]

[00015] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis, comprising orally administering to the patient 100 mg to 600 mg of ripretinib daily, for example, 100 mg to 250 mg, for example, 100 mg to 500 mg, for example, 100 mg to 250 mg, for example, 150 mg, for example, 300 mg, wherein the patient has previously been administered at least two tyrosine kinase inhibitors prior to administration of ripretinib.

[0016]

[00016] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis, comprising orally administering 150 mg of ripretinib once daily to the patient, wherein the patient has previously received at least two tyrosine kinase inhibitors prior to administration of ripretinib.

[0017]

[00017] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis (rheumatoid arthritis) comprising daily orally administering to the patient one or more tablets each containing ripretinib, e.g., tablets each containing 50 mg to 100 mg of ripretinib, wherein the patient has previously administered at least two tyrosine kinase inhibitors prior to administration of 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.

[0018]

[00018] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis, comprising orally administering 150 mg of ripretinib once daily to the patient, wherein the patient has previously received three or more tyrosine kinase inhibitors prior to administration of ripretinib. In some embodiments, after at least four weeks of daily ripretinib administration, the patient has a progression-free survival of at least five months as measured using mRECIST v1.1. In some embodiments, orally administering 150 mg of ripretinib once daily to the patient comprises administering three tablets to the patient, each tablet containing 50 mg of ripretinib. In some embodiments, one of the three or more kinase inhibitors is imatinib. In some embodiments, the patient has previously received imatinib, sunitinib, and regorafenib.

[0019]

[00019] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient with rituximab, comprising orally administering 150 mg of ripretinib daily to the patient, wherein the patient's tumor has progressed from or the patient was intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib.

[0020]

[00020] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis, comprising administering 150 mg of ripretinib once daily or involves two oral doses in which the patient's tumor has progressed from or the patient is intolerant to a previous first-line dose of imatinib.

[0021]

[00021] In another embodiment, described herein is a method for treating a patient with advanced gastrointestinal stromal tumors. 1. A method for achieving at least 5 months progression-free survival as determined by mRECIST 1.1 in a patient with refractory leukemia, the method comprising orally administering to the patient 100, 150, 200, or 300 mg of ripretinib daily or twice daily for at least 28 days.

[0022]

[00022] In another embodiment, described herein is a method for treating a patient with advanced gastrointestinal stromal tumors. 1. A method for achieving progression-free survival of at least 5 months as determined by mRECIST 1.1 in a patient with refractory leukemia, the method comprising orally administering to the patient 100, 150, or 200 mg of ripretinib daily or twice daily for at least 28 days.

[0023]

[00023] In another embodiment, described herein is 150 mg of ripretinib daily or twice daily while suffering from Grade 3 palmar-plantar erythrodysesthia, the method comprising withholding administration of ripretinib for at least 7 days or until the patient has Grade 1 or less palmar-plantar erythrodysesthia, and then administering 100 mg daily (e.g., 100 mg once daily) of ripretinib to the patient for at least 28 days.

[0024]

[00024] In another embodiment, described herein are 15 daily or twice daily doses of 1. A method of treating a patient suffering from Grade 2 palmar-plantar erythrodysesthesia syndrome upon administration of 0 mg ripretinib, the method further comprising: a) withholding administration of ripretinib until the patient has palmar-plantar erythrodysesthesia syndrome of Grade 1 or less or baseline; b) if the patient recovers from palmar-plantar erythrodysesthesia syndrome within 7 days of withholding administration, then administering 150 mg daily ripretinib to the patient; or c) if the patient has not recovered, then administering 100 mg daily ripretinib to the patient for at least 28 days.

[0025]

[00025] In another embodiment, described herein is a method for treating gastrointestinal stromal tumors. 1. A method of treating gastrointestinal stromal tumors in a patient having a gastrointestinal stromal tumor, wherein the patient is being concomitantly treated with a CYP3A4 inhibitor, the method comprising orally administering to the patient 100 mg or 150 mg of ripretinib, or a pharmaceutically acceptable salt thereof, once or twice daily, wherein upon administration of ripretinib and the CYP3A4 inhibitor, an area under the plasma concentration curve (AUC) of 80% or greater is achieved in the patient compared to administration of ripretinib without concomitant treatment with a CYP3A4 inhibitor. 0-inf ) and therefore the patient is at higher risk of adverse events; and monitoring the patient more frequently for adverse events compared to patients not treated with a CYP3A4 inhibitor.

[0026]

[00026] In another embodiment, described herein is a method for treating gastrointestinal stromal tumors. 1. A method of treating gastrointestinal stromal tumors in a patient comprising: a) administering to the patient 100 mg or 150 mg of ripretinib, or a pharmaceutically acceptable salt thereof, orally once or twice daily; and b) administering to the patient ripretinib and the proton pump inhibitor does not provide a clinically significant difference in plasma exposure of ripretinib in the patient compared to administering ripretinib without concomitant proton pump inhibitor treatment.

[0027]

[00027] In another embodiment, described herein is a method for treating gastrointestinal stromal tumors. 1. A method for treating gastrointestinal stromal tumors in a patient suffering from gastrointestinal stromal tumors, the method comprising orally administering to the patient 100 mg or 150 mg of ripretinib, or a pharmaceutically acceptable salt thereof, once or twice daily, wherein the ripretinib is administered to the patient with or without food. [Brief explanation of the drawings]

[0028] [Figure 1] 1 shows survival probability plots for progression-free survival (PFS) for ripretinib and placebo patients, as described in Example 2. [Figure 2] 1 shows survival probability plots for overall survival (OS) for ripretinib and placebo patients, as described in Example 2. [Figure 3] 1 shows plots illustrating survival probabilities for OS in patients on ripretinib, patients crossed over from placebo to ripretinib, and patients with no crossover. [Figure 4] Figure 1 shows PFS by choice of therapy for patients with GIST treated with 150 mg ripretinib daily. [Figure 5] FIG. 5A shows patient-reported outcomes according to the EQ-VAS visual scale (FIG. 5A) and the score change from baseline used to assess these scores (FIG. 5B) and corresponding patient percentage distribution (FIG. 5C) used in the study of Example 2 with 150 mg ripretinib QD. In the study, 70 patients received ripretinib and 32 received placebo. [Figure 6]The EORTC QLQ-C30 physical function questionnaire (FIG. 6A) and the corresponding patient score change from baseline (FIG. 6B) and corresponding patient percentage distribution (FIG. 6C) used in the study of Example 2 with 150 mg ripretinib QD are shown. Physical function scores improved by an average of 1.6 from baseline to C2D1 among patients receiving ripretinib, compared with placebo patients who experienced an average decrease of 8.9 from baseline to C2D1 (p=0.004). In this study, 71 patients received ripretinib and 32 received placebo. [Figure 7A] Figure 7A shows the EORTC QLQ-C30 role functioning questions used in the study of Example 2 with 150 mg ripretinib QD (Figure 7B) and the corresponding patient percentage distribution (Figure 7C) who responded. In the study, 70 patients received ripretinib and 32 received placebo. [Figure 7B] Figure 7A shows the EORTC QLQ-C30 role functioning questions used in the study of Example 2 with 150 mg ripretinib QD (Figure 7B) and the corresponding patient percentage distribution (Figure 7C) who responded. In the study, 70 patients received ripretinib and 32 received placebo. [Figure 7C] Figure 7A shows the EORTC QLQ-C30 role functioning questions used in the study of Example 2 with 150 mg ripretinib QD (Figure 7B) and the corresponding patient percentage distribution (Figure 7C) who responded. In the study, 70 patients received ripretinib and 32 received placebo. [Figure 8]Figure 8A shows the patient score change from baseline (Figure 8A) and percentage distribution (Figure 8B) in response to question C29 of the EORTC QLQ-C30 ("How would you rate your overall health during the last week?") from a scale of 1 ("very poor") to 7 ("excellent") in the study of Example 2 with 150 mg ripretinib QD. In the study, 70 patients received ripretinib and 32 received placebo. [Figure 9] Figure 9A shows patient score change from baseline in response to EORTC QLQ-C30 question C30 ("How would you rate your overall quality of life during the last week?") from a scale of 1 ("very poor") to 7 ("excellent") in the study of Example 2 with 150 mg ripretinib QD (Figure 9A) and corresponding patient percentage distribution (Figure 9B). In the study, 70 patients received ripretinib and 32 received placebo. [Figure 10] 1 shows the mean change in baseline scores on the EQ-VAS across various time points from Cycle 1, Day 15 to Cycle 15, Day 1 in the intention-to-treat population in the study of Example 2 with 150 mg ripretinib QD. [Figure 11] Figures 11A and 11B show the mean change in baseline scores in EORTC QLQ-C30 role functioning and EORTC QLQ-C30 physical functioning, respectively, across various time points from Cycle 1, Day 15 to Cycle 15, Day 1 in the intention-to-treat population in the study of Example 2 with 150 mg ripretinib QD. [Figure 12] Figures 12A and 12B show the mean change in baseline scores in EORTC QLQ-C30 question C29 response and EORTC QLQ-C30 question C30 response, respectively, across various time points from Cycle 1, Day 15 to Cycle 15, Day 1 in the intention-to-treat population in the study of Example 2 with 150 mg ripretinib QD. [Figure 13]1 shows exemplary PFS data for patients who crossed over from placebo to ripretinib in the study described in Example 2 with 150 mg ripretinib QD. [Figure 14] Figures 14A and 14B show progression-free survival (PFS) studies for patients dose-escalated from 150 mg ripretinib QD to 150 mg ripretinib BID during the double-blind and open-label periods of the study of Example 2. Figure 14C shows median PFS data and other parameters from these PFS studies. [Figure 15] 1 shows exemplary PFS data among patients with wild-type KIT mutations in the study of Example 2. [Figure 16] Figures 16A and 16B show progression-free survival (PFS) and overall survival (OS) data based on patients with primary exon 11 mutations or those with non-exon 11 mutations in the study of Example 2 with 150 mg ripretinib QD. [Figure 17] Figures 17A and 17B show progression-free survival (PFS) and overall survival (OS) data based on patients with primary exon 11 mutations or primary exon 9 mutations in the study of Example 2 with 150 mg ripretinib QD. [Figure 18] Figures 18A and 18B show progression-free survival (PFS) and overall survival (OS) data based on patients with a primary exon 11 mutation, or a primary exon 9 mutation, or another mutation, or wild-type (KIT and PDGFRA) in the study of Example 2 with 150 mg ripretinib QD. [Figure 19] Figures 19A and 19B show progression-free survival (PFS) studies for patients with certain primary mutations (exon 9 or exon 11) who were dose-escalated 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. [Figure 20]1 shows exemplary progression-free survival data for patients with other KIT and PGDFR mutations in the study of Example 2 with 150 mg ripretinib QD. [Figure 21] 1 shows the median first appearance and worst grade of alopecia and PPES in matched patients receiving ripretinib in the study described in Example 2. [Figure 22A] FIG. 22A shows the mean change from baseline for the EORTC-QLQ-C30 physical function patient-reported outcome in patients receiving ripretinib with and without alopecia in the study described in Example 2. [Figure 22B] Figure 22B shows the mean change from baseline for the EORTC-QLQ-C30 role functioning patient-reported outcome in patients receiving ripretinib with and without alopecia in the study described in Example 2. [Figure 22C] Figure 22C shows the mean change from baseline for the EORTC-QLQ-C30 physical function patient-reported outcome in patients receiving ripretinib with and without palmar-plantar erythrodysesthesia syndrome (PPES) in the study described in Example 2. [Figure 22D] Figure 22D shows the mean change from baseline for the EORTC-QLQ-C30 role functioning patient-reported outcome in patients receiving ripretinib with and without palmar-plantar erythrodysesthesia syndrome (PPES) in the study described in Example 2. [Figure 23A] Figure 23A shows the mean change from baseline for the EORTC-QLQ-C30 global health patient-reported outcome in patients receiving ripretinib with and without alopecia in the study described in Example 2. [Figure 23B] Figure 23B shows the mean change from baseline for the EORTC-QLQ-C30 global quality of life patient-reported outcome in patients receiving ripretinib with and without alopecia in the study described in Example 2. [Figure 23C] Figure 23C shows the mean change from baseline for the EORTC-QLQ-C30 global health patient-reported outcome in patients receiving ripretinib with and without palmar-plantar erythrodysesthesia syndrome (PPES) in the study described in Example 2. [Figure 23D] Figure 23D shows the mean change from baseline for the EORTC-QLQ-C30 global quality of life patient-reported outcome in patients receiving ripretinib with and without palmar-plantar erythrodysesthesia syndrome (PPES) in the study described in Example 2. [Figure 24A] Figure 24A shows the mean change from baseline for the EORTC-QLQ-C30 health status (VAS) patient-reported outcome in patients receiving ripretinib with and without alopecia in the study described in Example 2. [Figure 24B] Figure 24B shows the mean change from baseline for the EORTC-QLQ-C30 health status (VAS) patient-reported outcome in patients receiving ripretinib with and without palmar-plantar erythrodysesthesia syndrome (PPES) in the study described in Example 2. [Figure 25A] Figures 25A and 25B show exemplary PFS for subjects dose escalated to 150 mg BID, PFS before (PFS1) and after (PFS2) dose escalation. [Figure 25B] Figures 25A and 25B show exemplary PFS for subjects dose escalated to 150 mg BID, PFS before (PFS1) and after (PFS2) dose escalation. [Figure 26] Figures 26A-D show an exemplary comparison of PFS for patient subgroups harboring exon 9 (Figure 26A), exon 11 (Figure 26B), exon 13 (Figure 26C), or exon 17 (Figure 26D) KIT mutations. This exemplary data shows that ripretinib demonstrated a PFS benefit compared to placebo in all evaluated patient subgroups. [Figure 27]1 shows PFS data 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 comparable PFS in the second- and third-line populations. DETAILED DESCRIPTION OF THE INVENTION

[0029]

[00055] The features and other details of the present disclosure will now be more particularly described. Specific terms used in the examples and the appended claims are summarized here. These definitions should be read in light of the remainder of this disclosure as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0030] definition

[00056] As used herein, "ripretinib" is represented by the following structure: It is a compound that can be [ka]

[0031]

[00057] As used herein, "sunitinib" is represented by the following structure: The compound: [ka]

[0032]

[00058] As used herein, "imatinib" is represented by the following structure: The compound: [ka]

[0033]

[00059] As used herein, "regorafenib" is represented by the following structure: The compound is: [ka]

[0034]

[00060] As used herein, "Compound A" is represented by the following structure: It is a compound. [ka]

[0035]

[00061] "Individual," "patient," or "subject" are used interchangeably herein. This includes any animal, including mammals, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans. The compounds described herein can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the methods described herein is desirably a mammal, such as a human, in whom treatment of a disorder described herein is desired.

[0036]

[00062] The term "pharmaceutically acceptable salt" as used herein refers to a compound in a composition. The term "salt" refers to salts of acidic or basic groups that may be present in the compounds used in the present invention. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0037]

[00063] As used herein, "treating" refers to any effect, e.g., Includes attenuation, reduction, modulation, or elimination, resulting in the improvement of a condition, disease, disorder, or the like.

[0038]

[00064] A "therapeutically effective amount" is any amount determined by a researcher, veterinarian, physician, or other clinician. The therapeutically effective amount of a compound described herein includes an amount of a compound of interest that will induce a biological or medical response in a tissue, system, animal, or human. The compounds described herein, such as ripretinib, 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 preventive effect, such as an amount that results in the prevention or reduction of symptoms associated with the condition.

[0039]

[00065] As used herein, "AUC 0-24h " is described herein. As used herein, "AUC" refers to the area under the plasma concentration-time curve from time 0 to 24 hours for a compound. 0-inf " refers to the area under the plasma concentration-time curve from time 0 to time infinity for the compounds described herein. As used herein, "C max " refers to the maximum plasma concentration of the compounds described herein.

[0040]

[00066] The compounds described herein, for example, ripretinib, are pharmaceutically acceptable. The compositions may be formulated into pharmaceutical compositions using suitable carriers and administered by a variety of routes. In some embodiments, such compositions are for oral administration. In some embodiments, compositions formulated for oral administration are provided as tablets. In some embodiments, such compositions are for parenteral (by injection) administration (e.g., compositions formulated for local injection at the site of a tumor, e.g., diffuse giant cell tumor). In some embodiments, such compositions are for transdermal administration. In some embodiments, such compositions are for topical administration. In some embodiments, such compositions are for intravenous (IV) administration. In some embodiments, such compositions are for intramuscular (IM) administration. Such pharmaceutical compositions and processes for their preparation are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds., 1999). th ed., Mack Publishing Co., 1995).

[0041] Treatment method

[00067] Described herein are methods for treating gastrointestinal stromal tumors in patients in need of treatment. A method for treating gastrointestinal stromal tumors. For example, the present disclosure relates to a method for treating a patient suffering from an advanced gastrointestinal stromal tumor, comprising orally administering to the patient 100 mg or more of ripretinib daily, e.g., 100 mg to 5000 mg, e.g., 100 mg to 500 mg, 100 mg to 250 mg, e.g., 150 mg, wherein the patient's tumor has progressed from or the patient is intolerant to a previous first-line administration of imatinib. In some embodiments, the method comprises administering to the patient 110 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 120 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 130 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 140 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 150 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 200 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 250 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 300 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 350 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 400 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 450 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 500 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 550 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 600 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 650 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 700 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 750 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 800 mg of ripretinib daily.In some embodiments, the method comprises administering to the patient 850 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 900 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 950 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 1000 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 150 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 200 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 2. In some embodiments, the method comprises administering 50 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 300 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 350 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 400 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 450 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 500 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 550 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 600 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 650 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering 700 mg of ripretinib once daily to the patient. In some embodiments, the method comprises administering to the patient 750 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 800 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 850 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 900 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 950 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 1000 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 150 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 200 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 250 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 300 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 350 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 400 mg of ripretinib twice daily.In some embodiments, the methods comprise administering to the patient 450 mg of ripretinib twice daily. In some embodiments, the methods comprise administering to the patient 500 mg of ripretinib twice daily.

[0042]

[00068] In some embodiments, the patient has previously been treated with first-line administration of imatinib. For example, before administering ripretinib to the patient, the patient has only been administered imatinib, and no other therapeutic compounds have been administered to the patient. For example, the patient has not previously been administered sunitinib and / or regorafenib, for example, the patient has not previously been administered second-line sunitinib therapy and / or third-line regorafenib therapy.

[0043]

[00069] In some embodiments, the patient receives 21 days or more prior to the first dose of ripretinib. Patients have non-lymph node tumor disease within the 42-day cycle that is 1.0 cm or greater in the long axis or 2 slide thicknesses or greater in the long axis. The contemplated method of treatment involves administering ripretinib in 42-day cycles, including daily administration of ripretinib without administration of sunitinib. After at least one 42-day cycle including daily administration of ripretinib, patients meet mRECIST v1.1. In some embodiments, patients treated with daily administration of ripretinib may have a significant progression-free survival (e.g., about 3 months or more progression-free survival, e.g., about 6 months progression-free survival) compared to 2 weeks without daily administration after 4 weeks of second-line daily administration of 50 mg sunitinib in a 42-day cycle, and the patient's tumor has progressed from or the patient was intolerant to a previous first-line administration of imatinib.

[0044]

[00070] Contemplated treatment with ripretinib inhibits a wide range of KIT and PDGFRA For example, the 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 activating mutation. For example, the patient's tumor mutation is a PDGFRA D842V mutation.

[0045]

[00071] In some embodiments, the patient's tumor has a KIT exon 17 activation loop The patient has an imatinib-resistant mutation selected from the group consisting of a KIT exon 18 activation loop mutation, a KIT exon 13 mutation, a KIT exon 14 mutation, a KIT exon 18 mutation, a PDGFRA exon 12 mutation, a PDGFRA exon 14 mutation, a PDGRFA exon 15 mutation, and a PDGFRA exon 18 activation loop mutation. For example, the imatinib-resistant mutation is a PDGFRA D842V mutation.

[0046]

[00072] In some embodiments, the patient's tumor contains a KIT exon 13 or 14 mutation. The patient's tumor has an imatinib-resistant mutation selected from the group consisting of a PDGFRA exon 14 or 15 mutation, a KIT 17 or 18 activation loop mutation, and a PDGFRA 18 activation loop mutation. For example, the patient's tumor has an imatinib-resistant KIT exon 17 mutation.

[0047]

[00073] Also described herein are methods for treating patients with advanced gastrointestinal stromal tumors. A method for treating rheumatoid arthritis (HAT) comprising orally administering 100 mg or more, for example, up to about 600 mg, for example, up to about 250 mg, for example, 100 mg or 150 mg of ripretinib to a patient daily, wherein the patient's tumor has progressed from or the patient was intolerant to first-line imatinib, second-line sunitinib, and third-line regorafenib, or the patient has documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib. A contemplated method of treatment comprises orally administering 100 mg, 150 mg, or more of ripretinib daily without sunitinib in a 42-day cycle. 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 to the patient 130 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 140 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 150 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 200 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 250 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 300 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 350 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 400 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 450 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 500 mg of ripretinib daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient daily.In some embodiments, the method comprises administering to the patient 700 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 750 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 800 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 850 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 900 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 950 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 1000 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 150 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 200 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 250 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 300 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 350 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 400 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 450 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 500 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 550 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 600 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 650 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 700 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 750 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 800 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 850 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 900 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 950 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 1000 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 150 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 200 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 250 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 300 mg of ripretinib twice daily.In some embodiments, the method comprises administering to the patient 350 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 400 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 450 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 500 mg of ripretinib twice daily.

[0048]

[00074] In some embodiments, a patient suffering from advanced gastrointestinal stromal tumor is treated with Contemplated are methods of treatment comprising orally administering 100 mg or more of ripretinib daily to a patient, 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, and wherein the patient has previously received at least two tyrosine kinase inhibitors. Contemplated methods of treatment include orally administering 100 mg, 150 mg, or more of ripretinib daily without sunitinib in a 42-day cycle. In some embodiments, the methods involve administering 110 mg of ripretinib daily to a patient. In some embodiments, the methods involve administering 120 mg of ripretinib daily to a patient. In some embodiments, the methods involve administering 130 mg of ripretinib daily to a patient. In some embodiments, the methods involve administering 140 mg of ripretinib daily to a patient. In some embodiments, the method comprises administering 150 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 200 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 250 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 300 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 350 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 400 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 450 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 500 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 700 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 750 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 800 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 850 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 900 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 950 mg of ripretinib to the patient daily. In some embodiments, the method comprises administering 1000 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 100 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 150 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 200 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 250 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 300 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 350 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 400 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 450 mg of ripretinib daily. In some embodiments, the method comprises administering to the patient 500 mg of ripretinib once daily. In some embodiments, the method comprises administering 550 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 600 mg of ripretinib to the patient once daily. In some embodiments, the method comprises administering 650 mg of ripretinib to the patient once daily.In some embodiments, the method comprises administering to the patient 700 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 750 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 800 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 850 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 900 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 950 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 1000 mg of ripretinib once daily. In some embodiments, the method comprises administering to the patient 150 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 200 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 250 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 300 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 350 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 400 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 450 mg of ripretinib twice daily. In some embodiments, the method comprises administering to the patient 500 mg of ripretinib twice daily. In some embodiments, the patient has previously received two separate tyrosine kinase inhibitors, each selected from the group consisting of imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, vatalanib, crenolanib, and pharmaceutically acceptable salts thereof. In some embodiments, each of the tyrosine kinase inhibitors is independently selected from the group consisting of imatinib, sunitinib, and regorafenib. In some embodiments, each of the tyrosine kinase inhibitors is independently selected from the group consisting of imatinib mesylate, sunitinib malate, and regorafenib.

[0049]

[00075] In some embodiments of the methods described herein, the patient is receiving ripretinib. In some embodiments, the patient is orally administered one or more tablets containing ripretinib. For example, disclosed methods include methods of treating a patient afflicted with an advanced gastrointestinal stromal tumor, comprising orally administering to the patient one or more tablets containing ripretinib daily, e.g., tablets each containing 50 mg to 100 mg of ripretinib, wherein the patient's tumor has progressed from or the patient is intolerant to a previous first-line administration of imatinib. 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 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, patients are administered three tablets each containing 50 mg of ripretinib once daily. In some embodiments, patients are administered four tablets each containing 50 mg of ripretinib. In some embodiments, patients are administered four tablets each containing 50 mg of ripretinib once daily. In some embodiments, patients are administered five tablets each containing 50 mg of ripretinib. In some embodiments, patients are administered five tablets each containing 50 mg of ripretinib once daily. In some embodiments, patients are administered six tablets each containing 50 mg of ripretinib. In some embodiments, patients are administered six tablets each containing 50 mg of ripretinib once daily.

[0050]

[00076] Additionally, the disclosed methods can be used to treat patients suffering from advanced gastrointestinal stromal tumors. The present invention also includes a method of treating a tumor comprising daily orally administering to a patient one or more tablets each containing ripretinib, for example, tablets each containing 50 mg to 100 mg of ripretinib, wherein the patient's tumor has progressed from or the patient was intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or the patient has documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib. 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, patients are administered two tablets containing 50 mg of ripretinib once daily. In some embodiments, patients are administered three tablets containing 50 mg of ripretinib each. In some embodiments, patients are administered three tablets containing 50 mg of ripretinib once daily.

[0051]

[00077] In some embodiments, provided are methods for treating patients suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis (HART) comprising daily orally administering to the patient one or more tablets each containing ripretinib, e.g., tablets each containing 50 mg to 100 mg of ripretinib, wherein the patient has previously administered at least two tyrosine kinase inhibitors prior to administration of 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 the group consisting of imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, vatalanib, crenolanib, and pharmaceutically acceptable salts thereof. In some embodiments, each tyrosine kinase inhibitor is independently selected from the group consisting of imatinib, sunitinib, and regorafenib. In some embodiments, each tyrosine kinase inhibitor is independently selected from the group consisting of imatinib mesylate, sunitinib malate, and regorafenib.

[0052]

[00078] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient suffering from rheumatoid arthritis, comprising orally administering 150 mg of ripretinib once daily to the patient, wherein the patient has previously received three or more tyrosine kinase inhibitors prior to administration of ripretinib. In some embodiments, after at least four weeks of daily ripretinib administration, the patient has a progression-free survival of at least five months as measured using mRECIST v1.1. In some embodiments, orally administering 150 mg of ripretinib once daily to the patient comprises administering three tablets to the patient, each tablet containing 50 mg of ripretinib. In some embodiments, one of the three or more kinase inhibitors is imatinib. In some embodiments, the patient has previously received imatinib, sunitinib, and regorafenib.

[0053]

[00079] In some embodiments, the patient has Grade 3 pulmonary embolism upon administration of ripretinib. If palmar-plantar erythrodysesthesia syndrome is present, the method further comprises a) withholding administration of ripretinib for at least 7 days or until the patient has palmar-plantar erythrodysesthesia syndrome of Grade 1 or less, and then administering 100 mg daily (e.g., 100 mg once daily) of ripretinib to the patient for at least 28 days.

[0054]

[00080] In some embodiments, the patient has Grade 2 bowel disease upon administration of ripretinib. If palmar-plantar erythrodysesthesia syndrome is present, the method further comprises a) withholding administration of ripretinib until the patient has palmar-plantar erythrodysesthesia syndrome of Grade 1 or less or baseline; b) if the patient recovers from palmar-plantar erythrodysesthesia syndrome within 7 days of withholding administration, then administering 150 mg of ripretinib daily to the patient; or c) if the patient has not recovered, then administering 100 mg of ripretinib daily to the patient for at least 28 days.

[0055]

[00081] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient with rituximab, comprising orally administering 150 mg of ripretinib daily to the patient, wherein the patient's tumor has progressed from or the patient was intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib.

[0056]

[00082] In some embodiments, the patient has Grade 3 pulmonary embolism upon administration of ripretinib. If palmar-plantar erythrodysesthesia syndrome is present, the method further comprises a) withholding administration of ripretinib for at least 7 days or until the patient has palmar-plantar erythrodysesthesia syndrome of Grade 1 or less, and then administering 100 mg daily (e.g., 100 mg once daily) of ripretinib to the patient for at least 28 days.

[0057]

[00083] In some embodiments, the patient has Grade 2 bowel disease upon administration of ripretinib. If palmar-plantar erythrodysesthesia syndrome occurs, the method is: a) withholding administration of ripretinib until the patient has palmar-plantar erythrodysesthesia syndrome of grade 1 or less or baseline; b) if the patient recovers from palmar-plantar erythrodysesthesia syndrome within 7 days of withholding administration, then administering 150 mg daily ripretinib to the patient; or c) If the patient has not improved, then the method further comprises administering to the patient 100 mg of ripretinib daily for at least 28 days.

[0058]

[00084] In another embodiment, described herein is a method for treating a patient suffering from advanced gastrointestinal stromal tumors. A method of treating a patient with rituximab (rituximab) comprising orally administering 150 mg of ripretinib once or twice daily to the patient, wherein the patient's tumor has progressed from or the patient was intolerant to a previous first-line dose of imatinib. In some embodiments, if the patient develops Grade 3 palmar-plantar erythrodysesthesia syndrome upon administration of ripretinib, the method further comprises: a) withholding administration of ripretinib for at least 7 days or until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome, and then administering 100 mg daily (e.g., 100 mg once daily) of ripretinib to the patient for at least 28 days. In some embodiments, if the patient suffers from Grade 3 palmar-plantar erythrodysesthesia syndrome upon administration of ripretinib, the method further comprises a) withholding administration of ripretinib for at least 7 days or until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome, and then administering 100 mg daily (e.g., 100 mg once daily) of ripretinib to the patient for at least 28 days. In some embodiments, if the patient suffers from Grade 2 palmar-plantar erythrodysesthesia syndrome upon administration of ripretinib, the method further comprises a) withholding administration of ripretinib until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome or baseline, b) if the patient recovers from palmar-plantar erythrodysesthesia syndrome within 7 days of withholding administration, then administering 150 mg of ripretinib daily to the patient, or c) if the patient does not recover, then administering 100 mg of ripretinib daily to the patient for at least 28 days. In some embodiments, if the patient suffers from Grade 3 adverse disorder selected from arthralgia or myalgia upon administration of ripretinib, the method further comprises a) withholding administration of ripretinib until the patient has Grade 1 or less adverse disorder, 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 suffers from Grade 3 hypertension upon administration of ripretinib, the method further comprises withholding administration of ripretinib until the patient's blood pressure is controlled, and administering 150 mg of ripretinib daily to the patient if the patient has blood pressure below Grade 1, or 100 mg of ripretinib daily (e.g., 100 mg once daily) if the patient has blood pressure above Grade 1.

[0059]

[00085] In another embodiment, described herein is a method for treating a patient with advanced gastrointestinal stromal tumors. A method for achieving a progression-free survival of at least 5 months as determined by mRECIST 1.1 in a patient with refractory mCR1-positive leukemia, comprising orally administering 100, 150, 200, or 300 mg of ripretinib daily or twice daily for at least 28 days to the patient. In some embodiments, the patient has received at least one prior kinase inhibitor. In some embodiments, the patient has received at least three prior kinase inhibitors. In some embodiments, the at least one prior kinase inhibitor is imatinib. In some embodiments, the patient has received at least 100, 150, or 200 mg of ripretinib daily or twice daily for at least 4 months.

[0060]

[00086] In another embodiment, described herein is a method for treating a patient with advanced gastrointestinal stromal tumors. 1. A method for achieving a progression-free survival of at least 5 months as determined by mRECIST 1.1 in a patient with metastatic melanoma, comprising orally administering 100, 150, or 200 mg of ripretinib daily or twice daily for at least 28 days to the patient. In some embodiments, the patient has received at least one prior kinase inhibitor. In some embodiments, the patient has received at least three prior kinase inhibitors. In some embodiments, the patient has received at least one prior kinase inhibitor. In some embodiments, the patient receives 100, 150, or 200 mg of ripretinib orally daily or twice daily for at least four months.

[0061]

[00087] In another embodiment, described herein is 150 mg of ripretinib daily or twice daily while suffering from Grade 3 palmar-plantar erythrodysesthesia syndrome, the method comprising withholding administration of ripretinib for at least 7 days or until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome, and then administering 100 mg daily (e.g., 100 mg once daily) ripretinib to the patient for at least 28 days.

[0062]

[00088] In another embodiment, described herein are 15 daily or twice daily doses of 1. A method of treating a patient suffering from Grade 2 palmar-plantar erythrodysesthesia syndrome upon administration of 0 mg ripretinib, the method further comprising: a) withholding administration of ripretinib until the patient has palmar-plantar erythrodysesthesia syndrome of Grade 1 or less or baseline; b) if the patient recovers from palmar-plantar erythrodysesthesia syndrome within 7 days of withholding administration, then administering 150 mg daily ripretinib to the patient; or c) if the patient has not recovered, then administering 100 mg daily ripretinib to the patient for at least 28 days.

[0063]

[00089] In another embodiment, described herein is a method for treating a gastrointestinal stromal tumor. 1. A method of treating gastrointestinal stromal tumors in a patient having a gastrointestinal stromal tumor, wherein the patient is being concomitantly treated with a CYP3A4 inhibitor, the method comprising orally administering to the patient 100 mg or 150 mg of ripretinib, or a pharmaceutically acceptable salt thereof, once or twice daily, wherein upon administration of ripretinib and the CYP3A4 inhibitor, an area under the plasma concentration curve (AUC) of 80% or greater is achieved in the patient compared to administration of ripretinib without concomitant treatment with a CYP3A4 inhibitor.0-inf and monitoring the patient for adverse events more frequently compared to patients not treated with a CYP3A4 inhibitor. In some embodiments, if the patient experiences a Grade 3 palmar-plantar erythrodysesthesia syndrome adverse event, the method further comprises: a) withholding administration of ripretinib for at least 7 days or until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome, and then administering 100 mg of ripretinib daily to the patient for at least 28 days. In some embodiments, if the patient develops Grade 2 palmar-plantar erythrodysesthesia syndrome upon administration of ripretinib, the method further comprises: a) withholding administration of ripretinib until the patient has Grade 1 or less palmar-plantar erythrodysesthesia syndrome or baseline; b) if the patient recovers from palmar-plantar erythrodysesthesia syndrome within 7 days of withholding administration, then administering 150 mg of ripretinib daily to the patient; or c) if the patient has not recovered, then administering 100 mg of ripretinib daily to the patient for at least 28 days. In some embodiments, the CYP3A4 inhibitor is selected from the group consisting of itraconazole, ketoconazole, clarithromycin, and indinavir. In some embodiments, the CYP3A4 inhibitor is itraconazole. In some embodiments, the patient has previously been administered one or more tyrosine kinase inhibitors, each selected from the group consisting of imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, vatalanib, crenolanib, and pharmaceutically acceptable salts thereof.

[0064]

[00090] In another embodiment, described herein is a method for treating a gastrointestinal stromal tumor. 1. A method of treating gastrointestinal stromal tumors in a patient receiving concurrent treatment with a proton pump inhibitor, the method comprising administering to the patient 100 mg or 150 mg of ripretin. The present invention relates to a method for treating rheumatoid arthritis, comprising orally administering ripretinib, or a pharmaceutically acceptable salt thereof, once or twice daily to a patient, wherein administering ripretinib and a proton pump inhibitor to a patient does not result in a clinically significant difference in plasma exposure of ripretinib in the patient compared to administering ripretinib without concurrent treatment with a proton pump inhibitor. In some embodiments, the proton pump inhibitor is selected from the group consisting of pantoprazole, omeprazole, lansoprazole, rabeprazole, esomeprazole, and dexlansoprazole. In some embodiments, the proton pump inhibitor is pantoprazole. In some embodiments, the patient is concurrently treated with 40 mg of a proton pump inhibitor once daily.

[0065]

[00091] In another embodiment, described herein is a method for treating a gastrointestinal stromal tumor. A method for treating gastrointestinal stromal tumors in a patient, 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. In some embodiments, the food comprises a high-fat meal (e.g., a high-fat meal described herein).

[0066]

[00092] In some embodiments, the therapeutic efficacy of ripretinib is measured in solid tumors. The therapeutic efficacy of ripretinib is determined by the patient's progression-free survival after independent radiological review using Response Evaluation Criteria in Solid Tumors (RECIST). In some embodiments, the therapeutic efficacy of ripretinib is determined by the patient's objective response rate (ORR), time to tumor progression (TTP), or overall survival (OS) after independent radiological review using mRECIST. In some embodiments, the therapeutic efficacy of ripretinib is determined by the patient's progression-free survival based on investigator assessment. In some embodiments, the therapeutic efficacy of ripretinib is determined by the patient's quality of life according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer 30-item (EORTC-QLQ-C30) and EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaires. In some embodiments, the therapeutic efficacy of ripretinib is determined by the disease control rate of the patient. In some embodiments, the therapeutic efficacy of ripretinib is determined by the duration of the patient's response.

[0067]

[00093] After at least 1 month, 2 months, e.g., 42 days or more of treatment with ripretinib After administration of ripretinib daily, the patient may have a progression-free survival measured using mRECIST v1.1. As another example, the patient may have a progression-free survival of at least 5 months or 6 months compared to placebo after administration of ripretinib daily for at least 4 weeks, and / or have a significant 85% reduction in the risk of disease progression or death after administration of ripretinib daily for at least 4 weeks.

[0068]

[00094] In some embodiments, the patient receives 21 days or more prior to the first dose of ripretinib. In some embodiments, the patient has a non-lymph node tumor lesion measuring 1.0 cm or greater in the long axis or 2x slide thickness or greater in the long axis within 21 days prior to the first dose of ripretinib.

[0069]

[00095] In some embodiments, the patient's tumor is characterized by a KIT exon 9 mutation, a PDGF The patient has 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 PDGFRA D842V mutation. It is different.

[0070]

[00096] In some embodiments, the patient's tumor has a KIT exon 17 activation loop The patient has an imatinib-resistant, sunitinib-resistant, and / or regorafenib-resistant mutation selected from the group consisting of a KIT exon 18 activation loop mutation, a KIT exon 13 mutation, a KIT exon 14 mutation, a KIT exon 18 mutation, a PDGFRA exon 12 mutation, a PDGFRA exon 14 mutation, a PDGRFA exon 15 mutation, and a PDGFRA exon 18 activation loop mutation. For example, the resistance mutation is a PDGFRA D842V mutation.

[0071]

[00097] In some embodiments, the patient's tumor contains a KIT exon 13 or 14 mutation. The tumor has a drug-resistant mutation selected from the group consisting of a PDGFRA exon 14 or 15 mutation, a KIT 17 or 18 activation loop mutation, and a PDGFRA 18 activation loop mutation. For example, the tumor has a drug-resistant KIT exon 17 mutation.

[0072] Dose modification

[00098] Dose modifications may be made as a result of adverse events experienced by patients, as described herein. The dose modification may be performed in the method of administering ripretinib described above. In some embodiments, the dose modification is a dose interruption. In some embodiments, the dose modification is a permanent cessation of administration. In some embodiments, the dose modification is a dose reduction. In some embodiments, the dose of ripretinib administered to a 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 a 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 containing 50 mg of ripretinib. In some embodiments, the adverse reaction is selected from the group consisting of hand-foot skin reactions (e.g., palmar-plantar erythrodysesthesia syndrome), hypertension, arthralgia, and myalgia.

[0073]

[00099] In some embodiments, the adverse event is determined by the National Cancer The adverse event is graded according to the Institute Common Terminology Criteria for Adverse Events, version 4.03 (e.g., baseline, grade 1, grade 2, grade 3, or grade 4). In some embodiments, the dose modification is a dose interruption (e.g., dose interruption for at least 7 days) as a result of a grade 2 adverse event. In some embodiments, if the adverse event declines to grade 1 or baseline within a first time period (e.g., within 7 days), dosing resumes at the same dose level before dose interruption. In some embodiments, if the adverse event declines to grade 1 or baseline after the first time period (e.g., after 7 days), dosing resumes at the reduced dose level before dose interruption. In some embodiments, if the adverse event declines to grade 1 or baseline after the first time period but remains as a grade 1 or baseline adverse event after a second time period (e.g., after 28 days), the reduced dose level is re-escalated to the dose level before dose interruption. In some embodiments, the dose modification is a dose interruption (e.g., a dose interruption of at least 7 days to a maximum of 28 days) as a result of a Grade 3 adverse event. In some embodiments, dosing is continued at a reduced level after dose interruption. In some embodiments, the dose modification is a permanent cessation of dosing as a result of a Grade 4 adverse event (e.g., Grade 4 hypertension).

[0074] [000100] The patient may be administered additional treatment in response to or to prevent the occurrence of an adverse event. In some embodiments, a patient suffering from an adverse dermatological reaction, e.g., a palmar-plantar erythrodysesthesia syndrome, may be administered additional treatments. A topical composition (e.g., an emollient) is administered to treat a dermatological reaction. In some embodiments, the patient is administered a topical composition (e.g., an emollient) based on the severity of the adverse dermatological reaction, e.g., a Grade 2 or Grade 3 adverse dermatological reaction, e.g., a Grade 1, Grade 2, or Grade 3 palmar-plantar erythrodysesthesia syndrome reaction, e.g., a Grade 1, Grade 2, or Grade 3 palmar-plantar erythrodysesthesia syndrome reaction. In some embodiments, the topical composition (e.g., an emollient) is administered to the patient during a dose interruption of ripretinib. In some embodiments, the topical composition (e.g., an emollient) is administered to the patient contemporaneously with a dose of ripretinib, e.g., a reduced dose of ripretinib.

[0075] [000101] Patients may also be administered additional treatments before or during administration of ripretinib in accordance with the methods described herein to prevent or ameliorate adverse events. In some embodiments, patients are administered a topical composition (e.g., an emollient) before and / or during administration of ripretinib to prevent or ameliorate the development of adverse dermatological reactions, e.g., hand-foot skin reactions, e.g., palmar-plantar erythrodysesthesia syndrome. [Example]

[0076] Example 1. An open-label, randomized study to compare the efficacy of ripretinib versus sunitinib in patients with advanced GIST with prior imatinib therapy. [000102] Study Design. Approximately 358 eligible patients will be randomized 1:1 into two cohorts: one cohort will receive ripretinib at 150 mg daily in consecutive 42-day cycles (179 patients), and the other cohort will receive sunitinib at 50 mg daily for 4 weeks in 42-day cycles, followed by 2 weeks off (179 patients).

[0077] [000103] 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 evaluate ripretinib compared with sunitinib as second-line therapy in patients with GIST after imatinib therapy.

[0078] [000104] The primary endpoint of this study is to assess progression-free survival (PFS) of ripretinib by blinded independent central review (BICR) using modified Response Evaluation Criteria in Solid Tumors, version 1.1 (mRECIST v1.1). Key secondary efficacy endpoints include ORR assessed by BICR using mRECIST v1.1 and OS.

[0079] [000105] Statistical Analysis. PFS is defined as the time from randomization to the date of first documented progression of disease or death from any cause and is based on the BICR assessment of the primary endpoint. OS is defined as the time from randomization to the date of death from any cause. OS and PFS with 95% CI will be summarized using the Kaplan-Meier method, and point estimates of hazard ratios will be obtained from Cox regression models. Objective response will be defined as CR or PR by BICR assessment using mRECIST v1.1.

[0080] Example 2. A randomized, double-blind, placebo-controlled, international study to evaluate the safety, tolerability, and efficacy of ripretinib compared with placebo in patients with advanced GIST whose prior therapy included imatinib, sunitinib, and regorafenib. [000106] This study evaluated the safety, tolerability, and efficacy of ripretinib compared with placebo in 129 patients with advanced GIST whose prior therapy included at least imatinib, sunitinib, and regorafenib. This was a randomized (2:1), double-blind, placebo-controlled, international study to evaluate the efficacy and safety of ripretinib in patients with advanced or advanced ovarian cancer. Patients were randomized 2:1 to receive either 150 mg of ripretinib once daily or placebo. The primary efficacy endpoint was progression-free survival (PFS) as determined by independent radiological review using modified Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints, determined by independent radiological review using modified RECIST, included objective response rate (ORR), time to tumor progression (TTP), and overall survival (OS).

[0081] [000107] Results. This study achieved its primary endpoint of improved PFS as determined by blinded independent central radiological review using the modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

[0082] [000108] Ripretinib demonstrated a median PFS of 6.3 months (27.6 weeks) compared with 1.0 month (4.1 weeks) in the placebo group, significantly reducing the risk of disease progression or death by 85% compared with placebo (HR of 0.15, p<0.0001). The PFS rate at 6 months was 51% (95% CI: 39.4, 61.4) for ripretinib and 3.2% (95% CI: 0.2, 13.8) for placebo. Survival probability plots for PFS for ripretinib and placebo patients are shown in Figure 1.

[0083] [000109] For the key secondary endpoint of objective response rate (ORR), as determined by blinded independent central radiological review using modified RECIST v1.1, ripretinib demonstrated an ORR of 9.4% compared with 0% for placebo (p=0.0504), which was not statistically significant. Ripretinib in this study also demonstrated a clinically meaningful improvement over placebo for the secondary endpoint of overall survival (OS) (median OS 15.1 months vs. 6.6 months, HR=0.36, nominal p=0.0004; OS rates at 12 months were 65.4% (95% CI: 51.6, 76.1) for ripretinib and 25.9% (95% CI: 7.2, 49.9) for placebo). However, statistical significance was not reached for ORR, and therefore a formal hypothesis test for OS was not performed. Survival probability plots for OS for ripretinib and placebo patients are shown in Figure 2. According to the prespecified hierarchical testing procedure for endpoints, hypothesis testing for OS cannot be formally performed unless the ORR test is statistically significant. OS data for the placebo group include patients receiving placebo who crossed over to ripretinib treatment after progression. Plots illustrating survival probabilities for OS in ripretinib patients, patients who crossed over from placebo to ripretinib, and patients without crossover are shown in Figure 3. Plots and additional data illustrating survival probabilities for PFS in ripretinib patients, patients who crossed over from placebo to ripretinib, and patients without crossover are shown in Figure 13. Additionally, more patients receiving ripretinib had 12-week stable disease (SD) (40 [47.1%] vs. 2 [4.5%], respectively) and fewer PDs than patients on placebo (16 [18.8%] vs. 28 [63.6%], respectively). The majority of patients receiving ripretinib with stable disease (SD) is remarkable because lack of progression is considered an important marker of therapeutic benefit in GIST.Unlike many other advanced solid tumors, lack of progression (either partial response (PR) or SD) is predictive of PFS and OS benefit in patients with advanced GIST.

[0084] Patients who successfully crossed over from placebo had smaller tumors compared with non-crossovers (median sum of longest diameter of target lesions 119.4 mm vs. 183.3 mm). In addition, the median age of crossovers was higher than that of non-crossovers (68.0 vs. 58.0 years), and none had a baseline East Asian score of 2. None of the patients in the crossover group had a European Cooperative Oncology Group (ECOG) score of 2, while three patients in the non-crossover group had an ECOG score of 2. Crossover patients had a median PFS of 20.0 weeks [95% CI, 8.0-NE] compared with 27.6 weeks in the initial ripretinib group and 4.1 weeks in the initial placebo group, respectively. Median OS in crossover patients was 11.6 months compared with 15.1 months in patients initially randomized to ripretinib and 1.8 months in placebo patients who did not cross over. TEAEs during the crossover period did not suggest safety concerns when compared with the safety profile of patients initially assigned to ripretinib.

[0085] [000111] Ripretinib was generally well tolerated, and adverse event results were consistent with data from previously presented phase 1 study results. Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurred in 42 (49%) patients in the ripretinib group compared with 19 (44%) in the placebo group. Grade 3 or 4 TEAEs occurring in more than 5% of patients in the ripretinib group were anemia (9%; n = 8), abdominal pain (7%; n = 6), and hypertension (7%; n = 6). Grade 3 or 4 TEAEs occurring in more than 5% of patients in the placebo group were anemia (14%; n = 6). Table 1 lists TEAEs occurring in more than 15% of patients in the ripretinib group compared with placebo. [Table 1]

[0086] [000112] In Table 1, (1) indicates that the safety population included 128 patients. One patient was randomized to placebo but did not receive study drug.

[0087] Patient-reported outcomes [000113] Patient-reported outcomes were assessed by the EQ-5D-5L, which provides a visual analog scale (VAS), and the EORTC QLQ-C30, which provides physical and role functioning scales. The EQ-5D-5L VAS (or EQ-VAS) records the respondent's overall current health on a vertical visual analog scale and provides a quantitative measure of the patient's perception of overall health. These patient outcomes were reported over 28-day cycles of receiving 150 mg QD ripretinib or placebo.

[0088] [000114] Figure 5 shows patient-reported outcomes by EQ-VAS (Figure 5A), which shows the visual scale used to assess scores, score change from baseline (Figure 5B), and corresponding patient percentage distribution (Figure 5C). EQ-VAS scores improved by a mean of 3.7 from baseline to cycle 2, day 1 (C2D1) among patients receiving ripretinib, compared with placebo patients, who experienced a mean decrease of 8.9 from baseline to C2D1 (p=0.004). 70 patients received ripretinib and 32 received placebo.

[0089] [000115] The EORTC QLQ-C30 is a cancer patient assessment of function and symptoms of therapy and is not specific to any cancer. The EORTC QLQ-C30 includes 30 questions plus five functional scales, three symptom scales, and one global health scale.

[0090] [000116] Figure 6 shows the EORTC QLQ-C30 physical function question (Figure 6A), the change in patient scores from baseline (Figure 6B), and the corresponding patient percentage distribution (Figure 6C). Physical function scores improved by a mean of 1.6 from baseline to C2D1 among patients receiving ripretinib, compared with placebo patients, who experienced a mean decline of 8.9 from baseline to C2D1 (p=0.004). 71 patients received ripretinib and 32 received placebo.

[0091] [000117] Figure 7 shows the EORTC QLQ-C30 role functioning question (Figure 7A) and the change in patient scores from baseline (Figure 7B) and the corresponding patient percentage distribution (Figure 7C). Role functioning scores improved by a mean of 3.5 from baseline to C2D1 among patients receiving ripretinib compared with placebo patients, who showed a mean decline of 17.1 from baseline to C2D1 (p=0.001). 70 patients received ripretinib and 32 received placebo.

[0092] [000118] Figure 8 shows patient score change from baseline in response to question C29 of the EORTC QLQ-C30 ("How would you rate your overall health during the last week?") from a scale of 1 ("very poor") to 7 ("excellent") (Figure 8A) and the corresponding patient percentage distribution (Figure 8B). There was an improvement in C29 score of 0.20 in the ripretinib group compared with a decrease of 0.78 in the placebo group (p=0.001). 70 patients received ripretinib and 32 received placebo.

[0093] [000119] Figure 9 shows patient score change from baseline in response to question C30 of the EORTC QLQ-C30 ("How would you rate your overall quality of life during the last week?") from a scale of 1 ("very poor") to 7 ("excellent") (Figure 9A) and the corresponding patient percentage distribution (Figure 9B). There was an improvement in score of 0.28 in the ripretinib group compared with a decrease of 0.76 in the placebo group (p=0.001). 70 patients received ripretinib and 32 received placebo.

[0094] [000120] Figure 10 shows the mean change in baseline scores on the EQ-VAS across various time points from Cycle 1, Day 15 to Cycle 15, Day 1 in the intention-to-treat population. Figures 11A and 11B show the mean change in baseline scores in EORTC QLQ-C30 role function and EORTC QLQ-C30 physical function, respectively, across various time points from cycle 1, day 15 to cycle 15, day 1 for the intent-to-treat population. Figures 12A and 12B show the mean change in baseline scores in EORTC QLQ-C30 question C29 response and EORTC QLQ-C30 question C30 response, respectively, across various time points from cycle 1, day 15 to cycle 15, day 1 for the intent-to-treat population.

[0095] Open-label phase and dose escalation [000121] Patients whose disease progressed during the double-blind phase of the study were either escalated to 150 mg BID ripretinib, continued at the 150 mg QD dose, or discontinued in the open-label phase of the study. Table 8 shows a comparison of patients receiving 150 mg QD ripretinib at the data cutoff of the double-blind phase and the open-label phase. The data in Table 8 suggest that data recorded 9 months after the primary double-blind analysis showed improvements in mOS and similar mPFS in the ripretinib group.

[0096] [000122] In this study, at least 31 patients were dose-escalated to 150 mg ripretinib twice daily during the open-label phase upon disease progression. PFS studies for these patients during the double-blind and open-label periods are shown in Figures 14A and 14B, respectively, and Figure 14C shows the median PFS data.

[0097] Wild-type (KIT and PDGFRA) mutations [000123] PFS data among patients with wild-type KIT or PDGFRA mutations was further evaluated with 150 mg ripretinib QD. PFS data for these patients with wild-type KIT and PDGFRA mutations are shown in Figure 15. Additional mutation analysis

[0098] [000124] Progression-free survival (PFS) and overall survival (OS) data for patients with primary exon 11 mutations or non-exon 11 mutations are shown in Figures 16A (PFS) and 16B (OS) for 150 mg ripretinib QD. The data show that regardless of the primary mutation, GIST patients with either primary exon 11 or non-exon 11 primary mutations derive similar benefit from ripretinib compared to placebo.

[0099] [000125] Progression-free survival (PFS) and overall survival (OS) data for patients with primary exon 11 mutations or primary exon 9 mutations are shown in Figures 17A (PFS) and 17B (OS) for 150 mg ripretinib QD. The data show that both exon 11 and exon 9 GIST patients derive benefit from ripretinib over placebo, regardless of the primary mutation.

[0100] [000126] Additionally, progression-free survival (PFS) and overall survival (OS) data based on patients with primary exon 11 mutations, or primary exon 9 mutations, or other mutations, and wild-type (KIT and PDGFRA) are shown in Figures 18A (PFS) and 19B (OS) for 150 mg ripretinib QD.

[0101] [000127] A PFS study for patients with certain primary mutations (exon 9 or exon 11) dose-escalated to 150 mg BID ripretinib is shown in Figures 19A and 19B for the double-blind and open-label periods, respectively.

[0102] [000128] Additionally, Figure 20 shows exemplary progression-free survival (PFS) for patients with other KIT and PGDFR mutations in the study of Example 2 with 150 mg ripretinib QD. Lifetime data are shown.

[0103] [000129] Figures 26A-D show an exemplary comparison of PFS for patient subgroups with exon 9 (Figure 26A), exon 11 (Figure 26B), exon 13 (Figure 26C), or exon 17 (Figure 26D) KIT mutations. This exemplary data shows that ripretinib demonstrated a PFS benefit compared to placebo in all evaluated patient subgroups. Example 3. Results of a clinical study of ripretinib in patients with GIST, in addition to second to fourth line treatment.

[0104] [000130] Results. Data from 178 GIST patients receiving ripretinib at doses greater than 100 mg daily are listed in Table 2. The table includes investigator-assessed objective response rates (ORR) by best response, disease control rate (DCR), and median progression-free survival (mPFS), all of which were determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. [Table 2]

[0105] [000131] In Table 2, (1) indicates that the overall number of patients (n=178) remains the same as previous data presented at ESMO 2018; based on additional data cleaning, one patient from each of the second-line and fourth / ≥fourth-line treatments was reclassified as a third-line patient; (2) refers to the median treatment duration, which was second-line=44 weeks, third-line=48 weeks, fourth-line=46 weeks, and ≥fourth-line=29 weeks; (3) refers to the inclusion of 60 patients selected for intra-patient dose escalation from 150 mg QD to 150 mg BID; and (4) refers to the number of patients, including the 60 patients from the fourth line.

[0106] [000132] Ripretinib was generally well tolerated, and updated adverse events were consistent with previously presented phase 1 data in patients with GIST. Grade 3 or 4 treatment-emergent adverse events (TEAEs) in more than 5% of patients were increased lipase (18%; n = 33), anemia (11%; n = 20), hypertension (7%; n = 13), and abdominal pain (6%; n = 11). 13% (n = 24) of patients experienced TEAEs leading to discontinuation of study treatment, 17% (n = 31) experienced TEAEs leading to dose reduction, and 49% (n = 88) of patients had TEAEs leading to study drug interruption. Table 3 lists TEAEs occurring in more than 10% of GIST patients treated with more than 100 mg of ripretinib daily. [Table 3-1] [Table 3-2]

[0107] [000133] In Table 3, (1) indicates the inclusion of one patient who only participated in the food-effect portion of the Phase 1 study, and (2) indicates that a dermatological skin exam was performed to better evaluate skin lesions.

[0108] Example 4. Results from a clinical study of 150 mg QD ripretinib in patients with GIST in addition to second to fourth line therapy. [000134] Efficacy and safety results from the escalation and expansion phases of a Phase 1 study of patients with GIST treated with ripretinib 150 mg QD as the starting dose in 28-day cycles are presented. Local, investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response assessments were performed every two cycles, and patients in the expansion cohort who progressed according to RECIST 1.1 were dose-escalated to 150 mg BID.

[0109] [000135] 142 patients with GIST in the escalation and expansion phase were treated with 150 mg Patients were treated with a QD dose. The number of patients by therapy type was as follows: 31 second-line, 28 third-line, and 83 or more fourth-line. 135 patients (95.1%) had KIT-mutant GIST, and 7 patients (4.9%) had PDGFRA-mutant GIST.

[0110] [000136] The results regarding efficacy by therapy choice in patients with GIST receiving ripretinib 150 mg QD are presented in Table 4. For example, confirmed complete responses (CR), partial responses (PR), stable disease, and progressive disease are presented in Table 4. The objective response rate data in Table 4 relate to the proportion of patients with CR+PR. The median PFS data in Table 4 refer to progression-free survival according to investigator assessment by therapy choice. PFS plots by therapy choice are also shown in Figure 4. [Table 4] In Table 4, a 64 patients with GIST in the 150 mg QD dose group who were escalated to 150 mg BID. CI: 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.

[0111] [000137] In subjects who were dose-escalated to 150 mg BID, PFS was assessed before (PFS1) and after (PFS2) dose escalation and is shown in Figures 25A and 25B, respectively. The data support that, regardless of therapy choice, patients received additional clinical benefit as assessed by the investigator after dose escalation to 150 mg BID.

[0112] Mutation analysis [000138] Figure 27 shows PFS data for exemplary second- and third-line patients with KIT mutations in exons 9, 11, 13, or 17. The data show that in the second- and third-line populations, patients with these various KIT mutations have comparable PFS.

[0113] Example 5. Protocol for dose modification of ripretinib as a result of adverse reactions. [000139] If a dose modification of ripretinib is required due to adverse reactions, the following protocol will be applied: Dose reduction in 50 mg (1 tablet) increments, with the minimum recommended dose of ripretinib being 50 mg once daily. Ripretinib dosing reductions for adverse reactions are summarized in Table 5. [Table 5]

[0114] [000140] Dose will be reduced, interrupted, or discontinued for certain toxicities. See Table 6 for dose modification guidelines. [Table 6-1] [Table 6-2] [Table 6-3]

[0115] Example 6. Safety of ripretinib and the effect of alopecia and palmar-plantar erythrodysesthesia (PPES) on patient-reported outcomes. [000141] The safety of ripretinib and the impact of alopecia and palmar-plantar erythrodysesthesia (PPES) on patient-reported outcomes (PROs) of patients treated in the study described in Example 2 herein are described. Ripretinib had a favorable overall safety and tolerability profile in the study of Example 2. Patient-reported assessments of function, overall health, and overall quality of life were maintained over time when stratified by alopecia and PPES. For both alopecia and PPES, onset and peak severity occurred approximately simultaneously, indicating that these events generally did not progress and worsen. Overall, these results suggest that alopecia and PPES are manageable and that ripretinib treatment offsets any negative effects associated with these AEs.

[0116] [000142] Patient-reported outcomes (PROs) were assessed using questions from the EuroQol 5D (EQ 5D 5L) and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30).

[0117] [000143] Generalized estimating equation (GEE) models were used in the following statistical analyses: a repeated measures model across visits in which the outcome was one of the five PROs; the model was constructed for ripretinib patients only; for patients with alopecia, cycles 1 and 2 were excluded to account for the median time to alopecia onset; covariates were gender, alopecia / PPES (yes / no), and Eastern Cooperative Oncology Group (ECOG) score at baseline; and when there was no end date for an AE, it was conservatively coded as extending until the last visit of the double-blind period.

[0118] [000144] 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, so no patients had grade 3 / 4 alopecia in either group. Alopecia was slightly more common in women than in men in the ripretinib group (56.8% vs. 43.2%). In the ripretinib group, 21.2% of patients reported PPES, and no patients had grade 3 PPES (grade 3 is the highest severity classification for PPES). No serious adverse events of alopecia or PPES were reported. Within the ripretinib group, 7.1%, 23.5%, and 5.9% of patients experienced TEAEs leading to dose reduction, dose interruption, or death, respectively, compared with 2.3%, 20.9%, and 23.3% in the placebo group. In patients receiving ripretinib, the median worst grade of alopecia occurred very shortly after the median first occurrence (Figure 21). The median first occurrence and worst grade of PPES occurred simultaneously in patients receiving ripretinib (Figure 21).

[0119] [000145] Table 7 shows a summary of the GEE analysis of the association between alopecia and PPES using the five PRO scales in patients taking ripretinib. In repeated measures analysis, there was a trend toward improvement in the five PROs among patients with alopecia (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 association between PPES and the five PRO scales (Table 7). [Table 7]

[0120] [000146] Longitudinal graphs through Cycle 10, Day 1 demonstrate similar trends in the mean change from baseline for the five PROs for patients receiving ripretinib who developed alopecia or PPES and those who did not (Figures 22A, 22B, 22C, 22D, 23A, 23B, 23C, 23D, 24A, and 24B). [Table 8]

[0121] Example 7. Study of ripretinib and Compound A with a potent CYP3A inhibitor. [000147] Coadministration of 150 mg QD ripretinib with a strong CYP3A inhibitor may increase the exposure of ripretinib and its active metabolite (Compound A) and increase the risk of adverse reactions. Coadministration of ripretinib with itraconazole (a strong CYP3A inhibitor and also a P-gp inhibitor) increased ripretinib Cmax by 36% and AUC0-inf by 99%, and also increased Compound A AUC0-inf by 99%, without changing its Cmax.

[0122] Example 8. Study of ripretinib with proton pump inhibitors. [000148] The effect of proton pump inhibitors on ripretinib exposure was evaluated. When ripretinib was co-administered with pantoprazole, a proton pump inhibitor, no clinically significant differences in plasma exposure to ripretinib or Compound A were observed. Although ripretinib has pH-dependent solubility, co-administration of 150 mg QD ripretinib with 40 mg QD pantoprazole did not affect ripretinib exposure.

[0123] Example 9. Study of food effects on ripretinib and Compound A exposure. [000149] The effect of a high-fat breakfast on ripretinib and Compound A exposure was evaluated. The high-fat meal consisted of approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively. After administration of ripretinib with a high-fat meal at a dose of 150 mg, the AUC of ripretinib was 0-24h and C max are 30% and For metabolite compound A, AUC 0-24h and C max were 47% and 66% higher, respectively. The food effect was not considered clinically significant based on an exposure-response analysis. Therefore, ripretinib can be taken with or without food at approximately the same time each day.

[0124] equivalent [000150] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. Compounds represented by the following structure: 【Chemistry 1】 A pharmaceutical composition for use in a method of treating a patient suffering from progressive gastrointestinal stromal tumor, wherein the treatment comprises orally administering 150 mg of the compound once or twice daily to the patient, the patient having previously been administered imatinib prior to the administration of the compound, and the treatment results in a progression-free survival of three months or more, as measured using mRECIST 1.1, in the patient after at least one cycle of daily administration of the compound for 42 days.

2. The pharmaceutical composition according to claim 1, wherein the patient has been previously administered three or more kinase inhibitors, including imatinib, prior to the administration of the compound.

3. The pharmaceutical composition according to claim 2, wherein one or more kinase inhibitors previously administered are selected from imatinib, sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, batalanib, and clenolanib, respectively.

4. The pharmaceutical composition according to claim 2, wherein one or more kinase inhibitors previously administered are selected from imatinib, lapatinib, gefitinib, erlotinib, batalanib, and clenolanib, respectively.

5. The pharmaceutical composition according to claim 2, wherein the patient has previously received four or more lines of therapy.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the treatment comprises orally administering 150 mg of the compound to a patient once daily.

7. The pharmaceutical composition according to claim 6, comprising three tablets, each containing 50 mg of the compound, with a daily dose of 50 mg.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the treatment results in a progression-free survival of six months or more in a patient, as measured using mRECIST 1.1, after at least 10 cycles of daily administration of the compound for 42 days.

9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the patient has been previously administered at least three or more distinct tyrosine kinase inhibitors, one of which at least three or more distinct tyrosine kinase inhibitors is imatinib, and two of the distinct tyrosine kinase inhibitors are selected from the group consisting of sunitinib, regorafenib, lapatinib, gefitinib, erlotinib, batalanib, clenolanib, and pharmaceutically acceptable salts thereof, and the patient, who is human, achieves a progression-free survival of six months or more, as measured using mRECIST 1.1, after daily administration of the compound for at least 28 days.

10. The pharmaceutical composition according to claim 9, wherein a human patient has been previously administered three distinct tyrosine kinase inhibitors.

11. The pharmaceutical composition according to claim 10, wherein the three distinct tyrosine kinase inhibitors are imatinib, sunitinib, and regorafenib.

12. The pharmaceutical composition according to claim 9, wherein the patient, who is a human, has previously received four lines of therapy.

13. The pharmaceutical composition according to claim 9, wherein the patient's tumor has progressed from at least four lines of prior therapy, the first line of prior therapy being imatinib, and the treatment results in the patient having about 15 months of survival after daily administration of the compound for at least 42 days.

14. The pharmaceutical composition according to claim 13, wherein the second-line treatment to the previous therapy is administration of sunitinib.

15. A pharmaceutical composition according to any one of claims 1 to 14, wherein the patient's tumor has progressed from first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, and the patient achieves a progression-free survival of 6 months or more, as measured using mRECIST 1.1, after daily administration of the compound for at least 28 days.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the progressive gastrointestinal stromal tumor contains a wild-type KIT mutation.

Images